Dopamine d3 Schizophrenia

CNS & Neurological Disorders - Drug Targets, 2006, 5, 25-43
25
The Dopamine D3 Receptor: A Therapeutic Target for the Treatment of Neuropsychiatric Disorders
P. Sokoloff*,1, J. Diaz2, B. Le Foll1, O. Guillin1, L.Leriche1, E. Bezard3 and C. Gross3
1
INSERM, Unit de Neurobiologie et Pharmacologie, Molculaire (U573), Centre Paul Broca, 2ter rue d'Alsia, 75014 Paris, France
2
Universit Ren Descartes, Laboratoire de Physiologie, Facult de Pharmacie, Avenue de l'Observatoire, 75005 Paris, France CNRS UMR 5543, Basal Gang, Laboratoire de Neurophysiologie, Universit Victor Segalen, 33076 Bordeaux, France
Abstract: The role of the D3 receptor has remained largely elusive before the development of selective research tools, such as selective radioligands, antibodies, various highly specific pharmacological agents and knock-out mice. The data collected so far with these tools have removed some of the uncertainties regarding the functions mediated by the D3 receptor. The D3 receptor is an autoreceptor that controls the phasic, but not tonic activity of dopamine neurons. The D3 receptor, via regulation of its expression by the brain-derived neurotrophic factor (BDNF), mediates sensitization to dopamine indirect agonists. This process seems responsible for side-effects of levodopa (dyskinesia) in the treatment of Parkinsons disease (PD), as well as for some aspects of conditioning t o drugs of abuse. The D3 receptor mediates behavioral abnormalities elicited by glutamate/NMDA receptor blockade, which suggests D3 receptor-selective antagonists as novel antipsychotic drugs. These data allow us to propose novel treatment options in PD, schizophrenia and drug addiction, which are awaiting evaluation in clinical trials.
Keywords: Brain-derived neurotrophic factor, Autoreceptor, Parkinson's disease, Schizophrenia, Drug addiction, Depression. 1. INTRODUCTION The pleiotropic actions of dopamine have long been assumed to result from the interaction with two types of receptors, termed D1 and D2 receptors. In spite of previous suggestions of additional dopamine receptors, the discovery of the D3 receptor [1] was rather unexpected, as was that of D4 and D5 receptors that followed [2, 3]. From the beginning, attention has been attracted to the restricted distribution of the D3 receptor in the brain, seemingly related to functions of dopamine associated with the limbic brain. Hence, the hypothesis has been put forward that the D3 receptor could be involved in the pathophysiology of several psychiatric disorders, such as schizophrenia and drug addiction, which result from dysfunction of dopamine neurotransmission. The involvement of D3 receptors in pathological conditions has received some support from post-mortem clinical studies. Nevertheless, the initial lack of selective pharmacological tools, which delayed assessment of the role of D3 receptor in vivo, raised questions about the physiological significance of the D3 receptor. The D3 receptor belongs to the family of G proteincoupled receptors, whose topography is characterized by the occurrence of seven transmembrane domains. Its primary sequence is close to that of the D2 receptor, and to a lesser extent, to the D4 receptor. Information on the structure of the D3 receptor and its intracellular signaling has been published elsewhere [4-6]. The present chapter aims at measuring the
*Address correspondence to this author at the Institut de Recherche Pierre Fabre, Exploratory R&D Centre, Neurology-Psychiatry, 17 avenue JeanMoulin, 81106 Castres cedex, France; Tel: (33 ) 5 63 71 42 65; Fax: (33 1) 5 63 37 09 62; E-mail: pierre.sokoloff@pierre-fabre.com 1871-5273/06 $50. 00+. 00
progress accomplished in the field fifteen years after the identification of the D3 receptor and reviews the anatomical, pharmacological, genetic and clinical data presently available. These data, still incomplete to some extent, now reveal functions mediated by the D3 receptor and its involvement in the pathophysiology of several neuropsychiatric disorders. D3 receptor-selective pharmacological agents should also be considered as novel treatment options in these disorders. 2. PRE- AND POST-SYNAPTIC LOCALIZATIONS OF THE D3 RECEPTOR IN THE BRAIN In rat brain, in which the phenotypes of neurons expressing the D3 receptor have been characterized, the largest receptor densities occur in granule cells of the islands of Calleja and in medium-sized spiny neurons of the rostral and ventromedial shell of nucleus accumbens, which co-express the D1 receptor, substance P, dynorphin and/or neurotensin [7-9]. These output neurons from the nucleus accumbens receive their dopaminergic innervation from the ventral tegmental area and reach the entorhinal and prefrontal cortex after relays in the ventral pallidum and mediodorsal thalamus. In turn, the shell of nucleus accumbens receives projections from the cerebral cortex (infralimbic, ventral, agranular, insular and piriform areas), hippocampus and amygdala and also projects to the ventral tegmental area from which dopaminergic afferents originate [10, 11]. These various specific connections of the shell of nucleus accumbens, a part of the "extended amygdala" [12], suggest that this area is involved in a series of feedback or feedforward loops, involving notably the prefrontal cortex and ventral tegmental area and subserving control of emotions, motivation and reward.
2006 Bentham Science Publishers Ltd.
26
CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1
Sokoloff et al.
In the human and non-human primate brains, the phenotype of neurons expressing the D3 receptor are not yet identified, but several studies show their distribution to be rather similar to that in the rat (highest levels in islands of Calleja and nucleus accumbens, see Fig. 1) with, however, higher densities and larger distribution in the ventral part of the caudate putamen and the cerebral cortex [13-19]. One aspect of the localization and function of the D3 receptor, which has remained highly debated is its occurrence as an autoreceptor, regulating the activity of dopamine neurons. The existence of D3 autoreceptors was originally proposed on the basis of the expression of D3 receptor mRNA in substantia nigra and the ventral tegmental area, which strongly decreases after lesion of dopamine neurons [1]. This lesion, however, also downregulates postsynaptic D3 receptor in nucleus accumbens [20], by deprivation of brain-derived neurotrophic factor (BDNF), an anterograde factor of dopamine neurons (see below). Hence, the lesioninduced decrease in areas of dopamine cell bodies could reflect a similar process occurring in non-dopaminergic neurons. Dopamine release [21] and synthesis [22] are inhibited by stimulation of the D3 receptor expressed in a transfected mesencephalic cell line and various agonists, with limited preference for the D3 receptor [23], inhibit dopamine release, synthesis and neuron electrical activity (see [6] for a review), giving support to the existence of D3 autoreceptors. However, the selectivity of these agonists towards the D3 receptor in vivo has been strongly questioned, because they elicit similar inhibition of dopamine neuron activities in wild-type and D3 receptor-deficient mice [24]. In addition, dopamine autoreceptor functions are suppressed in D2 receptor-deficient mice [25, 26]. Nevertheless, dopamine extracellular levels in the nucleus accumbens [24] and
striatum [27] are twice as high in D3 receptor-deficient as in wild-type mice, suggesting a control of dopamine neurons activity by the D3 receptor. A selective anti-D3 receptor antibody has been developed, the immuno-reactivity of which perfectly matches D3 receptor binding (Fig. 2). This antibody allowed us to confirm the presence of D3 autoreceptors at the somato-dendritic level of all dopaminergic neurons in substantia nigra and ventral tegmental area [28]. D3 autoreceptors, together with D2 autoreceptors [25], may thus control the electrical activity of dopamine neurons, which would explain the elevated extracellular dopamine levels in projections areas of these neurons in D3 receptor-deficient mice. This control could have been masked in experiments using compounds inadequately selective of the D3 receptor [24], since the compounds used also activate the D2 receptor. The existence of a control of dopamine release by the D3 receptor has recently received support from the use of selective D3 receptor antagonists (see section 6). Alternatively, D3 autoreceptors could not be operant in anesthetized animals or in vitro in brain slices used in electrophysiological studies [24, 25], whereas dopamine extracellular levels were measured in freely moving animals.
Fig. (1). D3 receptor distribution in the human brain. A, D3 receptor binding, revealed with [3H]7-OHDPAT, a D3 receptorselective radioligand. Nuc. acc., nucleus accumbens; Par. Cx, parietal cortex. B, In situ hybridization signals with a D3 receptor-specific probe. C, In situ hybridization signals were quantified from 3 individuals and expressed as percentage of the level in nucleus accumbens (Nuc. acc.). Caudate, caudate nucleus; Cing. Cx, cingulate cortex; Dent Gyrus, dentate gyrus; Frontal Cx, frontal cortex; Isl Calleja, islands of Calleja; Par. Cx, parietal cortex; Sub. Nigra, substantia nigra pars compacta; Subth. nuc., subthalamic nucleus. Data from [17] and [18].
Fig. (2). Immunohistochemical localization of the D3 receptor i n rat brain. A, B Superimposable distributions of binding of [125I]trans-7-OH-PIPAT, a D3 receptor-selective ligand (A) D3 receptor immunoreactivity (B), with highest levels in the islands of Calleja (IcjM and IC) and moderate levels in the shell of nucleus accumbens (AccSh) (ac, anterior commissura. C, D, expression of D3 receptor immunoreactivity alone (in red in C) and in combination with tyrosine hydroxylase immunoreactivity (in green in B). All tyrosine hydroxylasepositive neurons in the mesencephalon express the D3 receptor. Data from [28].
The use of knockout mice has brought some clarifications, and also raised new questions. The decrease in extracellular levels of dopamine, induced by low doses of PD 128,907, a D3 receptor-preferring agonist, measured by
The Dopamine D3 Receptor
27
brain microdialysis, is attenuated in D3 receptor-deficient mice [29], suggesting that D3 receptors control dopamine release. However, the decrease in dialysate dopamine levels is abolished in D2 receptor-deficient mice [30]. Recent studies in transfected cells have shown that co-expression of D2 and D3 receptors enhances the potency of D2-like agonists for the inhibition of adenylate cyclase [31]. If there were a similar functional D2/D3 receptor interaction in dopamine neurons where the two receptors co-exist [28, 32], this would explain why D3 receptors could modulate extracellular dopamine levels by increasing the potency of dopamine at D2 receptor [30]. The hypothesis of a control exerted by D3 autoreceptors is also supported by the observations that D3 receptor-deficient mice display signs reminiscent of hyperdopaminergia, presumably resulting from the lack of autoreceptors controlling dopamine neuron activity. Thus, they have decreased expression of tyrosine hydroxylase and increased expression and function of the dopamine transporter; these alterations may represent adaptive changes to increased dopamine tone [33]. Another study found that subchronic treatment with pramipexole, D3-preferring agonist, lowered the Vmax of [3H]dopamine uptake, which is in line with the previous study, but that D3 receptor-deficient mice had lower Vmax of [3H]dopamine uptake than wild-type mice [34]. Finally, D3 autoreceptors may mediate yet unrecognized control by dopamine of other activities of dopamine neurons, such as synthesis or release of neuropeptides co-expressed with dopamine in these neurons, e.g. neurotensin, cholecystokinin or neurotrophins. 3. BRAIN-DERIVED NEUROTROPHIC FACTOR CONTROLS THE EXPRESSION OF THE D3 RECEPTOR AND TRIGGERS BEHAVIORAL SENSITIZATION The expression of the D3 receptor in medium-sized neurons of the nucleus accumbens is highly dependent upon dopaminergic innervation : in a rat model of PD, obtained by unilateral and extensive destruction of dopamine neurons by local infusion of 6-hydroxydopamine (6-OHDA), D3 receptor expression is decreased in the shell of the nucleus accumbens of the denervated side [20]. D3 receptor density is also decreased in PD patients [35] and in a non-human primate model of PD, i.e. in MPTP-treated monkeys [19]This paradoxical change (the D2 receptor is upregulated under these circumstances) was shown to depend on the deprivation of an anterogradely-transported factor from dopaminergic neurons, distinct from dopamine itself and its known peptide co-transmitters [20]. In rats, D3 receptor expression appears in the shell of the nucleus accumbens during the first postnatal week, coincident with its innervation by dopamine neurons, suggesting that the factor maintaining D3 receptor expression in adulthood also triggers this expression during development [36]. Brain-derived neurotrophic factor (BDNF) was a candidate factor for the regulation of D3 receptor expression. BDNF, like other neurotrophins, had initially been regarded as responsible for neuron proliferation, differentiation and survival, after its neuronal uptake and retrograde transport to the soma [37]. A more diverse role for BDNF as an extracellular transmitter has, nevertheless, been inferred from observations that it is anterogradely transported [38, 39], released upon neuron depolarization and triggers
rapid intracellular signals [37, 40] and action potentials in central neurons [41] via intracellular transduction of its highaffinity membrane receptor TrkB. TrkB (tropomyosin receptor kinase B) is a high affinity receptor for BDNF, which activates intracellular signaling via autophosphorylation of tyrosine residues. BDNF can alter fast synaptic transmission by speeding up the development of excitatory and inhibitory synapses [42], and by modulating synaptic efficacy [43]. In particular, BDNF is necessary for induction and maintenance of hippocampal long-term potentiation [43-45]. Although some observations suggest a role of BDNF in nociception [46] and learning [47, 48], little is known, about the consequences of BDNFinduced synaptic plasticity on physiological functions or pathophysiological conditions. The first insight for a role of BDNF in the regulation of D3 receptor expression came from the observation that Trk B and D3 receptor mRNAs co-localized in a high proportion of neurons in the shell of nucleus accumbens [49]. Moreover, in wild-type BDNF+/+ mice, D3 receptor binding and mRNA in the shell of the nucleus accumbens increased sharply from postnatal days 9-14 (P9-P14) to P17-P23, whereas in homozygous BDNF-/- mice, D3 receptor binding and mRNA were low at P9-P14, and did not increase at later stages (Fig. 3A), showing that BDNF is required for normal development of D3 receptor expression in the shell of the nucleus accumbens [49]. However, in the islands of Calleja, another brain region which expresses high levels of D3 receptor, the expression level was high at early stages of development and not decreased in D3 receptor-deficient mice [49, 50]. This suggests that there was both BDNF-dependent (in the nucleus accumbens) and BDNFindependent (in the islands of Calleja) population of D3 receptor-expressing neurons. This is consistent with the observation that the islands of Calleja do not express TrkB [49]. The BDNF gene mutation does not impair the early development of dopamine neurons [51], nor their later development, since tyrosine hydroxylase, a marker of these neurons, was not significantly affected by the lack of BDNF [49]. This suggests that BDNF acts directly on dopamine D3 receptor-expressing neurons rather than indirectly via an effect on the development of dopamine neurons. Note, however, that other studies suggest that BDNF can act directly on dopamine neuron development [52, 53]. It is also worth noting that BDNF deprivation selectively reduces the expression of the D3 receptor, and not that of the homologous D1 and D2 receptors [49], which are not, or only marginally, down-regulated by 6-OHDA lesions [54]. In unilaterally 6-OHDA-lesioned rats, repeated administration of levodopa, leading to extraneuronal dopamine formation, triggers D3 receptor overexpression not only in the shell of the nucleus accumbens, but also in the denervated striatum, a brain structure in which D3 receptor expression is hardly detectable [54] (Fig. 3B). During levodopa treatment of 6-OHDA-lesioned rats, infusion into the denervated striatum of a selective BDNF antagonist formed by fusion between the Fc-tail of human immunoglobin G (IgG) and a part of TrkB (IgG-TrkB) [55], impairs induction of both D3 receptor mRNA and protein expression (Fig. 3B). This indicates that BDNF is necessary for this process [49].
28
Sokoloff et al.
Fig. (3). BDNF controls D3 receptor expression during development and in adults. A, (top) Autoradiographic pictures of D3 receptor binding, obtained with [125I]7-OH-PIPAT, in wild-type BDNF+/+ or BDNF-/- mice at post-natal day 23 (P23). (bottom) D3 receptor binding ( Ci/ g) with animals at P9-P10 or P14-P23 were analysed. There was a significant effect of genotype (P < 0.0001), age (P = 0.0023) and genotype X age interaction (P = 0.019). * P < 0.05 vs. BDNF+/+ littermates. B, 7-day striatal infusion of IgG-TrkB, a BDNF antagonist, blocks the induction of D3 receptor binding by L-DOPA. (top):In situ hybridisation signals of D3 receptor mRNA i n animals receiving continuous infusions into the striatum of IgG (control animal, left) or IgG-TrkB (right) for 7 days and levodopa for 5 days. (bottom): Quantitative analysis showing a significant effect of treatment (P = 0.006). * P < 0.05 and ** P <0.01 versus IgGtreated animals. Data from [49]. C, Parallel changes in D3-receptor binding and levodopa-induced rotations in hemiparkinsonian rats during and after repeated administration of levodopa. Rats with an unilateral 6-hydroxy dopamine-induced lesion of the ascending mesencephalic dopaminergic pathways placed 3 weeks earlier, received levodopa (50 mg/kg, i.p., b.i.d.) for up to 15 days and were challenged with a single same dose of levodopa. Contralateral rotations were counted 35 min after and animals killed 4 h after the challenge and D3-receptor binding quantified on autoradiograms using [3H]7-OH-DPAT as the ligand. Data from [54]. D, Rotations were recorded after the first and last levodopa (L-DOPA) administrations in animals shown in B. There was a significant effect of the treatment (P =0.046). * P < 0.05 versus first L-DOPA injection. Data from [49] (A, B) and [54] (C, D).
D3 receptor overexpression induced by levodopa has been shown to be responsible for the development of behavioral sensitization to this drug, i.e. a progressive enhancement of responsiveness, which appears as an increased number of levodopa-induced rotations: the development and extinction of behavioral sensitization parallel D3 receptor expression in the striatum during the treatment with levodopa and after its cessation (Fig. 3C). Moreover, the increase in the number of
rotations is blocked by a preferential D3 receptor antagonist [54] and induced by a selective partial D3 receptor agonist [56]. Infusion of IgG-TrkB dose-dependently inhibits behavioral sensitization (Fig. 3D), indicating that behavioral sensitization is triggered by BDNF. Striatal BDNF in fact originates mainly from cortical neurons [39]. In agreement, cortical ablation partially impairs the induction of D3 receptor overexpression in the striatum
29
and behavioral sensitization, indicating that both processes require the participation of corticostriatal neurons [49]. Levodopa induces BDNF mRNA in the frontal cortex in the 6-hydroydopamine-lesioned side, mainly in cortical layer V containing pyramidal cell bodies and in layer VI, which sends projections to various subcortical areas, notably striatal and accumbal areas [57]. This effect critically depends upon activation of a D1 or D5 receptor [49] and is consistent with the presence of D1 receptors on cortical pyramidal cells [58] and with the observation that stimulation of a D1 or D5 receptor under similar circumstances phosphorylates cAMP response element-binding protein [59], a factor that activates BDNF gene transcription [60, 61]. Hence, induction of D3 receptor expression in striatum is triggered by a D1/D5 receptor stimulation-dependent elevation of BDNF in cortico-striatal neurons, a process that is more pronounced in the 6-OHDA-lesioned side as compared to the control side, which accounts for the induction of D3 receptor expression restricted to the lesioned side. Moreover, BDNF-induced D3 receptor expression might cause a more pronounced disequilibrium in responsiveness to dopamine between the two sides, which might lead to enhanced rotational behavior. 4. D3 RECEPTOR-SELECTIVE PHARMACOLOGICAL AGENTS Initial pharmacological studies with recombinant D3 receptor showed that dopamine, as well as some of its agonists, display higher affinity at D3 receptor than at D2 receptor [1, 62]. Among antagonists, antipsychotics display very similar affinities at D2 and D3 receptors (Table 1), but (+)AJ-76 and (+)UH 232, two aminotetralin derivatives acting as preferential dopamine autoreceptor antagonists [63], show a little preference for the D3 receptor, as compared to D2 receptor [1]. In fact, (+) UH 232 has been shown to exhibit partial agonistic properties at the D3 receptor [64]. An important step towards identifying selective D3 receptor ligands was the discovery that the dopamine agonist [3H](+)7-OH-DPAT selectively binds in vitro to the natural D3 receptor [65], permitting visualization of this receptor in rat [65] and human [66] brain slices and confirmation of its pharmacological properties. While an often used tool, there are some questions about selectivity in vivo (discussed in [67]), and a retention of activity in mice deficient for the D3 receptor [68, 69]. More recent compounds have been developed with a higher degree of selectivity both in vitro and in vivo. For instance, three putative D3 receptor antagonists, nafadotride [70], PNU-99194A [71] and S14297 [72] , display 7-20 times higher affinity for the D3 than the D2 receptor (Table 1). Nafadotride and PNU-99194A are devoid of agonistic activity, and they increase locomotor activity at low doses without affecting dopamine synthesis or release in rats [70, 71, 73], suggesting an inhibitory role of post-synaptic D3 receptors. This hypothesis is consistent with the observation that D3 receptor mutant mice display hyperactivity in a novel environment [74]. However, the selectivity of nafadotride and PNU-99194A have been questioned, since their stimulant effects on locomotor activity persist in D3 receptor mutant mice [68]. S14297, previously assumed as an antagonist [72], actually acts as a full agonist on D3 receptor-mediated mitogenesis and inhibition of cyclic AMP accumulation in recombinant cells [69], which questions the nature of the effects shown with
this compound. It follows that highly selective ligands were needed for assigning functional role(s) for the D3 receptor.
Table 1. Dopamine Receptor Affinity for Antagonists
Affinity (Ki, nM) Drug D1 Non selective: Amisulpride (+) Butaclamol Chlorpromazine Clozapine Eticlopride Flupentixol, cis Fluphenazine Haloperidol Olanzapine Pimozide Quetapine Raclopride Remoxipride Risperidone Spiperone Sulpiride Thioridazine YM-09151-2 D3 - selective: BP 897 (partial agonist) GR 103,691 GR 218,231 Nafadotride NGD 2904 S 33084 SB-277011A ST 198 PNU-99194A
a b a
Receptor subtype D2 D3 D4 D5
>1,000 5 35 35 >10,000 4 6 150 48 >10,000 390 >50,000 >10,000 560 380 >10,000 34 2,600
2.8 1 5 145 0.1 1.5 0.6 2 30 3 380 1 588 6 0.08 38 7 0.05
3.2 4.5 4 238 0.25 2.5 0.8 5 41 4 260 1.2 1,600 11 0.4 60 8 0.09
>1,000 45 16 29 25 30 6.5 36 30 1,050 2,100 3,200 16 0.1 280 10 0.13
>1,000 6.1 33 343 >10,000 12 8 170 74 560 2,400 >10,000 300 -
3,000 >1,000 890 >10,000 500 >1,000 25,000 -
61 24 63 3 217 32 1,030 780 2,280
0.9 0.4 1 0.3 1.4 0.3 11 12 223
300 81 10,000 1,780 >5,000 2,000 >1,000 5,000 >10,000
>10,000 1,300 >1,000 -
Data reviewed in [233] and data from [234], [56] and [81]. b Metabolites of this compound with higher affinities for D2 and D3 receptors have been identified.
Screening of a series of newly designed molecules [56] led to the identification of BP 897 (see the chemical structure in Fig. 8). This compound displays a high affinity at the D3 receptor (Ki = 0.92 nM), a 70 times lower affinity at the D2 receptor (Ki = 61 nM) and much lower affinity at D1 and D4 receptors (Table 1), as well at a variety of nondopamine receptors. In NG 108-15 cells expressing the human D3 receptor, BP 897 potently inhibits forskolininduced cyclic AMP accumulation and produces mitogenesis
30
Sokoloff et al.
(EC50 of ~1 nM), however to a maximal extent ( ~55 %) of that maximally elicited by dopamine or the full agonist quinpirole. In contrast, in cells expressing the D2 receptor, BP 897 fails to either inhibit cyclic AMP accumulation or trigger mitogenesis; it reversibly antagonizes quinpiroleinduced mitogenesis, however, only at concentrations largely exceeding those required to stimulate the D3 receptor. Hence, BP 897 appears as the first selective, potent, but partial (intrinsic activity ~ 0.6) D3 receptor agonist, and a weak D2 receptor antagonist in vitro. Other studies using [35S]GTP S binding or microphysiometry [75, 76] failed to sort out the agonistic activity of BP 897; however, in these studies, the agonist 7-OH-DPAT, which has high intrinsic activity in the mitogenesis assay [23], displays very low intrinsic activity suggesting that coupling was not optimal in these studies. In vivo, BP 897 at high dosage (10-20 mg/kg) occupies brain dopamine D2, receptors and, as a result of blockade of these receptors, displays typical neuroleptic-like properties (induction of catalepsy, antagonism of apomorphine-induced stereotypies). This indicates that selective occupancy of D3 receptors should be obtained at doses not exceeding 1 mg/kg, taking into ,account the in vitro selectivity of the compound (Table 1). At these low dosages, BP 897 does not affect spontaneous locomotor activity and body temperature. BP 897 agonist/antagonist potency in vivo was assessed on two presumably D3 receptor-mediated responses. In hemiparkinsonian rats repeatedly pretreated with levodopa, BP 897 potentiates rotations elicited by a D1 receptorselective agonist; this potentiation does not occur before levodopa treatment, i.e. before induction of D3 receptor expression and is abolished by co-treatment with nafadotride, indicating that BP 897 acts as an agonist for this response [56]. In the islands of Calleja of rats, BP 897 enhanced cfos mRNA, an effect similar in direction and amplitude to that produced by nafadotride [77]; in addition, in contrast to D2/D3 receptor agonists, BP 897 potentiates the response to a D1 receptor agonist [56]. This effect is abolished in D3 receptor mutant mice. Thus, in vivo, BP 897 increases D1 receptor-mediated responses by acting as either an agonist or an antagonist, depending upon the response considered, consistent with its partial agonist properties in vitro. BP 897 acts as a receptor agonist on rotations elicited in dopaminedepleted brain and as a receptor antagonist on c-fos expression maintained by a dopaminergic tone. More recently, two highly selective D3 receptor antagonists have been identified. S33084 has a Ki value of 0.25 nM at the D3 receptor and a 120 times lower affinity at the D2 receptor [78]. SB-277011A has a Ki value of 11 nM at the D3 receptor and a 100 times lower affinity at the D2 receptor [79]. Both compounds have much lower affinity at dopamine D1 and D4 receptors (Table 1), as well as various other non-dopaminergic receptors. In several functional in vitro assays, they display no agonistic activity and competitively antagonize dopamine or dopamine agonistinduced responses. Remarkably, both compounds have no effect on spontaneous locomotor activity or dopamine efflux, measured by brain microdialysis, but antagonize preferential D3 dopamine agonist-induced inhibition of dopamine efflux. This indicates that D3 receptors, presumably D3 autoreceptors, exert a phasic, but not tonic control of the activity of dopamine neurons. In agreement, the two D3 receptor antagonists do not modify spontaneous or
psychostimulant-induced locomotion. Finally, another D3 receptor-selective antagonist, ST 198 has been described [80, 81], which has Ki values of 12 nM and 780 nM for inhibiting binding to D3 and D2 receptors, respectively (Table 1). Interestingly, the selectivity of this compound, as well as that of BP 897 and nafadotride, for the D3 receptor in vivo has been assessed by using D3 receptor-deficient mice: the inhibition of dizocilpine (MK-801)-induced locomotor hyperactivity by the three compounds is abolished in D3 receptor mutant mice [81, 82]. 5. THE DISEASE D3 RECEPTOR AND PARKINSON'S
PD is associated with several symptoms such as akinesia, rigidity and tremor, which result from the lack of the brain neurotransmitter dopamine [83]. Substitution treatment for PD, e.g. by levodopa, initially reduces motor symptoms, but eventually induces, in most of patients, debilitating and pharmacoresistant involuntary movements, i.e. dyskinesia, presumably resulting from an excessive response to dopamine [84]. This excessive response to dopamine, formed from levodopa, results in behavioral sensitization to the drug. Enhanced responses to levodopa in 6-OHDA-lesioned rats could reflect either the progressive motor recovery occurring at treatment initiation or the development of levodopa-induced dyskinesia (LID) as is seen in long-term treated PD patients [85]. This could not be assessed in PDlike rats, which do not develop typical LID. For this reason, monkeys treated with 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), which destroys dopamine neuron terminals and cell bodies and produces a variety of PD-like symptoms, including akinesia and rigidity [86], were used. Long-term treatment of these monkeys with levodopa elicits dyskinesia, the repertoire and the severity of which are not distinguishable from LID occurring in PD patients [84]. MPTP alone produces a severe loss of D3 receptor binding in the caudate nucleus [81], a brain structure involved in associative locomotion (goal-oriented locomotion), an effect which is compensated by treatment with levodopa in MPTP-intoxicated animals without LID (Fig. 4). However, in MPTP-intoxicated monkeys with LID, D3 receptor binding is higher than in non-dyskinetic monkeys in the putamen and internal part of the globus pallidus and even higher than in normal monkeys [81] (Fig. 4). Moreover, D3 receptor binding levels in the putamen correlate with the occurrence and severity of LID. These results show that PD-like symptoms and LID are accompanied by down- and up-regulation of D3 receptor expression, respectively, while such a correlation does not exist for either D1 or D2 receptors under comparable experimental conditions [81, 84]. In addition, the occurrence of dyskinesia does not correlate with the severity of the lesion [81], which indicates that the level of D3 receptor expression level in the putamen and globus pallidus correlates well with dyskinesia . The changes in D3 receptor expression are likely to reflect fluctuations in D3 receptor function, as it is the case in PDlike rats, in which such changes are responsible for alterations of motor responses [49, 54]. To test this hypothesis, BP 897 was administered to dyskinetic MPTP-
31
intoxicated monkeys in combination with levodopa, and evaluated for LID and PD-like symptoms by experimenters unaware of the treatment received [81]. BP 897 attenuates LID by 66% (Fig. 5A), but has almost no influence on the therapeutic effect of levodopa, i.e. it does not reverse the improvement of PD-like symptoms (Fig. 5B). Both hyperkinesia (that is not true dyskinesia and thus not rated as one) and choreic/athetoid movements are improved. The kinetics of activity counts (Fig. 5C) highlighted this characteristic pharmacological behavior by showing the ability of BP 897 to undermine the levodopa-induced activity around the dyskinesia threshold, defined from a correlation with clinically assessed LID. The dissociation between the effects of BP 897 on LID and the therapeutic effects of levodopa seems to be related to the mixed agonistantagonist property of this compound, because nafadotride and ST 198, two D3 receptor-selective antagonists devoid of agonistic effects, elicit a reduction of LID similar to that obtained with BP 897 (Fig. 5A), which is, however, accompanied by a reappearance of PD-like symptoms (Fig. 5B-D).
Fig. (4). Dyskinesia is accompanied by D3 receptor overexpression. A, typical receptor autoradiograms obtained with [125I]7-OH-PIPAT, a selective D3 receptor radioligand, in the brain from a control monkey, untreated MPTP-intoxicated monkeys (MPTP), and non-dyskinetic and dyskinetic MPTPintoxicated monkeys treated by levodopa (LD). Cd, caudate nucleus; GPe, external part of globus pallidus; GPi, internal part of globus pallidus; Pu, putamen. b, quantitative analysis of autoradiograms obtained as in A. Results are mean + S.E.M. of values in Ci/mg. Treatments had significant effects in Cd (P = 0.007 by analysis of variance), Pu (P = 0.026) and GPi (P = 0.028), but not in GPe (P = 0.22). *, P < 0.05 vs. control; , P <0.05; , P < 0.01 vs. non-dyskinetic. Data from [81].
Fig. (5). A partial D3 receptor agonist, but not D3 receptor antagonists, reduced LID without affecting the therapeutic effects of levodopa. A-C, LID (A), PD-like symptoms (B) and locomotor activity (C) as a function of time in MPTPintoxicated monkeys treated with either placebo, the D3 receptor partial agonist BP 897 administered at an optimal dosage, or the D3 receptor antagonists nafadotride or ST 198, both administered at a minimal dosage. In C, the on-time threshold of locomotor activity is defined as the transition from immobility, the dyskinesia threshold as the normal locomotor activity i n normal animals. D3 receptor-acting agents significantly affected both the dyskinesia disability score (P < 0.05) and PD disability score (Fr = 42.3 with 4 d.f., P < 0.05) over the time course (e.g. at t = 60 min, with 3 d.f., Fr = 16.8, P < 0.05 and Fr = 8.7, P < 0.05 for dyskinesia and PD disability scores, respectively; at t = 150 min, Fr = 17.9, P < 0.05 and Fr = 7.1, P < 0.05, for dyskinesia and PD disability scores, respectively). * P < 0.05 vs. placebo. D, ontime duration (min) measured from locomotor activity counts over a 5 hr-period of time (F3,9 = 5.50, P = 0.001). * P < 0.05 vs. placebo. Data from [81].
It should be stressed that the results obtained with D3 receptor-selective agents are highly dependent on the experimental model. The results depicted above were obtained with MPTP-intoxicated macaques, in which LID appears very slowly and progressively after months of treatment with levodopa, at the minimal dose tailored for
each monkey, designed to produce a full reversal of parkinsonism. These experimental conditions are similar to the treatment given to patients with PD. On the contrary, in MPTP-intoxicated squirrel monkeys, in which dyskinesia is produced as early as after a single acute treatment with levodopa, BP 897 similarly reduces LID and the effects of levodopa on PD-like disability [87]. Furthermore, in MPTPintoxicated marmosets, S33084 does not reduce dyskinesia, which is obtained after short-term treatment with levodopa, but potentiates the effect on disability of the antiparkinsonian agent ropinirole [88]. Treatment with levodopa only partially reversed D3 receptor expression in squirrel monkeys and marmosets [89]. Therefore, the nature and pathophysiological mechanisms of LID may be different in macaques and other monkey species, and implicate D2 rather than D3 receptors in the latter. This may explain why BP 897 reduced both parkinsonian symptoms and LID, at doses producing 4-5 higher plasma levels [87] than in macaques monkeys in which it attenuates LID only. The
32
Sokoloff et al.
ultimate question relates to how useful BP 897 will be in treating LIDs in PD patients. The current status of D3 dopamine receptors in the basal ganglia of patients with PD is uncertain. D3 receptor levels have been reported either decreased in the striatum of pathologically-defined PD cases treated with levodopa [35] or increased, however only in patients with a robust response to levodopa therapy [90]. These results confirm that D3 receptors might be a factor contributing to dopaminergic drug responsiveness in PD, but clinical trials with D3 receptor-selective agent are necessary for assessing their relevance to LID. Activation of D3 receptor has been suggested to protect dopaminergic neurons from degeneration in Parkinson's disease. [34, 91]. Clinical studies with pramipexole and ropinirole, two D3 receptor-preferring agonists, showed less decline in markers of dopamine neuron integrity, compared to levodopa [92, 93]. Nevertheless, the interpretations of these data is equivocal, insofar as chronic treatment with pramipexole lowers the Vmax of the dopamine transporter [34], which is related to dopamine neuron degeneration in one study [92]. In addition, although the data suggest a beneficial effect of dopamine agonist treatment, a detrimental effect of levodopa on progressive dopamine neuron degeneration cannot be completely ruled out [94, 95]. 6. THE D3 RECEPTOR AND SCHIZOPHRENIA Before the discovery of the novel dopamine receptor subtype, it was assumed that the therapeutic action of antipsychotic drugs could be attributed to blockade of dopamine D2 rather than D1 receptors [96]. However, the cloning of several dopamine D2-like receptors, i.e. D2, D3, and D4 receptors, has raised the question of the role of these three proteins as targets for antipsychotics. Initially, the positive correlation between drug affinity at D2-like receptor binding site and drug plasma level identified these receptors as common targets for all antipsychotics [97, 98]. This was apparently confirmed when D2-like receptor occupancy in striatum was determined by PET and found to be 70-80 % in most cases [99, 100]. It remains to be established whether successful treatment of schizophrenia is also accompanied by significant occupancy of D3 or D4 receptor, a difficult task in view of their relative low abundance, which could not be undertaken so far because of the lack of a suitable PET scan probe. Nevertheless, acomparison of the affinities of antipsychotic drugs at recombinant D2 and D3 receptor (Table 1) indicates that these compounds generally show some, but very limited preference for the D2 receptor. Hence, it can be assumed that significant D3 receptor occupancy occurs during antipsychotic treatments resulting in 70-80 % D2 receptor occupancy (D2 receptor occupancy up to 80 % resulting in extrapyramidal side effect [101]). In contrast with D2 or D3, D4 receptor occupancy cannot account for the antipsychotic activity of all drugs, since effective compounds, such as thioproperazine or the benzamides show low affinity at the D4 receptor (Table 1). In addition, clinical trials with D4 selective antagonists have shown a lack of antipsychotic activity [16]. Remoxipride apparently shows marked preference for the D2 over D3 receptor, but the compound may act indirectly, by generating active metabolites, which display an inverse pharmacological profile [101, 102]. In the case of clozapine, only limited D3 receptor occupancy can be expected in view of the rather low affinity for this receptor.
Several lines of evidence suggest that the efficacy of clozapine might rely on D3 receptor antagonism. Clozapine plasma levels of successfully treated patients [103] exceeds by one order of magnitude the affinity constant of clozapine at D3 receptors, suggesting that the D3 receptor may be blocked by clozapine. Moreover, a higher affinity of clozapine for the D3 over the D2L isoform, which acts mainly at postsynaptic sites [104], was described [105]. Furthermore, the atypical response to clozapine on _FosBlike immunoreactivity in rats is abolished in D3 receptordeficient mice [106]. Finally, clozapine inhibits MK-801induced locomotor activity, a test predictive to the antipsychotic activity, with the same pattern as D3 receptorselective ligands, contrary to haloperidol (see below) [82]. Tolerance to antipsychotic drug-induced extrapyramidal side-effect develops in treated psychotic patients, who present a progressive decrease in extrapyramidal side-effects occurring during the first weeks of treatment and the appearance of tardive dyskinesia after several years. By contrast, no tolerance seems to occur at the level of (the) dopamine receptor subtype(s) involved in the antipsychotic activity, since this activity does not diminish upon long term treatment. It is, therefore, noteworthy that repeated administration of haloperidol for two weeks to rats failed to trigger any significant upregulation in D3 receptor mRNA or binding in various brain areas, whereas in the same treatment upregulated D2 receptor mRNA [20]. The absence of upregulation of D3 receptor mRNA and binding following repeated antipsychotic treatment is in agreement with other studies [107-109]. In addition, the reduction in neurotensin gene transcript in the ventromedial shell of nucleus accumbens, a typical response to D3 receptor blockade [7], does not show tolerance following repeated administration of haloperidol, whereas the reverse response in the core of nucleus accumbens, mediated by the D2 receptor, diminished upon repeated haloperidol administration [7]. These observations indirectly support the idea that the antipsychotic activity of neuroleptic drugs is related to D3 rather than D2 receptor blockade A link between the D3 receptor and schizophrenia was also suggested from the main expression of this receptor in forebrain limbic area that participates in the control of the activity of the prefrontal cortex (see above). Indeed, many functional imaging and neuropsychological studies have implicated the prefrontal cortex in integrative functions (memory, speech, focused attention) and in the disorder of these functions observed in schizophrenia [110]. Moreover, D3 receptor levels have been found elevated in the brain of drug-free schizophrenic patients, but not in patients under medication with antipsychotics at the time of death [108]. This suggests that the increase in D3 receptor expression is a hallmark of the disease, and not of its treatment, and that antipsychotic medications normalize this receptor expression. D3 receptor overexpression in the etiology of schizophrenia raises the question of mechanisms governing this receptor expression during development. D3 receptor expression during embryonic and early postnatal development is characterized by an appearance of transcripts at early stages in neuroblasts or migrating neurons in the rat [36] or human brain [101], in which it was already detected at week 6. However, the cortical neuroepithelium giving rise
33
to the cerebral neocortex was heavily labeled in the human, but not in the rat embryo [101]. Tentatively, the D3 receptor expressed in neuroepithelial cells lining the cerebral ventricles might regulate their mitotic activity since, activation of the recombinant receptors enhances mitogenesis [111]. Putative dopaminergic neurons were seen in the human brain, adjacent to the ventricle, presumably in the germinal zone at 16 days of gestation [112]. Being the only dopamine receptor subtype expressed in these dividing neuroepithelial cells and owing to its high sensitivity to dopamine (allowing dopamine to act at a certain distance from its release), the D3 receptor could have a role in the control of the proliferation of these cells elicited by dopamine and, therefore, in the number of neurons of their progeny [113, 114]. Note, however, that a role of D3 receptor in neurogenesis in the adult subventricular zone is documented only in rats [115], and that D3 receptor-knockout mice have apparently normal development [76]. The latter observations suggest that the role of D3 receptor in neuron proliferation and differentiation may not be critical. Among the cerebral morphometric abnormalities detected in either in vivo or post-mortem studies, ventricular enlargement, reduction in neocortical and hippocampal neuronal density could result from an abnormal control of their progenitors in the neuroepithelium during early development. Moreover, a role for BDNF can be hypothesized in this process, as well as in the etiology of schizophrenia, since BDNF controls D3 receptor expression during development and in adults (see above). However, the role of BDNF is difficult to establish in schizophrenia, because both an increase [116, 117] and a decrease [118, 119] in BDNF levels or BDNF mRNA have been found in cortical areas of antipsychotic-treated schizophrenic patients. Genetic factors are possible other factors controlling D3 receptor in schizophrenia, which is an inheritable disorder. A very large series of studies (nearly seventy) has been published so far aiming at assessing the implication of the D3 receptor gene in schizophrenia, responsiveness to its treatments and the side-effects of these treatments. These studies have started after the identification of polymorphisms 9 of this gene, notably a mutation substituting a Gly for a 9 Ser in the N-terminus of the receptor and creating a Bal I restriction site [120]. Crocq and coworkers were the first to detect, in French and Welsh populations, evidence for an association of homozygosity of either allele 1 (Ser-Ser) or allele 2 (Gly-Gly) with schizophrenia [121]. A flurry of other association studies has followed, the majority of which did not confirm the initial studies. Nevertheless, two independent meta-analyses of a large number of association studies were performed in an attempt to minimize the lack of statistical power of individual studies and to control for population heterogeneity in a total population of over 2,500 patients and 2,500 controls and convergent conclusions were obtained [122, 123]. Significant, although limited excess of homozygotes for both alleles were found, clearly suggesting that having the 1-1 allele (or the 2-2 allele) of the D3 receptor gene slightly enhances susceptibility to the disease over having the 1-2 allele. However, a recent meta-analysis [124] including more studies (comprising a total of 8,761 subjects) indicates that the association, while persisting, is very loose and that, at most, the D3 receptor gene contributes very modestly to the susceptibility to schizophrenia. Convergent
genetic studies also suggest a role of the D3 receptor gene in tardive dyskinesia, a frequent motor side-effect of antipsychotic drugs [125]. Glutamate has also been suggested to be involved in schizophrenia from the following clinical observations. Phencyclidine (PCP), a non-competitive antagonist at the Nmethyl-D-aspartate (NMDA) subtype of glutamate receptor, is an anesthetic agent that has psychotomimetic properties in man [126]. PCP produces schizophrenic-like symptoms in healthy volunteers or abusers [127, 128] and precipitates psychosis in schizophrenic patients [129]. By contrast, drugs facilitating glutamate neurotransmission by acting at the glycine accessory site of the NMDA receptor, such as Dcycloserine, improve schizophrenia and enhance the efficacy of antipsychotic drugs, notably against the negative symptoms of the disease [130]. Moreover, direct evidence for altered NMDA receptor function in schizophrenia has been recently reported [131] and genetic linkage studies in schizophrenia now show that the most plausible susceptibility genes (neuregulin 1, dysbindin, proline dehydrogenase and others) functionally interact with glutamate pathways [132]. These observations led to the proposal that schizophrenia may result from glutamate deficiency. In animals, PCP or dizocilpine (MK-801), another non competitive NMDA receptor antagonist [133], elicits behavioral abnormalities, including hyperactivity, disruption of sensorimotor gating and social deficit that are circumvented by antipsychotic drugs, particularly of the atypical type [128]. The ability of PCP to simulate schizophrenia has led to the proposal that the behavioral abnormalities evident in schizophrenic patients and PCPexposed humans are caused by dysfunction of common neural substrates. The effect of PCP or its cognate molecules on brain dopamine systems has received particular attention [128, 134], since alteration in dopaminergic systems has been hypothesized in schizophrenia [135]. Systemic administration of phencyclidine or MK-801 increases dopamine cell firing rate in the ventral tegmental area (VTA), dopamine metabolism [136-138] and extracellular dopamine concentrations in the nucleus accumbens [139]. Hyperlocomotion induced in rodents by systemically administered NMDA receptor antagonists is blocked by 6hydroxydopamine lesions of the VTA [137] or depletion of dopamine from neuronal stores [140]. Hence, convergent data strongly suggest that locomotor effects of NMDA receptor antagonists at low doses are mediated via increased dopamine function, but the dopamine receptors involved have not been fully characterized. To investigate the role of the D3 receptor in the schizophrenia-like behavioral abnormalities produced by NMDA receptor blockade, the effects of D3 receptor-selective agents have been studied in wild-type and D3 receptorknockout mice administered with MK-801 [82]. Hyperactivity produced by low doses of MK-801 was potently and completely inhibited by haloperidol, clozapine, nafadotride, or BP 897 with ED50 values ranging from 0.05 to 0.2 mg/kg (Fig. 6). Unlike the other agents, haloperidol also inhibited spontaneous locomotor activity at the same
34
Sokoloff et al.
tegmental area to the nucleus accumbens, frontal cortex, olfactory tubercle, amygdala and septal area, is an important substrate for the rewarding/reinforcing effects of abused drugs. One of the major projection areas of mesolimbic dopamine neurons, the shell of nucleus accumbens where both D3 receptor protein and mRNA are highly expressed, projects to the ventral tegmental area and receives projections from the prefrontal cortex, hippocampus and amygdala [10, 11]. These various specific connections within the shell of nucleus accumbens are part of the "extended amygdala" [142], making it a critical structure in the control of motivation and the effects of drug-associated conditioned stimuli. The density of D3 receptor is elevated in long-term cocaine abusers [143, 144], and in animals chronically treated with cocaine [145] or nicotine [146], suggesting that D3 receptor over-expression is due to drug exposure. These effects appear selective for the D3 receptor, since no changes in D1 or D2 expression have been found in the brains of these animals [145]. Although the functional consequences of such an upregulation are not fully understood, preclinical evidence suggests that this upregulation is involved in phenomena such as behavioral sensitization that are thought to play an important role in drug dependence [147].
Fig. (6). Effect of antipsychotic drugs and D3 receptor antagonists on MK-801-induced locomotor hyperactivity. Saline (Sal), BP 897, nafadotride, clozapine, or haloperidol were administered at the indicated dosage and the spontaneous activity (empty columns) and activity after MK-801 (0.12 mg/kg, filled columns) recorded. * P < 0.05, ** P < 0.01, *** P < 0.005 vs. respective Sal. Data from [82].
doses. That the D3 receptor mediated the effects of MK-801, was confirmed by the dramatic decrease in MK-801-induced hyperactivity in D3 receptor knockout mice (Fig. 7). The inhibitory effects nafadotride and BP 897 were completely suppressed, whereas that of clozapine was partially suppressed (Fig. 7B). These results indicate that the MK801-induced hyperactivity involves stimulation of the D3 receptor. Nevertheless, the hyperactivity remaining in D3 receptor-knockout mice depends on other receptors. These results show that activation of the D3 receptor is a major mechanism underlying locomotor effects of NMDA receptor antagonists at low doses. Blockade of the D3 receptor produces an effect very similar to that produced by antipsychotics on MK-801-induced hyperactivity, which, therefore, supports the growing evidence suggesting that D3 receptor blockers might have antipsychotic properties. They also suggest that the D3 receptor may be an intermediary linking glutamate and dopamine dysfunctions in schizophrenia. This hypothesis has received recent support by the preliminary results of the first double-blind placebocontrolled study of BP 897 in schizophrenia, which showed exposure-dependent antipsychotic effects [141]. Taken together, these recent results add to the previously gained evidence indicating that the D3 receptor plays an important role in schizophrenia and its treatment. 7. THE D3 RECEPTOR AND DRUG ADDICTION Converging evidence supports the idea that the mesocorticolimbic system, which projects from the ventral
Fig. (7). Effect of D3 receptor gene deletion on MK-801-induced hyperactivity and its inhibition by clozapine and D3 receptor antagonists. A, Following a 30-min period of habituation, saline (Sal) or MK-801 (MK, 0.12 mg/kg) was injected (arrow) to wildtype (D3R+/+) or D3 receptor-deficient mice (D3R-/-) and locomotor activity was recorded during 60 min. * P < 0.05, ** P < 0.01, vs. respective saline-treated mice, # P < 0.05, ## P < 0.01 vs. MK801-treated D3R-/- mice. B, Effect of saline (SAL), BP 897 (1 mg/kg), nafadotride (NAF, 1 mg/kg) or clozapine (CLOZ, 1 mg/kg) on MK-801-induced hyperactivity on wild-type (D3R+/+) or D3 receptor-deficient (D3R-/-) mice. The clozapine effects in D3/mice indicate that the MK-801-induced hyperactivity in these mice is independent of the D3 receptor, and may involve other clozapines targets (noradrenalin or serotonin receptors). * P < 0.001 vs. saline-treated D3R+/+ mice, # P < 0.05 vs. saline-treated D3R-/- mice. Data from [82].
Repeated intermittent administration of drugs of abuse induces a sensitization strikingly similar to that produced by levodopa in hemiparkinsonian rats, which is characterized by enhanced behavioral responses (see [148] for a review). Interestingly, it appears that D3 receptor overexpression is facilitated by the interaction of the effects of drugs with drug-associated environmental stimuli [145]. Moreover, D3 receptor overexpression that is induced by repeated nicotine
35
administration is more pronounced in rats repeatedly receiving nicotine injections in a distinctive environment designed to facilitate drug-induced conditioning, than in rats receiving nicotine in their home-cages [149]. Interestingly, BDNF, which controls D3 receptor expression, has also been directly implicated in drug addiction processes. BDNF is synthesized in the hippocampus, amygdala, dopamine neurons and prefrontal cortex [150] that project to the nucleus accumbens. BDNF infusion in the nucleus accumbens enhances, whereas a reduction in BDNF levels reduces cocaine-conditioning [151, 152]. Furthermore, BDNF expression increases following exposure to cocaine-associated stimuli and after prolonged cocaine withdrawal [145, 153], factors that may promote long-lasting changes facilitating drug-seeking behavior [154] or cocaine craving [155]. Both BDNF [145, 151] and D3 receptors (see below) have been implicated in paradigms that involve classically conditioned effects of drugs of abuse. Drug conditioning necessitates repeated associations of distinctive environmental stimuli with drug effects. Nevertheless, it has been shown that a single stimulus associated with a single cocaine experience can acquire motivational value and elicit long-lasting cocaine-seeking in rats [156]. A single administration of various drugs of abuse, including cocaine, methamphetamine, morphine and, to a lesser extent, nicotine, induces a transient increase in BDNF expression in the prefrontal cortex, associated with a longlasting increase in D3 receptor binding and mRNA levels in the shell of the nucleus accumbens [157]. Thus, the lack of permanent increase of BDNF expression after cocaine administration, allows phasic changes of BDNF release to be associated with each presentation of environmental stimuli. On the contrary, the much longer time scale for increase in D3 receptor levels permits additive effects of repeated presentations. Therefore, these results suggest that the BDNF/D3 receptor pathway, activated by drugs as soon as at their first administration, is involved in the initiation and maintenance of drug conditioning. Pharmacological data, obtained with non selective dopamine receptor ligands, suggested the involvement of the D3 receptor in the reinforcing effects of cocaine (see [158] for a review). Pretreatment with the D3 receptor-preferring agonists, pramipexole, quinelorane and PD 128,907, dose dependently decreases cocaine self-administration [159, 160] in a manner suggesting that these agonists potentiate, rather than reduce the reinforcing effects of cocaine. In addition, the relative potencies of these different agonists in decreasing cocaine self-administration are highly correlated with their functional potency at the D3, but not the D2 receptor [161]. Finally, preferential agonists at D3 receptor substitute for cocaine in rhesus monkeys trained to discriminate cocaine from saline [162], and there is a correlation between the potencies of several preferential agonists at D3 receptor in reproducing the discriminative stimulus effects of cocaine in squirrel monkeys and their in vitro potencies at the D3 receptor, but not D2 receptor [163]. All of these observations suggest that stimulation of D3 receptor can enhance the reinforcing effects of cocaine. However, several recent studies using more selective ligands and D3 receptor-deficient mice now indicate that the ability of D3 receptor blockade to decrease the motivation to
take drugs appears to depend on the price the animal has to pay (in terms of efforts) to get the drug. In other words, the more the number of lever pressures is high to get the drug, the more self-administration is inhibited by D3 receptor blockade. Thus, under small fixed-ratio schedules, where one or two responses are required to produce each injection, BP 897 or SB-277011A does not alter cocaine selfadministration in rats [56, 164]. Recent findings obtained using transgenic mice confirm the lack of involvement of D3 receptor in the reinforcing effects of cocaine, since deletion of the D3 receptor in transgenic mice does not produce any change in cocaine self-administration [165]. Similar findings have been described with nicotine [166] and ethanol [167, 168]. Nevertheless, the D3 receptor controls the motivation to self-administered drugs under FR (fixed ratio) schedules of reinforcement with high response requirements or progressive-ratio schedules. Thus, SB-277011A reduces cocaine self-administration under both a progressive-ratio schedule and a fixed-ratio schedule with a relatively high response requirement [169]. The fact that blockade of the D3 receptor produces different effects under different schedules of reinforcement is consistent with a behavioral economic analysis [170]: the ability of D3 receptor blockade to decrease the motivation to take drugs depends on the price of drug; drugs being self-administered under high price conditions appear to be more sensitive to the effects of D3 receptor blockade. Drug-associated environmental stimuli are major factors that can cause relapse to drug use in abstinent drug addicts. This process is critical for psychostimulants, but also for nicotine and heroin addiction [171-174]. Moreover, in animals, such stimuli can induce and maintain drug-seeking behavior in the absence of drug and can also reinstate extinguished drug-seeking behavior [175-180]. In a secondorder schedule of reinforcement in which a drug-associated stimulus progressively gains motivational salience and, as a conditioned reinforcer, maintains and controls drug-seeking behavior, BP 897 [56] (see Fig. 8) and SB-277011A [164] dose-dependently reduce cocaine-seeking behavior. These effects occur in the absence of any observable non-specific effects (e.g. motor disturbances), effects that might have disrupted performance. Thus, these ligands have no demonstrated reinforcing effects;for instance BP 897 is not self-administered in rats [56] and monkeys [181], but are able to reduce cocaine-seeking behavior maintained by presentation of cocaine-associated stimuli. Priming injections of drug and environmental stressors have also been identified as factors that can trigger relapse to drug-seeking and drug-taking behavior in humans and experimental animals [182, 183]. SB-277011A administration inhibits stress-induced reinstatement of cocaine-seeking behavior [184] and also reinstatement of nicotine-seeking behavior produced by a priming injection of nicotine in rats [166]. Thus, it appears that D3 blockade can decrease the influence of various factors producing relapse in animals and humans. Since D3 receptor-selective ligands are able to disrupt drug-seeking behavior induced by the presentation of cocaine-associated stimuli, it has been suggested that these ligands may be useful tools for suppressing reactivity to
36
Sokoloff et al.
Fig. (8). The D3 receptor-selective partial agonist BP 897 inhibits cue-controlled cocaine-seeking but has no reinforcing effects. A, during repeated sessions, rats are trained to self administer i.v. cocaine by a lever pressing. BP 897, tested when a stable pattern of self-administration is acquired, has no effect on cocaine self-administration session, i.e. no reinforcing effect. B, Progressively, a light stimulus is associated with cocaine self-administration, which gains reinforcing properties and finally maintains drug-seeking behavior, even without drug delivery (C). During this last phase, the behavior of the animal, which reflects the motivation to take drug induced by the conditioned stimulus is dose-dependently reduced by BP 897. (*P<0.05 and ** P<0.01 vs. saline). Data from [56], reprinted from [239].
drug-associated environmental stimuli [56, 149, 185]. These stimuli are thought to gain motivational value through Pavlovian conditioning processes. A variety of procedures have been used to assess the influence of D3 receptor on Pavlovian-conditioned behavioral responses [145, 149]. Thus, an animal model frequently used to explore the control over behavior that can be exerted by drugs of abuse is the conditioned place preference (CPP) procedure. CPP occurs when repeated administration of a drug followed by placement in a distinctive environment (e.g. one compartment of a two- or three-compartment apparatus) results in the ability of that environment to elicit approach behavior and increased time contact (conditioned place preference) in the absence of the previously administered drug. It has been argued that CPP, like drug self-administration and a number of related phenomena, can be considered a measure of drugseeking behavior [186, 187]. Thus, CPP procedures, like second-order schedules of drug injection, provide a means of measuring the influence of drug-related environmental stimuli on behavior. D3 receptor-selective ligands block CPP, as well as various conditioned responses to different drugs of abuse (Table 2). Remarkably, these ligands have no effect on responses associated with natural reward, such as food. With CPP procedures, it is possible to assess the effects of D3 receptor-selective ligands on the acquisition of drug-
induced place preferences, as well as on the expression of CPP in the absence of the drug. Although acquisition of drug-induced CPP has often been considered a reliable measure of the rewarding effects of drugs, in fact, this procedure measures the progressive acquisition by initially neutral stimuli, of conditioned motivational effects resulting from their association with the interoceptive effects produced by drug administration. SB-277011A prevents the development of cocaine- [188] and heroin-[189] induced CPP. Similar findings have been described with BP 897 [190]. In contrast, the development of morphine-induced CPP was not significantly altered by BP 897 in rats [190]; BP 897, however, facilitates the acquisition of morphineinduced CPP in mice [191]. Effects of D3 receptor-selective ligands during the acquisition of CPP processes may reflect blockade of the direct rewarding effects of the drug, but may also reflect blockade of the ability to form conditioned associations, which subsequently allow the stimuli to influence the behavior. However, BP 897 has no effect on the recall of environmental stimuli or on recognition of environmental stimuli, not associated with drug effects. For instance, BP 897 does not alter habituation to an open field during consecutive sessions and has no effect on passive avoidance of a stressful stimulus, a mild electric shock [145].
37
Table 2.
Effects of D3 Receptor Ligands on Various Conditioned Responses

Drug cue-controlled response Drug-seeking behavior Conditioned place preference Conditioned locomotor activity Conditioned locomotor activity Drug-seeking behavior Conditioned place preference Conditioned place preference (mice) Conditioned place preference (rats) Conditioned place preference Conditioned locomotor activity Seeking behavior Seeking behavior BP 897 Effects of D3 receptor ligands BP 897
a
Reinforcer Cocaine Cocaine Cocaine Amphetamine Heroin Heroin Morphine Morphine Nicotine Nicotine Ethanol Food
a
Reference [235] [190] [145] [236] [235] [189] [203] [190] [237] [149] [238] [235]
; SB-277011A
BP 897 ; SB-277011A BP 897 BP 897 is inactive SB-277011A BP 897 BP 897 is inactive BP 897 BP 897 ; ST 198
; SB-277011A
SB-277011A BP 897 and SB-277011A are inactive
attenuate.
The mechanisms underlying the effects of D3 receptorselective ligands in animal models of drug dependence are beginning to be revealed. There has been considerable attention to D3 receptor in the nucleus accumbens, but D3 receptors are also expressed in the ventral tegmental area and the amygdala, brain regions implicated in the effects of drugs of abuse and in reactivity to drug associated cues. Since D3 receptors are overexpressed in the brain of cocaine addicts [143] and of cocaine and nicotine-treated animals [145, 149], D3 receptor-selective ligands may act by attenuating exacerbated dopamine transmission in the nucleus accumbens. In agreement, Xi et al. recently reported that local administration of SB-277011A, into the nucleus accumbens block the reinstatement of cocaine-seeking behavior induced by stress in rats [184]. Nevertheless, there is evidence that BP 897 may also act through D3 autoreceptors. Thus, stimulation of D3 autoreceptors by BP 897, acting as an agonist, would reduce dopaminergic transmission and, therefore, drug-seeking behavior [192]. This hypothesis has been put forward based on the effects of BP 897 on c-fos gene expression in various brain regions of cocaine-conditioned mice. Exposure to cocaine-associated stimuli increases in c-fos gene expression in various subcortical limbic areas, including the nucleus accumbens, caudate-putamen, ventral tegmental area and amygdala [145]. Surprisingly, although BP 897 reduces hyperactivity induced by presentation of cocaine-associated stimuli, there is no effect on c-fos gene expression in the nucleus accumbens, supporting the hypothesis that BP 897 does not act directly at postsynaptic D3 receptors. Nevertheless, this hypothesis is not consistent with the observation that infusion of BP 897 into the nucleus accumbens blocks the expression of amphetamineconditioned locomotor hyperactivity [193]. In contrast, BP 897 decreased c-fos gene expression in the ventral tegmental area, probably reflecting inhibition of activity of dopaminergic neurons, the major neuronal population in this area [194]. This hypothesis is consistent with the activation of dopaminergic neurons induced by reward-predicting
stimuli [195] and by increases of dopaminergic neurotransmission often associated with presentation of drugassociated stimuli [196, 197]. These putative and distinct mechanisms of action may explain why D3 receptor partial agonists and antagonists, behave slightly differentially in different models of addiction [56, 164]. D3 receptor ligands may also act through D3 receptors in the amygdala [65]. This brain area in particular the basolateral nucleus of amygdala, is involved in drug addiction [198, 199] and in associative functions underlying drug-conditioned behavior,[179, 200-202]. Moreover, drugassociated stimuli have been reported to increase extracellular levels of dopamine in the amygdala [197] and to increase cfos gene expression [145]. Interestingly, BP 897 administration increases c-fos gene expression in the amygdala of cocaine-conditioned mice, an effect that may be due to a direct effect of BP 897 on D3 receptors in the amygdala, or to an indirect effect through regulation of dopaminergic neuron activity [145]. In agreement with this hypothesis. BP 897 blocks the expression of amphetamineconditioned locomotor hyperactivity when infused into the basolateral amygdala [193]. Another important brain area may be the somatosensory cortex, where environmental stimuli are integrated. BP 897 inhibits c-fos expression in the somatosensory cortex, which is induced by the presentation of cocaine-associated stimuli in rodents [145]. In view of the low D3 receptor expression level in the somatosensory cortex, the effect of BP 897 may be indirect in this region, via decreased activity of VTA neurons and subsequent changes in the amygdala and thalamo-cortical pathways. These effects have been confirmed by c-fos analysis in the brain of mice after development of morphineinduced CPP; BP 897 decreased c-fos expression in the somatosensory cortex of wild-type animals, and these effects were abolished in D3 receptor-deficient mice [203] (Fig. 9). Thus, D3 receptor-selective ligands appear to modulate the motivation to self-administer drugs under situations where the drugs have a high price. Numerous experiments also indicate that the D3 receptor is involved in reactivity to
38
Sokoloff et al.
Fig. (9). Effect of BP 897 on morphine-induced CPP (A) and on c-fos expression (B) in wild-type (D3R+/+) and D3 receptor-deficient (D3R-/-) mice. A, Time spent on the least preferred floor measured before and after pairing with saline or morphine at the dose of 3 2 mg/kg and changes is expressed as the time difference. Saline or BP 897 (1 mg/kg), was injected 30 min before the test session. *P < 0.05; *** P < 0.001 vs. vehicle-treated D3R+/+ mice. B, c-fos expression in cortical areas of mice taken at the end of the CPP test session. C-fos mRNA levels were analysed by densitometry in cingulate (left panels) or somatosensory (right panels) cortex. * P < 0.01 vs. saline. Data from [203].
environmental stimuli associated with the effects of many abused drugs. These stimuli, especially those associated with psychostimulants such as cocaine and nicotine, can elicit reports of craving and precipitate relapse in abstinent human substance abusers [171-173, 204]. D3 receptor-selective ligands may therefore provide an effective means of preventing relapse to drug use. Moreover, a therapeutic intervention with D3 receptor-selective ligands would not interfere with normal activities, since these ligands do not
alter conditioned responses to aversive stimuli or to natural reinforcers, such as food. 8. THE D3 RECEPTOR AND DEPRESSION BDNF is an important factor for the plasticity of the dopamine mesolimbic system, of which the role in appetitive motivation and positive reinforcement has been emphasized above. Experimental evidence also supports the view that secondary adaptive changes in the function of
39
dopamine systems participate in the effects of stress and chronic antidepressant treatments. Acute stress activates the mesocortical dopaminergic system [205], but chronic stress triggers adaptive processes leading to decreased dopaminergic transmission in the shell of nucleus accumbens [206, 207]. By contrast, antidepressant drugs, such as imipramine [208] and electroconvulsive shocks (ECT) [209] induce a subsensitivity of dopamine autoreceptors, leading to a persistent enhancement of dopamine neuron electrical activity [210, 211]. Although antidepressant drug treatments have variable effects on basal extracellular dopamine in the nucleus accumbens [212], they increase amphetamine-evoked dopamine release [213, 214] and ECT treatments enhance spontaneous dopamine release [215]. Hence, the data in the literature are rather consistent with a decreased activity of mesolimbocortical dopamine neurons by chronic stress and in depression, which is reversed by chronic antidepressant treatments. The convergent effects of antidepressant drugs with different serotonin/norepinephrine pharmacological selectivities on dopamine neuron activity can be explained as an adaptation of these neurons to the inhibitory actions of both serotonin and norepinephrine, suggested by various anatomical and functional studies [216, 217]. BDNF is expressed by mesolimbic dopamine neurons [150] and is released in a neuron activity-dependent manner [218]. Therefore, changes in mesolimbic dopamine neuron activity after stress or chronic antidepressant treatment would alter the expression of BDNF-regulated genes in target neurons. In agreement, various antidepressant treatments, including tricyclic antidepressants, serotonin-selective reuptake inhibitors, inhibitors of monoamine oxidase and ECT, all selectively increase D3 receptor expression in the shell subdivision of the nucleus accumbens [219, 220] (Table 3), whereas changes in D1 or D2 receptor expression, receptors which are not regulated by BDNF [49], are more variable, limited in amplitude, short-lasting or occur in other brain regions [212, 220-222]. These results are in agreement with previous observations that administration of antidepressant drugs in rats produces a variety of changes in dopamine responsiveness, most notably a sensitization of behavioral responses to agonists acting at dopamine D2/D3 receptors within the nucleus accumbens [223-226]. Some features of the response to these antidepressant treatments suggest that enhanced dopamine neurotransmission through the D3 receptor participates in the adaptive changes leading to antidepressant activity. First, antidepressant drugs enhanced D3 receptor expression after chronic, but not acute treatment (Table 3), which is in agreement with the delayed therapeutic action of these drugs in depressed patients. Several antidepressant drugs had actually a limited or even an opposite effect when tested after a single administration [219, 220] (Table 3). Moreover, a progressive and strong downregulation of D3 receptor binding occurs after repeated handling and injections, even though no drug was administered and might be interpreted as a stressinduced effect [220]. Second, this common effect of antidepressant drugs is restricted to the shell of nucleus accumbens that various studies have shown to subserve the role of dopamine in appetitive motivation, positive reinforcement, pleasurable effect of reinforcing stimuli. Interestingly enough, ECT produced the most rapid and robust increase in D3 receptor protein and mRNA expression
(Table 3), as compared to antidepressant drugs, which is in agreement with their therapeutic efficacy in refractory depression.
Table 3. Changes in D3 Receptor Expression in the Shell of Nucleus Accumbens After Antidepressant Treatments
Acute D3 R mRNA (1 day) Desipramine Imipramine Amitriptyline Fluoxetine Tranylcypromine Electroconvulsive shocks nd - 24%* - 31%** + 24% - 22%* nd Chronic D3 R mRNA (21 days) + 54%** + 35%** + 35%** - 30 %* + 38%* + 49%* D3 R binding (42 days) nd nd + 46%* + 42%* nd + 42%**
Treatment
nd, not determined; * P<0.05, ** P<0.01 vs saline-treated animals. Data from [220].
These results indicate that D3 receptor expression and function are downregulated in stress and, possibly, depression, and that these changes are reversed by antidepressant treatments. This hypothesis is in agreement with data showing that pramipexole, a preferential D3 receptor agonist [23, 227], displays antidepressant-like effects in animals [228, 229] and is efficacious as antidepressant in humans [230, 231]. 9. CONCLUSION The various data collected so far and reported above are compelling enough to remove some of the uncertainties regarding the functions mediated by the D3 receptor, that can be summarized below. It appears that, acting as an autoreceptor, the D3 receptor controls the phasic, but not tonic activity of dopamine neurons. This hypothesis is consistent with the presence of D3 receptors on all mesencephalic dopamine neurons [28] and with the observations that a selective D3 receptor agonist inhibits dopamine efflux and that selective D3 receptor antagonists reverse dopamine-agonist induced inhibition of dopamine efflux [78, 79]. It is also consistent with observations that selective D3 receptor antagonists do not affect spontaneous locomotor activity nor dopamine efflux [78, 79]. Phasic activity of dopamine neurons may be induced by novelty, which may account for the hyperactivity displayed by D3 receptor-deficient mice in a novel environment [74, 232], or presentation of drug-conditioned cues, which may account for the inhibition by a selective and partial D3 receptor agonist of cocaine cue-controlled seeking behavior [56]. The data so far obtained with selective D3 receptor agents do not support the idea that postsynaptic D3 receptors exert an inhibitory role on spontaneous locomotor activity, as previously put forward [70, 71]. On the contrary, they suggest a stimulatory role on locomotion, at least in hemiparkinsonian rats [54] and parkinsonian monkeys [81]. Moreover, D3 receptor-dependent enhancement of responses to levodopa appears to be responsible for dyskinesia, at least in one monkey species, which suggests D3 receptor-selective partial agonists as add-on in the levodopatherapy of PD.
40
CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1 [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45]
Sokoloff et al. Diaz, J.; Lvesque, D.; Lammers, C.H.; Griffon, N.; Martres, M.P.; Schwartz, J.-C.; Sokoloff, P. Neuroscience, 1995, 65, 731-745. Le Moine, C.; Bloch, B. Neuroscience, 1996, 73, 131-143. Zahm, D.S.; Brog, J.S. Neuroscience, 1992, 50, 751-767. Pennartz, C.M.; Groenewegen, H.J.; Lopes da Silva, F.H. Prog. Neurobiol., 1994, 42, 719-761. Heimer, L. Brain Res. Brain Res. Rev., 2000, 31, 205-235. Landwehrmeyer, B.; Mengod, G.; Palacios, J.M. Mol. Brain Res., 1993, 18, 187-192. Murray, A.M.; Ryoo, H.L.; Gurevich, E.; Joyce, J.N. Proc. Natl. Acad. Sci. USA, 1994, 91, 11271-11275. Meador-Woodruff, J.H.; Grandy, D.K.; Van Tol, H.H.M.; Damask, S.P.; Little, K.Y.; Civelli, O.; Watson, S.J. Neuropsychopharmacol., 1994, 10, 239-248. Lahti, R.A.; Roberts, R.C.; Tamminga, C.A. Neuroreport, 1995, 6, 2505-2512. Hall, H.; Halldin, C.; Dijkstra, D.; Wikstrom, H.; Wise, L.D.; Pugsley, T.A.; Sokoloff, P.; Pauli, S.; Farde, L.; Sedvall, G. Psychopharmacology, 1996, 128, 240-247. Suzuki, M.; Hurd, Y.l.; Sokoloff, P.; Schwartz, J.C.; Sedvall, G. Brain Res., 1998, 779, 58-74. Morissette, M.; Goulet, M.; Grondin, R.; Blanchet, P.; Bedard, P.J.; Di Paolo, T.; Levesque, D. Eur. J. Neurosci., 1998, 10, 2565-2573. Lvesque, D.; Martres, M.-P.; Diaz, J.; Griffon, N.; Lammers, C.H.; Sokoloff, P.; Schwartz, J.-C. Proc. Natl. Acad. Sci. USA, 1995, 92, 1719-1723. Tang, L.; Todd, R.D.; O'Malley, K.L. J. Pharmacol. Exp. Ther., 1994, 270, 475-479. O'Hara, C.M.; Uhland-Smith, A.; O'Malley, K.L.; Todd, R.D. J. Pharmacol. Exp. Ther., 1996, 277, 186-192. Sautel, F.; Griffon, N.; Lvesque, D.; Pilon, C.; Schwartz, J.-C.; Sokoloff, P. Neuroreport, 1995, 6, 329-332. Koeltzow, T.E.; Xu, M.; Cooper, D.C.; Hu, X.T.; Tonegawa, S.; Wolf, M.E.; White, F.J. J. Neurosci., 1998, 18, 2231-2238. Mercuri, N.B.; Saiardi, A.; Picetti, R.; Calabresi, P.; Bernardi, G.; Borelli, E. Neuroscience, 1997, 79, 323-327. L'hirondel, M.; Chramy, A.; Gedeheu, G.; Artaud, F.; Saiardi, A.; Borrelli, E.; Glowinski, J. Brain Res., 1998, 792, 253-262. Joseph, J.D.; Wang, Y.-M.; Miles, P.R.; Budygin, E.A.; Picetti, R.; Gainetdinov, R.R.; Caron, M.G.; Wightman, R.M. Neuroscience, 2002, 112, 39-49. Diaz, J.; Pilon, C.; Le Foll, B.; Gros, C.; Triller, A.; Schwartz, J.-C.; Sokoloff, P. J. Neurosci., 2000, 20, 8677-8684. Zapata, A.; Witkins, J.M.; Shippenberg, T.S. Neuropharmacology, 2001, 41, 351-359. Zapata, A.; Shippenberg, T.S. Neuropharmacology, 2005, 48, 4350. Scarselli, M.; Novi, F.; Schallmach, E.; Lin, R.; Baragli, A.; Colzi, A.; Griffon, N.; Corsini, G.U.; Sokoloff, P.; Levenson, R.; Vogel, Z.; Maggio, R. J. Biol. Chem., 2001, 276, 30308-30314. Levey, A.I.; Hersch, S.M.; Rye, D.B.; Sunahara, R.K.; Niznik, H.B.; Kitt, C.A.; Price, D.L.; Maggid, R.; Brann, M.R.; Ciliax, B.J. Proc. Natl. Acad. Sci. USA, 1993, 90, 8861-8865. Le Foll, B.; Diaz, J.; Sokoloff, P. Life Sci., 2005, 76, 1281-1296. Joyce, J.N.; Woolsey, C.; Ryoo, H.L.; Borwege, S.; Hagner, D. BMC Biology, 2004, 2, 22. Ryoo, H.L.; Pierrotti, D.; Joyce, J.N. Mov. Disord., 1998, 13, 788797. Diaz, J.; Ridray, S.; Mignon, V.; Griffon, N.; Schwartz, J.-C.; Sokoloff, P. J. Neurosci., 1997, 17, 4282-4292. Thoenen, H. Science, 1995, 270, 593-598. von Bartheld, C.S.; Byers, M.R.; Williams, R.; Bothwell, M. Nature, 1996, 379, 830-833. Altar, C.A.; Cai, N.; Bliven, T.; Juhasz, M.; Conner, J.M.; Acheson, A.L.; Lindsay, R.M.; Wiegand, S.J. Nature, 1997, 389, 856-860. Altar, C.A.; DiStefano, P.S. Trends Neurosci., 1998, 21, 433-437. Kafitz, K.W.; Rose, C.R.; Thoenen, H.; Konnerth, A. Nature, 1999, 401, 918-921. Vicario-Abejon, C.; Collin, C.; McKay, R.D.G.; Segal, M. J. Neurosci., 1998, 18, 7256-7271. Korte, M.; Carroll, P.; Wolf, E.; Brem, G.; Thoenen, H.; Bonhoeffer, T. Proc. Nat. Acad. Sci. USA, 1995, 92, 8856-8860. Figurov, A.; Pozzo-Miller, L.D.; Olafsson, P.; Wang, T.; Lu, B. Nature, 1996, 381, 706-709. Patterson, S.L.; Abel, T.; Deuel, T.A.S.; Martin, K.C.; Rose, J.C.; Kandel, E.R. Neuron, 1996, 16, 1137-1145.
Various converging anatomical, pharmacological, and genetic observations also suggest that the D3 receptor might be implicated in schizophrenia [101]. In particular, the D3 receptor mediates behavioral abnormalities, such as locomotor hyperactivity in mice, which are elicited by glutamate/NMDA receptor blockade. Since, glutamate/ NMDA neurotransmission is thought to be deficient in schizophrenia, this suggests that D3 receptor-selective antagonists may be useful as novel antipsychotic drugs. This proposal has received some support from a preliminary clinical trial [141]. D3 receptors are not involved in the direct reinforcing effects of drugs of abuse, but modulate the motivation to self-administrated drugs under situations where the drugs have a high price and mediate the effects of environmental stimuli associated with the effects of many abused drugs. These stimuli, especially those associated with psychostimulants such as cocaine and nicotine, can elicit reports of craving and precipitate relapse in abstinent human substance abusers. D3 receptor-selective ligands may therefore provide an effective means of preventing relapse to drug use. Moreover, a therapeutic intervention with D3 receptor ligands would not interfere with normal activities, since these ligands do not alter conditioned responses to aversive stimuli or to natural reinforcers, such as food. These novel treatment options could not be conceivable before the identification of D3 receptor-selective agents. The forthcoming introduction into the clinics of these agents will be decisive for evaluating the therapeutic interest of the D3 receptor in the treatment of various neuropsychiatry disorders. ABBREVIATIONS BDNF CPP PD MK-801 LID MPTP NMDA 6-OHDA PD = Brain-derived neurotrophic factor = Conditionned place preference = Parkinson's disease = Dizocilpine = Levodopa-induced dyskinesia = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine = N-methyl-D-aspartate = 6-hydroxydopamine = Parkinsons disease
REFERENCES
[1] [2] [3] [4] [5] [6] [7] Sokoloff, P.; Giros, B.; Martres, M.-P.; Bouthenet, M.-L.; Schwartz, J.-C. Nature, 1990, 347, 146-151. Van Tol, H.H.M.; Bunzow, J.R.; Guan, H.C.; Sunahara, R.K.; Seeman, P.; Niznik, H.B.; Civelli, O. Nature, 1991, 350, 610-614. Sunahara, R.K.; Guan, H.C.; O'Dowd, B.F.; Seeman, P.; Laurier, L.G.; Ng, G.; George, S.R.; Torchia, J.; Van Tol, H.H.M.; Niznik, H.B. Nature, 1991, 350, 614-619. Sokoloff, P.; Schwartz, J.-C. Trends Pharmacol. Sci., 1995, 16, 270-275. Missale, C.; Nash, S.R.; Robinson, S.W.; Jaber, M.; Caron, M.G. Physiol. Rev., 1998, 78, 189-225. Levant, B. Pharmacol. Rev., 1997, 49, 231-252. Diaz, J.; Lvesque, D.; Griffon, N.; Lammers, C.H.; Martres, M.P.; Sokoloff, P.; Schwartz, J.-C. Eur. J. Neurosci., 1994, 6, 13841387.
The Dopamine D3 Receptor [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] Kerr, B.J.; Bradbury, E.J.; Bennett, D.L.H.; Triverdi, P.M.; Dassan, P.; French, J.; Shelton, D.B.; McMahon, S.B.; Thompson, S.W.N. J. Neurosci., 1999, 19, 5138-5148. Linnarsson, S.; Bjorklund, A.; Ernfors, P. Eur. J. Neurosci., 1997, 9, 2581-2587. Minichiello, L.; Korte, M.; Wolfer, D.; Khn, R.; Unsicker, K.; Cestari, V.; Rossi-Arnaud, C.; Lipp, H.-P.; Bonhoeffer, T.; Klein, R. Neuron, 1999, 24, 401-414. Guillin, O.; Diaz, J.; Carroll, P.; Griffon, N.; Schwartz, J.-C.; Sokoloff, P. Nature, 2001, 411, 86-89. Gurevich, E.V.; Himes, J.W.; Joyce, J.N. J. Pharmacol. Exp. Ther., 1999, 289, 587-598. Ernfors, P.; Lee, K.-F.; Jaenisch, R. Nature, 1994, 368, 147-150. Hyman, C.; Hofer, M.; Barde, Y.-A.; Juhasz, M.; Ynacopoulos, G.D.; Squinto, S.P.; Lindsay, R.M. Nature, 1991, 350, 230-232. Dluzen, D.E.; McDermot, J.L.; Anderson, L.I.; Kucera, J.; Joyce, J.N.; Osredkar, T.; Walro, J.M. Neuroscience, 2004, 128, 201208. Bordet, R.; Ridray, S.; Carboni, S.; Diaz, J.; Sokoloff, P.; Schwartz, J.-C. Proc. Natl. Acad. Sci. USA, 1997, 94, 3363-3367. Cabelli, R.J.; Shelton, D.L.; Segal, R.A.; Shatz, C.J. Neuron, 1997, 19, 63-76. Pilla, M.; Perachon, S.; Sautel, F.; Garrido, F.; Mann, A.; Wermuth, C.G.; Schwartz, J.-C.; Everitt, B.J.; Sokoloff, P. Nature, 1999, 400, 371-375. Berendse, H.W.; Galis-de-Graaf, Y.; Groenewegen, H.J. J. Comp. Neurol., 1992, 316, 314-347. Huang, Q.; Zhou, D.; Chase, K.; Gusella, J.F.; Aronin, N.; Difiglia, M. Proc. Natl. Acad. Sci. USA, 1992, 89, 11988-11992. Cole, D.G.; Kobierski, L.A.; Konradi, C.; Hyman, S.E. Proc. Natl. Acad. Sci. USA, 1994, 91, 9631-9635. Shieh, P.B.; Hu, S.C.; Bobb, K.; Timmusk, T.; Ghosh, A. Neuron, 1998, 20, 727-740. Tao, X.; Finkbeiner, S.; Arnold, D.B.; Shaywitz, A.J.; Greenberg, M.E. Neuron, 1998, 20, 709-726. Sokoloff, P.; Andrieux, M.; Besanon, R.; Pilon, C.; Martres, M.-P.; Giros, B.; Schwartz, J.-C. Eur. J. Pharmacol. Mol. Pharmacol. Sect. 1992, 225, 331-337. Svensson, K.; Carlsson, M.; Carlsson, A.; Hjorth, S.; Johansson, A.M.; Eriksson, E. Eur. J. Pharmacol., 1986, 130, 237-242. Griffon, N.C.P.; Schwartz, J.-C.; Sokoloff, P. Eur. J. Pharmacol., 1995, 282, R3-R4. Lvesque, D.; Diaz, J.; Pilon, C.; Martres, M.-P.; Giros, B.; Souil, E.; Schott, D.; Morgat, J.-L.; Schwartz, J.-C.; Sokoloff, P. Proc. Natl. Acad. Sci. USA, 1992, 89, 8155-8159. Herroelen, L.; De Backer, J.-P.; Wilczak, N.; Flamez, A.; Vauquelin, G.; De Keyser, J. Brain Res., 1994, 222-228. Lvesque, D. Biochem. Pharmacol., 1996, 52, 511-518. Xu, M.; Koeltzow, T.E.; Cooper, D.C.; Tonegawa, S.; White, F.J. Synapse, 1999, 31, 210-215. Perachon, S.; Betancur, C.; Pilon, C.; Rostene, W.; Schwartz, J.-C.; Sokoloff, P. Neuroreport, 2000, 11, 221-225. Sautel, F.; Griffon, N.; Sokoloff, P.; Schwartz, J.-C.; Launay, C.; Simon, P.; Costentin, J.; Schoenfelder, A.; Garrido, F.; Mann, A.; Wermuth, C.G. J. Pharmacol. Exp. Ther., 1995, 275, 1239-1246. Waters, N.; Svensson, K.; Haadsma-Svensson, S.R.; Smith, M.W.; Carlsson, A. J. Neural Transm. [Gen. Sect.], 1993, 94, 11-19. Newman-Tancredi, A.; Audinot, V.; Jacques, V.; Peglion, J.l.; Millan, M.J. Neuropharmacology, 1995, 34, 1693-6. Haadsma-Svensson, S.R.; Smith, M.W.; Svensson, K.; Waters, N.; Carlsson, A. J. Neural Transm. Gen. Sect., 1995, 99, 1. Accili, D.; Fishburn, C.S.; Drago, J.; Steiner, H.; Lachowicz, J.E.; Park, B.-H.; Gauda, E.B.; Lee, E.J.; Cool, M.H.; Sibley, D.R.; Gerfen, C.R.; Westphal, H.; Fuchs, S. Proc. Natl. Acad. Sci. USA, 1996, 93, 1945-1949. Wicke, K.; Garcia-Ladona, J. Eur. J. Pharmacol., 2001, 424, 8590. Wood, M.D.; Boyfield, I.; Nash, D.J.; Jewitt, F.R.; Avenell, K.Y.; Riley, G.J. Eur. J. Pharmacol., 2000, 407, 47-51. Ridray, S.; Griffon, N.; Mignon, V.; Souil, E.; Carboni S; Diaz, J.; Schwartz, J.C.; Sokoloff, P. Eur J. Neurosci., 1998, 10, 1676-86. Millan, M.J.; Gobert, A.; Newman-Tancredi, A.; Lejeune, F.; Cussac, D.; Rivet, J.-M.; Audinot, V.; Dubuffet, T.; Lavielle, G. J. Pharmacol. Exp. Ther., 2000, 293, 1048-1062. Reavill, C.; Taylor, S.G.; Wood, M.D.; Ashmeade, T.; Austin, N.E.; Avenell, K.Y.; Boyfield, I.; Branch, C.L.; Cilia, J.; Coldwell, M.C.; Hadley, M.S.; Hunter, A.J.; Jeffrey, P.; Jewitt, F.; Johnson,
41
[80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93]
[94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116]
[75] [76] [77] [78] [79]
C.N.; Jones, D.N.C.; Medhurst, A.D.; Middlemiss, D.N.; Nash, D.J.; Riley, G.J.; Routledge, C.; Stemp, G.; Thewlis, K.M.; Trail, B.; Vong, A.K.K.; Hagan, J.J. J. Pharmacol. Exp. Ther., 2000, 294, 1154-1165. Weber, B.; Schlicker, E.; Sokoloff, P.; Stark, H. Br. J. Pharmacol., 2001, 133, 1243-1248. Bezard, E.; Ferry, S.; Mach, U.; Leriche, L.; Boraud, T.; Stark, H.; Gross, C.; Sokoloff, P. Nat. Med., 2003, 6, 762-767. Leriche, L.; Schwartz, J.C.; Sokoloff, P. Neuropharmacology, 2003, 45, 174-181. Hornykiewicz, O. Wien. Klin. Wochenschr., 1963, 75, 309-312. Bezard, E.; Brotchie, J.M.; Gross, C.E. Nat. Rev. Neurosci., 2001, 2, 577-587. Cotzias, G.C.; Papavasiliou, P.S.; Gellene, R. New Eng. J. Med., 1969, 280, 337-345. Burns, R.S.; Chiueh, C.C.; Markey, S.P.; Ebert, M.H.; Jacobowitz, D.M.; Kopin, I.J. Proc. Natl. Acad. Sci. USA, 1983, 80, 4546-4550. Hsu, A.; Togasaki, D.M.; Bezard, E.; Sokoloff, P.; Langston, J.W.; Di Monte, D.A.; Quik, M. J. Pharmacol. Exp. Ther. 2004, 311, 770-7. Silverdale, M.A.; Nicholson, S.L.; Ravenscroft, P.; Crossman, A.R.; Millan, M.J.; Brotchie, J.M. Exp. Neurol., 2004, 188, 128-38. Quik, M.; Police, S.; He, L.; Di Monte, D.A.; Langston, J.W. Neuroscience, 2000, 98, 263-273. Joyce, J.N.; Ryoo, H.L.; Beach, T.B.; Caviness, J.N.; Stacy, M.; Gurevich, E.V.; Reiser, M.; Adler, C.H. Brain Res., 2002, 955, 138-52. Carvey, P.M.; McGuire, S.O.; Ling, Z.D. Parkinsonism Relat. Disord., 2001, 7, 213-223. Group, P.S. JAMA, 2002, 287, 1653-1661. Whone, A.L.; Watts, R.L.; Stoessl, A.J.; Davis, M.; Reske, S.; Nahmias, C.; Lang, A.E.; Rascol, O.; Ribeiro, M.J.; Remy, P.; Poewe, W.H.; Hauser, r.A.; Brooks, D.J. Ann. Neurol., 2003, 54, 93-101. Ahlskog, J.E. Neurology, 2003, 60, 381-389. Albin, R.L.; Frey, K.A. Neurology, 2003, 60, 390-394. Seeman, P. Pharmacol. Rev., 1980, 32, 229. Seeman, P.; Lee, T.; Chau-Wong, M.; Wong, K. Nature, 1976, 261, 717-719. Snyder, S.H. Am. J. Psychiatry, 1976, 133, 197-202. Farde, L.; Wiesel, F.A.; Nordstrm, A.L.; Sedval, G. Psychopharmacology, 1989, 99, S28-S31. Farde, L.; Nordstrom, A.L. Psychopharmacol. Ser., 1993, 10, 94100. Schwartz, J.-C.; Diaz, J.; Pilon, C.; Sokoloff, P. Brain Res. Brain Res. Rev., 2000, 31, 277-287. Mohel, N.; Sallemark, M.; Rosqvist, S.; Malmberg, A.; Hogberg, T.; Jackson, D.M. Eur. J. Pharmacol., 1993, 6, 121-125. Schulte, P. Clin. Pharmacokinet., 2003, 42, 607-18. Usiello, A.; Baik, J.H.; Rouge-Pont, F.; Picetti, R.; Dierich, A.; LeMeur, M.; Piazza, P.V.; Borrelli, E. Nature, 2000, 408, 199-203. Malmberg, A.; Jackson, D.M.; Eriksson, A.; Mohell, N. Mol. Pharmacol., 1993, 43, 749-754. Robertson, G.S.; Lee, C.J.; Sridhar, K.; Nakabeppu, Y.; Cheng, M.; Wang, Y.M.; Caron, M.G. Eur. J. Neurosci., 2004, 20, 3189-94. Tarazi, F.I.; Florijn, W.J.; Creese, I. Neuroscience, 1997, 78, 98596. Gurevich, E.V.; Bordelon, Y.; Shapiro, R.M.; Arnold, S.E.; Gur, R.E.; Joyce, J.N. Arch. Gen. Psychiatry, 1997, 54, 225-232. Fishburn, C.S.; David, C.; Carmon, S.; Fuchs, S. FEBS Lett., 1994, 339, 63-66. Ross, C.A.; Pearlson, G.D. Trends Neurosci., 1996, 19, 717-176. Pilon, C.; Lvesque, D.; Dimitriadou, V.; Griffon, N.; Martres, M.P.; Schwartz, J.-C.; Sokoloff, P. Eur. J. Pharmacol. [Mol. Pharmacol. Sect.], 1994, 268, 129-139. Freeman, T.B.; Spence, M.S.; Boss, B.D.; Spector, D.H.; Strecker, R.E.; Olanow, C.W.; Kordower, J.H. Exp. Neurol., 1991, 113, 344-353. Van Kampen, J.M.; Hagg, T.; Robertson, H.A. Eur. J. Neurosci., 2004, 19, 2377-2387. Coronas, V.; Bantubungi, K.; Fombonne, J.; Krantic, S.; Schiffmann, S.N.; Roger, M. J. Neurochem., 2004, 91, 1292-1301. Baker, S.A.; Baker, K.A.; Hagg, T. Neurobiol. Dis., 2005, 18, 523527. Takahashi, M.; Shirakawa, O.; Toyooka, K.; Kitamura, N.; Hashimoto, T.; Maeda, K.; Koizumi, S.; Wakabayashi, K.;
42
CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1 Takahashi, H.; Someya, T.; Nawa, H. Mol. Psychiatry, 2000, 5, 293-300. Durany, N.; Michel, T.; Zochling, R.; Boissl, K.W.; Cruz-Sanchez, F.F.; Riederer, P.; Thome, J. Schizophr. Res., 2001, 52, 79-86. Weickert, C.S.; Hyde, T.M.; Lipska, B.K.; Herman, M.M.; Weinberger, D.R.; Kleinman, J.E. Mol. Psychiatry, 2003, 8, 592610. Hashimoto, T.; Bergen, S.E.; Nguyen, Q.L.; Xu, B.; Monteggia, L.M.; Pierri, J.N.; Sun, Z.; Sampson, A.R.; Lewis, D.A. J. Neurosci., 2005, 25, 372-83. Lannfelt, L.; Sokoloff, P.; Martres, M.P.; Pilon, C.; Giros, B.; Jnsson, E.; Sedvall, G.; Schwartz, J.C. Psychiatr. Genet., 1992, 2, 249-256. Crocq, M.A.; Mant, R.; Asherson, P.; Williams, J.; Hode, Y.; Mayerova, A.; Collier, D.; Lannfelt, L.; Sokoloff, P.; Schwartz, J.C.; Gill, M.; Macher, J.-P.; McGuffin, P.; Owen, M.J. J. Med. Genet., 1992, 29, 858-860. Dubertret, C.; Gorwod, P.; Ades, J.; Feingold, J.; Schwartz, J.-C.; Sokoloff, P. Am. J. Med. Genet. [Neuropsychiatric Genetics], 1998, 81, 318-322. Williams, J.; Spurlock, G.; Holmans, P.; Mant, R.; Murphy, K.; Jones, L.; Cardno, A.; Asherson, P.; Blackwood, D.; Muir, W.; Meszaros, K.; Aschauer, H.; Mallet, J.; Laurent, C.; Pekkarinen, P.; Seppala, J.; Stefanis, C.N.; Papadimitriou, G.N.; Macciardi, F.; Verga, M.; Pato, C.; Azevedo, H.; Crocq, M.-A.; Gurling, H.; Kalsi, G.; Curtis, D.; McGuffin, P.; Owen, M.J. Mol. Psychiatry, 1998, 3, 141-149. Jonsson, E.G.; Kaiser, R.; Brockmoller, J.; Nimgaonkar, V.L.; Crocq, M.A. Psychiatr. Genet., 2004, 14, 9-12. Lerer, B.; Segman, R.H.; Fangerau, H.; Daly, A.K.; Basile, V.S.; Cavallaro, R.; Aschauer, H.N.; McCreadie, R.G.; Ohlraun, S.; Ferrier, N.; Masellis, M.; Verga, M.; Scharfetter, J.; Rietschel, M.; Lovlie, R.; Levy, U.H.; Meltzer, H.Y.; Kennedy, J.L.; Steen, V.M.; Macciardi, F. Neuropsychopharmacology, 2002, 27, 10519. Javitt, D.C.; Zukin, S.R. Am. J. Psychiat., 1991, 148, 1301-1308. Snyder, S.H. Nature, 1980, 285, 355-356. Jentsch, J.; Roth, R. Neuropsychopharmacology, 1999, 20, 201225. Ital, T.; Keskiner, A.; Kiremitci, N.; Holde, J.M.C. Can. Psychiat. Assoc. J., 1967, 12, 209-212. Goff, D.C.; Coyle, J.T. Am. J. Psychiat., 2001, 158, 1367-1377. Emamian, E.S.; Karayiorgou, M.; Gogos, J.A. J. Neurosci., 2004, 24, 1561-4. Collier, D.A.; Li, T. Eur. J. Pharmacol., 2003, 480, 177-84. Wong, E.H.F.; Kemp, J.A.; Priestley, T.; Knight, A.R.; Woodruff, G.N.; Iversen, L.L. Proc. Natl. Acad. Sci. USA, 1986, 83, 71047108. Svensson, T.H. Brain Res. Brain Res. Rev., 2000, 31, 320-329. Carlsson, A. Neuropsychopharmacol., 1988, 1, 179-186. Freeman, A.S.; Bunney, B.S. Eur. J. Pharmacol, 1984, 104, 187. French, E.D.; Pilapil, C.; Quirion, R. Eur. J. Pharmacol., 1985, 116, 1-9. Murase, S.; Math, J.M.; Grenhoff, J.; Svensson, T.H. J. Neural Transm., 1992, 91, 13-25. Math, J.M.; Nomikos, G.G.; Hildebrand, B.E.; Hertel, P.; Svensson, T.H. Eur. J. Pharmacol., 1996, 309, 1-11. Fessler, R.G.; Sturgeon, R.D.; Meltzer, H.Y. Pharmacol. Biochem. Behav., 1980, 13, 835-842. Lecrubier, Y. Eur. Neuropsychopharmacol., 2003, 13 (Suppl. 4), S167-S168. Heimer, L.; Zham, D.S.; Alheid, G.F. Basal ganglia, in The Rat Nervous System, G. Paxinos, Editor. 1995, Academic Press: New York. pp. 579-628. Staley, J.K.; Mash, D.C. J. Neurosci., 1996, 16, 6100-6106. Segal, D.M.; Moraes, C.T.; Mash, D.C. Mol. Brain Res., 1997, 45, 335-339. Le Foll, B.; Francs, H.; Diaz, J.; Schwartz, J.-C.; Sokoloff, P. Eur. J. Neurosci., 2002, 15, 2016-2026. Le Foll, B.; Diaz, J.; Sokoloff, P. Synapse, 2003, 47, 176-183. Robinson, T.E.; Berridge, K.C. Addiction, 2001, 96, 103-14. Kalivas, P.W.; Stewart, J. Brain Res. Brain Res. Rev., 1991, 16, 223-244. Le Foll, B.; Schwartz, J.-C.; Sokoloff, P. Mol. Psychiat., 2003, 8, 225-230. Seroogy, K.B.; Lundgren, K.H.; Tran, T.M.; Guthrie, K.M.; Isackson, P.J.; Gall, C.M. J. Comp. Neurol., 1994, 342, 321-334. [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172]
Sokoloff et al. Horger, B.A.; Lyasere, C.A.; Berhow, M.T.; Messer, C.J.; Nestler, E.J.; Taylor, J.R. J. Neurosci., 1999, 19, 4110-4122. Hall, F.S.; Drgonova, J.; Goeb, M.; Uhl, G.R. Neuropsychopharmacology, 2003, 28, 1485-90. Grimm, J.W.; Lu, L.; Hayashi, T.; Hope, B.T.; Su, T.P.; Shaham, Y. J. Neurosci., 2003, 23, 742-747. Lu, L.; Dempsey, J.; Liu, S.Y.; Bossert, J.M.; Shaham, Y. J. Neurosci., 2004, 24, 1604-11. Grimm, J.W.; Hope, B.T.; Wise, R.A.; Shaham, Y. Nature, 2001, 412, 141-2. Ciccocioppo, R.; Martin-Fardon, R.; Weiss, F. Nat. Neurosci., 2004, 7, 495-6. Le Foll, B.; Diaz, J.; Sokoloff, P. Neuroreport, 2005, (in press). Carelli, R.M.; Ijames, S.G. Brain Res., 2001, 907, 156-61. Caine, S.B.; Koob, G.F. Science, 1993, 260, 1814-1816. Caine, S.B.; Koob, G.F. Behavi. Pharmacol., 1995, 6, 333-347. Caine, S.B.; Koob, G.F.; Parsons, L.H.; Everitt, B.J.; Schwartz, J.C.; Sokoloff, P. Neuroreport, 1997, 8, 2373-2377. Lamas, X.; Negus, S.S.; Nader, M.A.; Mello, N.K. Psychopharmacology (Berl.), 1996, 124, 306-314. Spealman, R.D. J. Pharmacol. Exp. Ther., 1996, 278, 1128-1137. Di Ciano, P.; Understood, R.J.; Hagan, J.J.; Everitt, B.J. Neuropsychopharmacology, 2003, 28, 329-338. Caine, S.B. 66th Annual Scientific Meeting of the College on Problems of drug Dependence, Porto Rico, 2004. Andreoli, M.; Tessari, M.; Pilla, M.; Valerio, E.; Hagan, J.J.; Heidbreder, C.A. Neuropsychopharmacology, 2003, 28, 1272-80. McQuade, J.A.; Xu, M.; Woods, S.C.; Seeley, R.J.; Benoit, S.C. Addict. Biol., 2003, 8, 295-303. Boyce-Rustay, J.M.; Risinger, F.O. Pharmacol. Biochem. Behav., 2003, 75, 373-9. Gilbert, J.; Xi, Z.X.; Campos, A.C.; Ashby, C.R. Jr.; Heidbreder, C.A.; Gardner, E.L. Soc. Neurosci., 2003, Abstr. 322.8. Bickel, W.K.; Marsch, L.A.; Carroll, M.E. Psychopharmacology (Berl), 2000, 153, 44-56. Wikler, A. Arch. Gen. Psychiat., 1973, 28, 611-616. Childress, E. R.; Roohsenow, D.J.; Robbins, S.H.; O'Brien, C.P. Classically conditioned factors in drug dependence, in Substance abuse: a comprehensive text book, W. Lowinson, et al. Editors. 1992, Williams and Wilkins: Baltimore. pp. 56-69. O'Brien, C.P.; Childress, A.R.; McMellan, A.T.; Ehrman, R.A. Res. Publ. Assoc. Res. Nerv. Ment. Dis., 1992, 70, 157-177. O'Brien, C.P.; McLellan, A.T. Lancet, 1996, 347, 237-40. de Wit, H.; Stewart, J. Psychopharmacol., 1981, 75, 134-143. Stewart, J. Prog. Neuropsychopharmacol. Biol. Psychiat., 1983, 7, 591-597. Self, D.W. Ann. Med., 1998, 30, 379-389. Meil, W.M.; See, R.E. Behav. Pharmacol., 1996, 7, 754-763. Meil, W.M.; See, R.E. Behav. Brain. Res., 1997, 87, 139-148. Arroyo, M.; Markou, A.; Robbins, T.W.; Everitt, B.J. Psychopharmacology, 1999, 140, 331-344. Beardsley, P.M.; Sokoloff, P.; Balster, R.L.; Schwartz, J.-C. Behav. Pharmacol., 2001, 12, 1-11. Shaham, Y.; Shalev, U.; Lu, L.; De Wit, H.; Stewart, J. Psychopharmacol. (Berl.), 2003, 168, 3-20. Katz, J.L.; Higgins, S.T. Psychopharmacol. (Berl.), 2003, 168, 2130. Xi, Z.X.; Gilbert, J.; Campos, A.C.; Kline, N.; Ashby, C.R. Jr.; Hagan, J.J.; Heidbreder, C.A.; Gardner, E.L. Psychopharmacol. (Berl.), 2004, 176, 57-65. Le Foll, B.; Schwartz, J.-C.; Sokoloff, P. Eur. Psychiat., 2000, 15, 140-146. Bardo, M.T.; Bevins, R.A. Psychopharmacol. (Berl.), 2000, 153, 31-43. Le Foll, B.; Goldberg, S.R. Psychopharmacol. (Berl.), 2004. Vorel, S.R.; Ashby, C.R.J.; Paul, M.; Liu, X.; Hayes, R.; Hagan, J.J.; Middlemiss, D.N.; Stemp, G.; Gardner, E.L. J. Neurosci., 2002, 22, 9595-9603. Ashby, C.R.J.; Mousumi, P.; Gardner, E.L.; Heibreder, C.A.; Hagan, J.J. Synapse, 2003, 48, 154-156. Duarte, C.; Lefebvre, C.; Chaperon, F.; Hamon, M.; Thiebot, M.H. Neuropsychopharmacology, 2003, 28, 1903-15. Frances, H.; Smirnova, M.; Leriche, L.; Sokoloff, P. Psychopharmacol. (Berl.), 2004, 175, 127-33. Phillips, P.E.; Stuber, G.D.; Heien, M.L.; Wightman, R.M.; Carelli, R.M. Nature, 2003, 422, 614-8. Aujla, H.; Beninger, R.J. Behav. Neurosci., 2004, 118, 1324-30.
[117] [118] [119] [120] [121]
[122] [123]
[124] [125]
[126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150]
[173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193]
The Dopamine D3 Receptor [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] [210] [211] [212] [213] [214] [215] [216] [217] [218] Fallon, J.H.; Loughlin, S.E. Substantia nigra, In The Rat Nervous System, G. Paxinos, Editor. 1995, Academic Press: San Diego. pp. 215-237. Mirenowicz, J.; Schultz, W. Nature, 1996, 379, 449-451. Di Ciano, P.; Blaha, C.D.; Phillips, A.G. Eur. J. Neurosci., 1998, 10, 1121-1127. Weiss, F.; Maldonado-Vlaar, C.S.; Parsons, L.H.; Kerr, T.M.; Smith, D.L.; Ben-Shahar, O. Proc. Natl. Acad. Sci. USA, 2000, 97, 4321-6. Callahan, P.M.; Bryan, S.K.; Cunningham, K.A. Pharmacol. Biochem. Behav., 1995, 51, 759-66. Hurd, Y.L.; McGregor, A.; Ponten, M. Eur. J. Neurosci., 1997, 9, 2541-8. Cador, M.; Robbins, T.W.; Everitt, B.J. Neuroscience, 1989, 30, 77-86. Hiroi, N.; White, N.M. J. Neurosci., 1991, 11, 2107-16. Whitelaw, R.B.; Markou, A.; Robbins, T.W.; Everitt, B.J. Psychopharmacol. (Berl.), 1996, 127, 213-24. Frances, H.; Le Foll, B.; Diaz, J.; Smirnova, M.; Sokoloff, P. Neuroreport, 2004, 15, 2245-9. O'Brien, C.P.; McMellan, A.T. Lancet, 1996, 347, 237-240. Thierry, A.-M.; Tassin, J.-P.; Blanc, G.; Glowinski, J. Nature, 1976, 263, 242-244. Finlay, J.M.; Zigmond, M.J. Neurochem. Res., 1997, 22, 13871394. Gambarana, C.; Masi, F.; Tagliamonte, A.; Scheggi, S.; Ghiglieri, O.; G. D.M.M. J. Neurochem., 1999, 72, 2039-46. Chiodo, L.A.; Antelman, S.M. Nature, 1980, 287, 451-454. Chiodo, L.A.; Antelman, S.M. Science, 1980, 210, 799-801. Chiodo, L.A.; Bunney, B.S. J. Neurosci., 1983, 3, 1607-1619. White, F.J.; Wang, R.Y. Science, 1983, 221, 1054-1057. Ainsworth, K.; Smith, S.E.; Zetterstrom, T.S.; Franklin, M.; Sharp, T. Psychopharmacology. (Berl.), 1998, 140, 470-477. Brown, E.E.; Nomikos, G.G.; Wilson, C.; Fibiger, H.C. Eur. J. Pharmacol., 1991, 202, 125-7. Stewart, J.; Rajabi, H. Synapse, 1996, 23, 258-64. Nomikos, G.G.; Zis, A.P.; Damsma, G.; Fibiger, H.C. Neuropsychopharmacology, 1991, 4, 65-69. Prisco, S.; Esposito, E. Br. J. Pharmacol., 1995, 116, 1923-1931. Grenhoff, J.; Nisell, M.; Ferre, S.; Aston-jones, G.; Svensson, T.H. J. Neural. Transm., 1993, 93, 11-25. Zafra, F.; Hengerer, B.; Leibrock, J.; Thoenen, H. EMBO J., 1990, 9, 3545-3550.
CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1 [219] [220] [221] [222] [223] [224] [225] [226] [227] [228] [229] [230] [231] [232] [233]
43
[234] [235] [236] [237] [238] [239]
Maj, J.; Dziedzicka-Wasylewska, M.; Rogoz, E.; Rogoz, Z. Eur. J. Pharmacol., 1998, 351, 31-37. Lammers, C.H.; Diaz, J.; Schwartz, J.-C.; Sokoloff, P. Mol. Psychiat., 2000, 5, 378-388. Dziedzicka-Wasylewska, M.; Rogoz, R.; Klimek, V.; Maj, J. J. Neural. Transm., 1997, 104, 515-524. Dziedzicka-Wasylewska, M.; Willner, P.; Papp, M. Behav. Pharmacol., 1997, 8, 607-618. Maj, J.; Rogoz, Z.; Skuza, G.; Sowinska, H. J. Pharm. Pharmacol., 1984, 36, 127-130. Willner, P. Int. Clin. Psychopharmacol., 1997, 12, S7-S14. Barkai, A.I.; Durkin, M.; Nelson, H.D. Brain Res., 1990, 529, 208213. Smith, S.E.; Sharp, T. Psychopharmacology, 1997, 133, 77-84. Mierau, J.; Schingnitz, G. Eur. J. Pharmacol., 1992, 215, 161-170. Maj, J.; Rogoz, Z.; Skuza, G.; Kolodziejczyk, K. J. Neural Transm., 1997, 104, 525-533. Willner, P.; Lappas, S.; Cheeta, S.; Muscat, R. Psychopharmacol. (Berl.), 1994, 115, 454-462. Goldberg, J.F.; Frye, M.A.; Dunn, R.T. Am. J. Psychiat., 1999, 156, 798. Szegedi, A.; Wetzel, J.; Hillert, A.; Kleiser, E.; Gaebel, W.; Benkert, O. Mov. Disord, 1996, 11(Suppl.1), 266. Xu, M.; Koeltzow, T.E.; Santiago, G.T.; Moratalla, R.; Cooper, D.C.; Hu, X.T.; White, N.M.; Graybiel, A.M.; White, F.J.; Tonegawa, S. Neuron, 1997, 19, 837-48. Neve, K.A.; DuRand, C.J.; Teeter, M.M. Structural analysis of the mammalian D2 , D3 and D4 dopamine receptors, in Dopamine Receptors and Transporters. Function, Imaging and Clinical Implication (Second edition), A. Sidhu; Laruelle, M.; Vernier, P. Editors. 2003, Marcel Dekker, Inc.: New York. pp. 77-144. Schoemaker, H.; Claustre, Y.; Fage, D.; Rouquier, L.; Chergui, K.; Curet, O.; Oblin, A.; Gonon, F.; Carter, C.; Benavides, J.; Scatton, B. J. Pharmacol. Exp. Ther., 1997, 280, 83-97. Pilla, M.; Hutcheson, D.M.; Adib-Samil, P.; Everitt, B.J. Soc. Neurosci. Abstr., 2001, 27, No 647.16. Aujla, H.; Sokoloff, P.; Beninger, B.J. Neuroreport, 2002, 13, 173176. Le Foll, B.; Sokoloff, P.; Stark, H.; Goldberg, S.R. Neuropsychopharmacology, 2005, in press. Heidbreder, C.A.; Andreoli, M.; Marcon, C.; Thanos, P.K.; Ashby, C.R. Jr.; Gardner, E.L. Drugs Today (Barc.), 2004, 40, 355-65. Sokoloff, P.; Schwartz, J.-C. Mdecine/Sciences, 1999, 15, 10679.
Received: July 7, 2005
Revised: November 2, 2005
Accepted: November 2, 2005

Dopamine d3 Schizophrenia

Caricato da

Informazioni sul documento

Descrizione originale:

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Dopamine d3 Schizophrenia

Caricato da

Copyright:

Formati disponibili

CNS & Neurological Disorders - Drug Targets, 2006, 5, 25-43

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

2.8 1 5 145 0.1 1.5 0.6 2 30 3 380 1 588 6 0.08 38 7 0.05

>1,000 45 16 29 25 30 6.5 36 30 1,050 2,100 3,200 16 0.1 280 10 0.13

>1,000 6.1 33 343 >10,000 12 8 170 74 560 2,400 >10,000 300 -

3,000 >1,000 890 >10,000 500 >1,000 25,000 -

61 24 63 3 217 32 1,030 780 2,280

0.9 0.4 1 0.3 1.4 0.3 11 12 223

300 81 10,000 1,780 >5,000 2,000 >1,000 5,000 >10,000

>10,000 1,300 >1,000 -

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

Effects of D3 Receptor Ligands on Various Conditioned Responses

SB-277011A BP 897 and SB-277011A are inactive

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

The Dopamine D3 Receptor

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

CNS & Neurological Disorders - Drug Targets, 2006, Vol. 5, No. 1

[75] [76] [77] [78] [79]

[117] [118] [119] [120] [121]

[234] [235] [236] [237] [238] [239]

Received: July 7, 2005

Revised: November 2, 2005

Accepted: November 2, 2005

Potrebbero piacerti anche