Pharmacology B~othemtstr3 & Behavior, Vol 24, pp 365-379, 1986 Ankho Internatmnal Inc Pnnted In the U S A

0091-3057/86 $3 00 + 00

Comparative Effects of LSD and Lisuride: Clues to Specific Hallucinogenic Drug Actions
FRANCIS J. W H I T E

Umverslty o f llhnols at Urbana-Champatgn, D e p a r t m e n t o f Psychology 603 East Daniel Street, Champaign, IL 61820

WHITE, F J Comparative effet ts of LSD and h~urzde Clues to specific hallutmogentc drug actions PHARMACOL BIOCHEM BEHAV 24(2) 365-379, 1986 --This review compares the effects of LSD and its nonhallucmogemc congener hsurlde hydrogen maleate (LHM) on various biochemical, behavioral and electrophyslological radices of neuronal function The underlying rationale is that any differences between the effects of LSD and LHM might be relevant to neuronal actions which are unique and specific to hallucinogenic drugs and thereby provide clues to the neuroblologlcal substrates of halluclnogenesls In biochemical studies, LHM appears to be very similar to LSD with respect to its actions on monoamlnerglc (5-HT, DA, NE) systems The major difference between the two ergots appears quantitative in nature since LHM is more potent than LSD, especially on DA neurochemlstry Needed at the present time are additional comparative studies of LSD and LHM with respect to other biochemical measures, for example on the release of 5-HT and DA and comparisons at more molecular levels such as subcellular compartmentatlon Also necessary are more intensive regional analyses on specific subpopulatlons of 5-HT and DA systems (mesohmblc, mesostnatal and mesocortlcal) Behavioral studies are relatively uniform in their characterization of the greater DA-erglc activity of LHM as compared to LSD In particular, the drug discrimination (DD) procedure has indicated a more specific interaction of LSD with 5-HT neuronal systems as compared to LHM and has successfully differentiated the relative roles of 5-HT and DA systems in the behavioral effects of LSD and LHM Electrophyslologlcal studies have been consistent with both biochemical and behavioral findings with respect to the much greater effect of LHM on DA receptors In fact, the effects of LSD on DAcontaining neurons are both weak and heterogeneous, again Indicating a need for more detailed analyses of specific DA projection systems The greater potency of LHM than LSD on 5-HT containing dorsal raphe neurons has lessened the attractiveness of the once popular theory that hallucinogenic efficacy is related to diminution of impulse flow in 5-HT systems but has also spawned greater interest in the possible role of postsynaptlc 5-HT receptors in hallucinogenic drug action Thus far, the most interesting finding is the ability of LSD and other hallucinogens, but not LHM, to potentiate an excltomodulatory effect of 5-HT in the facial motor nucleus If such a phenomenon occurs more generally in the CNS, the importance of this finding will be greatly enhanced Preliminary data is presented which suggests that LSD may also induce such an effect in a hmbtc forebraln structure, the nucleus accumbens In a concluding summary, it is proposed that those 5-HT receptors which seem most likely to be involved in the halluclnogemc experience are those at which LSD is active but LHM is not (or is less so) and at which 5-HT antagonists are effective in reducing the LSD effect LSD Llsunde L ~pamlne receptors Hallucinogens

Drug discrimination

Serotonm neurons Dopamlne neurons Nucleus accumbens

Serotonln receptors

S I N C E H o f f m a n ' s s e r e n d i p i t o u s d i s c o v e r y o f the p o t e n t hall u c i n o g e n i c a c t i o n s o f lysergic acid d l e t h y l a m l d e (LSD) in 1943 [52], r e s e a r c h e r s h a v e a t t e m p t e d to elucidate the n e u r o p h a r m a c o l o g l c a l c h a n g e s w h i c h c a u s e or, at least, correlate with the b e h a v i o r a l and p e r c e p t u a l m a n i f e s t a t i o n s c h a r a c t e r i s t i c o f the L S D e x p e r i e n c e N e v e r t h e l e s s , d e s p i t e the use o f m a n y d i v e r s e physiological, p h a r m a c o l o g i c a l and b e h a v i o r a l p r o c e d u r e s , the m e c h a n i s m s u n d e r l y i n g the complex spectrum of L S D ' s blobehavloral actions remain u n d i s c e r n e d O f c o u r s e , this should not b e surprising in v i e w o f the m y r i a d c o m p o n e n t s o f the L S D " t r i p " and the gradual unfolding o f s e q u e n t i a l stages, all o f w h i c h are likely to result f r o m the i n t e r a c t i o n s o f s e p a r a t e and p e r h a p s subtle neurobiological substrates Historically, the b e h a v i o r a l e f f e c t s o f L S D h a v e b e e n

linked to the e n d o g e n o u s m o n o a m l n e n e u r o t r a n s m l t t e r s , particularly the lndoleamlne sertonln (5-hydroxyt r y p t a m m e , 5-HT), but also to a l e s s e r e x t e n t t h e c a t e c h o l a m l n e s (CA), d o p a m l n e (DA) a n d n o r e p l n e p h r m e (NE) The first h y p o t h e s i s regarding the m e c h a n i s m o f action o f L S D was b a s e d o n a n t a g o n i s m o f this a m i n e in isolated s m o o t h m u s c l e p r e p a r a t i o n s [43,114] T h u s , It w a s p r o p o s e d that L S D - i n d u c e d hallucinations might be d e p e n d ent u p o n a similar 5-HT a n t a g o n i s m in the c e n t r a l n e r v o u s s y s t e m (CNS) As k n o w l e d g e o f the C N S a n a t o m y and p h y s iology o f the m o n o a m m e s e m e r g e d , due primarily to p i o n e e r i n g h l s t o f l u o r e s c e n c e visualization o f a m i n e c o n t a i n ing n e u r o n s [30], c h a r a c t e r i z a t i o n o f L S D ' s neurobIologtcal a c t i o n s a c c r u e d c o n c o m i t a n t l y , s u c h effects o f L S D h a v e p r o v e n to be m u c h m o r e c o m p l e x t h a n the simple 5-HT an-

365

366

WHITE

tagonlsm observed m smooth muscle and many questions remain as to the exact nature of L S D ' s interactions with central 5-HT neurons and receptors Nevertheless, the fact that 5-HT neuronal systems are involved in those actions and resultant hypotheses regarding 5-HT mediation of hallucinogenic efficacy have been widely accepted The emphasis on central serotonerglc systems as likely mediators of L S D ' s potent hallucinogenic effects was prompted in the early 1960's by Freedman and colleagues who discovered that LSD increased the whole brain concentrations of 5-HT and decreased the levels of its major metabollte 5-hydroxylndoleacetic acid (5-HIAA) [37, 38.40, 83] An important aspect of these findings, as well as subsequent pharmacological analyses, was the mablhty of bromLSD (BOL) to mimic the action of LSD BOL and LSD are nearly equipotent m their effects on peripheral 5-HT systems [22], but unlike LSD, BOL is, at best, only a very weak hallucinogenic agent [ 17] This differential hallucinogenic potency of BOL and LSD provided investigators with a valuable tool for dissecting relevant neuroblologlcal substrates (correlates) of hallucinogenic activity Thus, any central effect of LSD which was mimicked by BOL could be ruled out (at least tentatively) as an accountable mechanism For example, it has been reported that LSD and other hallucinogens act as antagonists of central H-1 [36] and H-2 [47] histamine receptors, yet BOL is as effective as LSD at both receptors Therefore, the relevance of these receptors for LSD-lnduced hallucinosis seems questionable Using the LSD vs B O L strategy, a variety of CNS effects specific to LSD have been identified over the past two decades [58] However, an even more powerful lever for prying specific hallucinogenic neuronal substrates has recently become available The identification of the close structural LSD-congener hsurlde hydrogen maleate (LHM) (Fig 1) as a nonhalluclnogenlc ergot d e n v a t w e [48] has been of considerable importance because of its strlklngly similar pharmacological profile to L S D Thus, L H M has been found to mimic many of the CNS effects of LSD and, in most cases, is actually more potent than LSD itself By systematically comparing the commonahtles and differences between the actions of these two ergots, it is possible to identify with greater precision those mechanisms which are likely to be responsible for components of the LSD experience The purpose of the present discussion is to provide a review and appraisal of those neuropharmacologlcal assays in which LSD and L H M have been compared directly (with particular emphasis on those systems employed by the author), as well as those systems thus far lacking in precise comparative data For purposes of organization and clarity, the material has been divided into sections covenng biochemical, behavioral and electrophyslologlcal studies
BIOCHEMICAL Anllll ~ Tllr/lot, er STUDIES

LYSERGIC ACID DIETHYLAMIDE (LSDI

C~N H..~ ~C2H 5

II IC2H5
--CH 3 "~H

LISURIDE HYDROGEN MALEATE ILHM]

-~--c-n~.

O II

~C2H~ C2H5

~CH 3

FIG 1 Chemical structures of LSD and LHM

The comparative biochemical effects of L S D and LH M have been reviewed recently [39] Therefore, the present discussion will attempt to highlight and update the previous review The first study which caused researchers to question the theory that 5-HT neuronal systems mediate in some way the hallucinogenic property of LSD was performed by Pleri et al [74] who compared the biochemical changes occurnng in rat brain following peripheral administration of LSD and L H M These two compounds produced strikingly similar effects, particularly a decrease in 5-HT turnover, except that

LHM-induced changes were somewhat more pronounced than those of LSD On the basis of these results, Pleri et al [74] concluded that "'the biochemical changes induced by both hsuride and LS D may solely represent an eplphenomenon unrelated to the halluclnosis " In addition to the common ability of LSD and L H M to increase concentrations of 5-HT and decrease 5-HIAA, these two ergots also caused similar increases in DA levels and decreases in the levels of the DA metabohte dihydroxyphenylacetlc acid (DOPAC) Moreover, both LSD and L H M Increased N E turnover [74] The major difference between LSD and LH M was a quantitative one, L H M was more potent than LSD, especially with regard to changes in the C A ' s Similar results have been obtained by other investigators [62-64] For example, using an in ~tvo method of measuring the immediate precursors of 5-HT and DA, i e , 5-hydroxytryptophan (5-HTP) and dihydroxyphenylalanine (DOPA), after inhibiting aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazlne, Kehr [62] found that both LH M and LSD reduced the synthesis and metabolism of 5-HT and, whereas L H M was a potent DA agonlst (inhibited DA synthesis), LSD was only a weak DA agonlst and, at higher doses, showed DA antagonist activity, l e , increased DA synthesis There are several biochemical effects of LH M which are not shared by LSD First, L H M antagonizes methlothepIninduced increases in 5-HT turnover [74] Second, L H M decreases DOPA accumulaUon tn DA-rJch brain regions [74] Third, L H M reduces concentrations of the DA metabohte homovanllhc acid (HVA) whereas LSD tends to increase H V A levels [64] However, not yet as evident are biochemical effects of LSD that are not mimicked by LHM, such effects may be of particular interest in determining halluctnogemc efficacy
Re~ eptol Binding a n d A d e n v l a t e Cv~ la s e

Both LSD and L H M displace ~H-splroperldol from DA receptors in rat stnatal membranes at low concentrations

LSD, LISURIDE AND H A L L U C I N O S I S [41,55] In rabbit caudate, LHM displaces ~H-ADTN (2amlno-6,7-dlhydro-l,2,3,4-tetrahydronaphtalene) [84], whmh labels DA receptors [28], and aH-LSD [84] which labels both DA and 5-HT receptors [20] In rat frontal cortex, LHM potently displaces the three serotonerglc hgands, ~HLSD, ~H-5-HT and ~H-splropendol [55,84] Conversely, LSD potently d~splaces ~H-LHM binding m both strlatum and frontal cortex [15] Thus, ~t ~s apparent that LSD and LHM are strikingly slmdar with respect to receptor activity as determined by m vitro binding assays Both LSD and LHM have been shown to st,mulate a 5-HT sensitive adenylate cyclase in frontal cortex and this stlmulatmn is antagomzed by the DA and 5-HT antagonist mohndone [7,84] Some researchers have reported that LSD [7, 31, 98], but not LHM [74,84], stimulates DA-sensltwe adenylate cyclase activity m the strlatum Others have reported that LHM can stimulate DA-senslt~ve cyclase m stnatal homogenates [ 1I] and shces [85] Both LSD and LHM antagomze DA-sttmulated cyclase act~wty [31, 74, 84, 98]
Releaae Evpertments

367 catalogue the effects of this extremely potent compound on behavior, but also to identify the neuropharmacologlcal mechanisms underlying such changes In conducting such experiments, behavioral pharmacologists have relied on a vast array of disparate behavioral techniques and animal species Probably the simplest and most frequently used procedures in behavioral pharmacology involve observing drug-induced changes in gross behavior, typical measures Include general motor activity and repetitive, stereotyplc behaviors (gnawing, hcklng, etc ) In fact, these behaviors have generally been thought to indicate an increase in DA leceptor activity [34,78] Since LSD has been reported to cause both of these behaviors, effects which are reversed by DA antagonists, it was suggested early on that LSD acts as a DA agonlst [32,35] However, one consistent aspect of these experiments is that the doses of LSD which produce such effects are e v t r e m e l 3 high (5 0-10 0 mg/kg) and have httle, if any, relevance to doses which produce effects on the finng of CNS neurons (0 02-0 10 mg/kg) or induce halluclnosls in man (0 0025-0 005 mg/kg) Moreover, careful examination of the descriptive accounts of the LSD-induced stereotyptes lndmate that many of the indwldual behaviors (head weaving, tremor, splayed hlndhmbs) are now considered to be components of a 5-HT syndrome (see below) LHM exerts a bl-phaslc effect on motor behavmr m rodents [67,99] At low doses (0 1 mg/kg) this compound, hke apomorphme, produces a decrease in activity [67,99], presumably by activating DA autoreceptors [31] At higher doses (>0 1 mg/kg), LHM causes increases in locomotor activity and stereotyp~es, all of which are blocked by DA antagomsts [54] Clearly, with respect to motor act~wty and stereotypy, LHM is a more potent DA agonlst than LSD Another behavmral model for studying DA action ~s rotatmnal behavior reduced by DA agonlsts in rats with undateral 6-hydroxydopamlne (6-OHDA)-lnduced lesions of the substantla nlgra [96] Such turning behavmr is contralateral to the lesmned side after a direct DA agomst, but is lpsdateral after an indirect DA agomst LSD has been shown to induce contralateral turning in th~s paradigm and the rotation is blocked by DA antagonists such as halopendol or p~moztde [75] In addition, LSD increases locomotor activity m 6-OHDA lesioned rats These results have thus strengthened the view that LSD acts as a DA agonlst [65,75] However, both the sensmwty and specificity of the rotational assay are somewhat questionable because the doses of LSD that rehably produce these effects are relatwely high (0 5 to 2 0 mg/kg) and the DA receptors, through which this behaworal episode is mediated, are not only supersensmve [97] but also nonspeofic [26] Furthermore, LSD-lnduced mrchng has not always been rephcated [70,77] LHM also induces contralateral circling indicative of a direct acting DA agonist [42,76], m fact, LHM is at least five times more potent than apomorphme in this model [42] Pmn et al [76] compared directly the rotatmnal behavior reduced by LSD, LHM, and apomorphme in rats with unilateral nlgrostrlatal lesmns produced by either 6-OHDA or 5,6-dlhydroxytryptamme (5,6-DHT), a neurotoxln which depletes 5-HT as well as DA [16] The rotatmn induced by LHM or LSD was more pronounced m rats with 6-OHDA lesions than in those w~th 5,6-DHT lesmns There were no differences between the two lesmn groups with respect to apomorphme-induced cwchng The authors suggested that this was an lndmatmn of serotonerglc involvement m the actmns of LSD and LHM because 5,6-DHT depletes both 5-HT and DA, and 5-HT modulates turning behavmr m a

In a recent interesting report, Hetey et al [49] have shown that LSD and other hallucinogens (mescaline, DMT), but not LHM, dose-dependently inhibit the K+-evoked ~H-DA release from crude synaptosomal fractmns of rat nucleus accumbens (NAc) Because these effects were blocked by both halopendol and methlothepin, it was postulated that the effect of the hallucinogens depended upon both DA and 5-HT receptors located presynaptlcally on DA nerve terminals [49] Whde this is an intriguing finding suggesting a common effect of structurally dlsslmdar hallucinogens which is not mimicked by LHM, the lack of effect of LHM is surprising since ~t suggests that LHM does not stimulate presynaptlc DA receptors on DA nerve terminals (autoreceptors) Although a similar conclusion was reached by Kebabmn and Kebabmn [61] who found that LHM did not inhibit tyroslne hydroxylatlon tn ~lttO, other studies have shown that LHM does inhibit DA synthesis under certain m i'ttto assay conditions [93] Moreover, several reports have indicated that LHM is a relatively potent stimulant of DA autoreceptors tn VlVO [62, 67, 99, 100, 110, 112] Direct ewdence for LHM-induced stimulation of the DA autoreceptors which modulate impulse-flow m DA neurons is presented below (see Electrophyslolog~cal Studies) Thus far lacking and sorely needed are comparative studies of LSD and LHM on 5-HT release and its controlhng mechanisms, as well as addmonal studies on DA release, both m vitro and m vtvo, perhaps with push-pull cannulae, m lVO voltammetry or mtracerebral dialysis Moreover, comparative studies at more molecular levels such as subcellular compartmentatlon and nerve terminal membranes, of both DA and 5-HT neurons, would be informative [39] Also needed are regional analyses of LSD's and L H M ' s effects on specific subpopulatlons of 5-HT and DA systems (cortical, hmblc, strmtal, etc ) Comparisons of LSD- and LHMreduced alteratmns of NE systems have thus far been hmited and additional detailed studms also seem warranted

B E H A V I O R A L STUDIES

D A - D e p e n d e n t Behavtor~

Over the past twenty years an enormous amount of behavioral research has been conducted with LSD, not only to

368 dtrecUon opposite to DA [29,70] Thus the net effect of slmulatmg two neuronal systems, both with supersensmve receptors (5,6-DHT group), was an overall reduction in rotation as compared to the apomorphlne group (DA stimulation alone) or to the rats with only DA depleted (6-OHDA group) LHM was about 10-20 times more potent and considerably longer acting than LSD [76] Haloperldol completely blocked the LHM circling but only partially diminished LSD rotation, again demonstratmg the greater dopamlnerglc activity of LHM and the fact that LSD-lnduced clrchng involves non-DA mechanisms Both LHM and LSD also counteracted the catalepsy induced by the neuroleptic prochlorperazlne, another effect thought to reflect DA receptor stimulation [76], LHM was also more potent and longer acting than LSD In this model

WHITE TABLE 1 ANTAGONISMOF THE LIMB-FLICK(LF) RESPONSE ELICITEDBY LSD OR LHM* Antagomst No antagomst Halopendol Halopendol lhzotffen Dose (mg/kg) -01 05 50 LSD (0 08 mg/kg) 49 0 _+ 12 2 225 _+ 72 60_+ 34? 05 _+ 03~LHM (0 02 mg/kg) 50 2 _+ 16 8 284_+ 11 7 1 0_+ 04+ 62 + 2Yt

*Data are presented as the mean number of LF/hour _+SEM (n=6 m all experiments) +Sigmficantly less than LSD or LHM alone (p<0 05)

5-HT Dependent Behavtors

Another set of drug-induced behavioral changes m rats has been suggested to indicate a spectfic interaction with 5-HT receptors [46,57], and has thus been termed the "serotonin syndrome" [57] This syndrome is distinguishable from the stereotypy induced by DA agonists by the appearance of head weaving, reciprocal forepaw treading, hind limb abduction, resting tremor, and Straub tall (rinsed and rigid position) The syndrome is reliably produced by inhibition of monoamme oxldase (MAO) in conjunction with injections of either of the amino acid precursors of 5-HT, L-tryptophan or 5-HTP [46] In addition, drugs which act as central 5-HT agonists produce the syndrome, including LSD, 5-methoxy-N,N-dlmethyltryptamme (5-MeODMT) and qulpazlne [57, 90, 95] By comparing the abdlty of LHM and LSD to produce the "serotonin syndrome," Sllbergeld and Hruska [87] found that both compounds Induced signs of the syndrome, but LHM was more potent Pretreatment with haloperldol potentiated and prolonged the LSD-lnduced syndrome but had no effect on LHM-lnduced behawors, this may occur because DA receptor blockade decreases the DA agonlst effect of LSD and thus allows a clearer expression of the serotonln syndrome The failure to observe the same interaction with LHM was explained by the greater potency of LHM for DA receptors [87] The 5-HT antagonist methyserglde partmlly blocked the effects of LSD, but not those of LHM Unfortunately, complete dose-response analyses with 5-HT and DA blockers were not performed and more specific 5-HT antagonists were not studied Again, one must view this behavioral syndrome with caution since the effective doses of both LSD (1 0-2 0 mg/kg) and LHM (! 0-1 5 mg/kg) were extremely high as compared to most behavioral test systems (below) (Table 1) Pharmacological investigations Into neuronal mechanisms responsible for LSD and LHM induced LF/AG have demonstrated that although the 5-HT antagonist pizotlfen (BC-105) blocked the effects produced by LSD [50,107], the DA antagonist halopendol was also effectwe [92a, 107] Moreover, we found that both of these antagonists also prevented LHM-induced LF [107] Interestingly, Jacobs and co-workers reported that the 5-HT antagonist mianserln blocked the LF/AG response induced by LSD but not that induced by LHM [50] Whether this discrepancy is due to the different 5-HT antagonists employed is an important matter worthy of future study Nevertheless, the fact that LSD and LHM are so similar in this model and the effects of both ergots can be blocked by both 5-HT and DA antagonists casts some doubt on the utility of this model for distinguishIng specific neuronal mechanisms relevant for hallucinatory activity [107]

Hallu~ mogen-lndu~ ed Ltmb-Jerl~mg m Monhew

Schlemmer and Davis [86] have recently reported that hallucinogenic drugs produce several behavioral effects m the monkey (stumptai1 macaques), among the most interestlng were two emergent behaviors, limb-jerking and body shaking These behaviors are almost never seen in undrugged monkeys but are induced in a dose-dependent manner by a vanety of halluclnogemc drugs, LSD (as usual) being the most potent Important for the present discussion is the fact that LHM was ineffective at inducing these behawors [86,86a] As for antagonism of these behaviors, both 5-HT and DA antagonists effectively reduced the LSD effect although 5-HT blockers were more potent [86] More detailed study of the receptor mechanisms and locations responsible for this behavior seem warranted

The Ltmb-Fhck Model

The ability of LSD and other hallucinogens to elicit hmb-fllckmg (LF) and abortive grooming (AG) in cats has been proposed as a specific animal behavior model for hallucinogenic drug action [59] However, upon closer scrutiny, it has been revealed that this model, like most, is not specific to hallucinogens [106] Nevertheless, this behavioral model has proven quite useful for simultaneous behavioral and electrophyslological investigations of LSD's effects [50, 92a] In companng LHM and LSD in this model, most studies have found that LHM is at least as potent as LSD in ehciting these behaviors [50, 106, 107], actually, we have found LHM to be about four times more potent than LSD

Disruption of Operant Behavtor

In the mid 1960's, Appel and Freedman [8] reported the ability of LSD and other psychotomlmetic drugs to disrupt the bar-pressing behavior of rats trained on fixed-ratio (FR) schedules of food or water reinforcement The disruption of FR responding induced by hallucinogens such as LSD is characterized by an abrupt cessation of responding, the length of which IS dose-dependent, and a somewhat less abrupt return to the pre-disruptlon mode of responses [8] A considerable amount of work has been conducted with respect to LSD's effects in this paradigm, most of which lndi-

LSD, LISURIDE AND HALLUCINOSIS cates an almost exclusive role for 5-HT systems In this effect [8, 33. 60, 79] Recently, M o k l e r et al [71] c o m p a r e d the effects of L S D and L H M on disruption of FR-40 responding (40 responses are required per reinforcer) and reported that L H M was almost three times as potent as L S D in disrupting FR p e r f o r m a n c e Interestingly, 5-HT antagonists, but not DA antagonists, blocked the effects of both L S D and L H M [71] The 5-HT antagonist c m a r s e n n was an e x c e p t i o n in that it blocked the effects of L S D but potentiated the effect of L H M , unfortunately, the authors offered no explanations for this rather puzzling finding [71] F o r addmonal information reg,trdmg LSD s ettects on FR responding, see Sparber I89al
D r l t , D I s t t II?llll~lllOll

369

TABLE 2
C O M P A R I S O N O F T H E DISCRIMINATIVE S T I M U L U S PROPERTIES OF LSD A N D L H M

Test Drug Substitution Tests 5-HT Agomsts Qmpazlne MK-212 5-MeODMT DA Agomsts Apomorphlne Lergotrde Amphetamine Antagomsm Tests 5-HT Antagomsts Cyproheptadlne BC-105 Ketanserln DA Antagonists Haloperldol 5-HT and Antagomst Methmthepln

LSD vs Saline

LHM vs Saline

LSD vs LHM

* * * 0 0 0

t t ~* * 0

* for LSD

* for LHM

The drug discrimination (DD) procedure has been particularly successful in the study of neuronal m e c h a n i s m s underlying the effects of a v a n e t y of p s y c h o a c t i v e c o m p o u n d s (for recent review see [44]) In this procedure, animals are trained to discriminate b e t w e e n the presence and absence of a drug (drug vs saline) or the presence of one drug or another drug (drug vs drug) DD has several advantages o v e r many of the other behavioral p r o c e d u r e s described a b o v e in that (1) ~t ~s exqmsltely sensitive to low doses of L S D and other drugs [10], (2) It is relatively specific within pharmacological classes and to particular neuronal actions [10, 13, 44, 82], (3) it is reliable and stable o v e r time [10,44], and (4) ~t is the animal b e h a v i o r whmh most closely models the subjective e x p e r i e n c e of drug effects in humans [82] With respect to the L S D discriminative stimulus (DS) effect or cue, a decade of research has provided substantial e v i d e n c e that this effect of L S D is mediated by actions at postsynaptlc 5-HT receptors Thus, the L S D cue (1) is readily mimicked by other postsynaptic 5-HT r e c e p t o r agomsts 166,104], (2) Is blocked specifically by 5 - H T antagomsts [25, 66, 104, 113], (3) is potentiated by pharm,tcologlcal procedures which deplete 5-HT and increase ~H-LSD binding [ 10,108], (4) is dlscrlmmably similar to electncal snmulatlon of 5-HT cell bodies in the dorsal raphe nucleus [5 l], a manipulation which increases 5-HT release in terminal areas, and (5) is only partially mimicked by direct application of L S D into the dorsal raphe nucleus [82], the site of somatodendrltlC 5-HT a u t o r e c e p t o r s We have used the DD p r o c e d u r e and, in particular, a drug vs drug discrimination to c o m p a r e and contrast the DS properties of L S D and L H M (Table 2) In the first experiment, two groups o f water-deprived male rats were trained to discriminate 0 08 mg/kg of rather L S D or L H M from saline in a manner described in detail elsewhere [101-104] Briefly, rats were injected lntraperitoneally (IP) with either the training drug or sahne 15 mm before being placed in experimental c h a m b e r s containing two levers The rats were trained to respond differentially on one of the levers (depending on the solution injected) for water reinforcers Note that, prior to delivery of the first reinforcer, the only cue the animal could use to determine the correct lever was the drug-reduced " s t a t e '" For this reason, dlscrimlnablhty was always assessed prior to delivery of the first reinforcer or, in test sess,ons, during extinction periods in which no w a t e r was delivered and the session ended after 32 responses had o c c u r r e d on one of the levers Following acquisition of the L S D and L H M discriminations, each group o f rats was divided into three equal subgroups which were trained to discriminate either 0 02, 0 08 or 0 32 mg/kg of each drug by progressively altering dose [103,104] Thus, at the end of training (55 ses-

+ * * 0 t

0 0 0 * t

*Complete substltutmn or antagomsm rincomplete subsntutlon or antagonism ~ - N o effect

slons), the rats were accurately discriminating a wide range of doses of L S D or L H M from saline Figure 2 shows the results of substitution tests in which different doses of L S D and L H M were administered to assess the Slmllanty of the two ergots It is apparent that L S D and L H M exerted similar discriminable effects across a wide range of doses In each group the percentage o f druglever responding elicited by at least one dose of the novel drug was significant N e v e r t h e l e s s , particularly n o t e w o r t h y is the fact that the extent of substitution of the novel drug was usually less than that of the tramlng drug A similar substitution of L H M m LSD-tralned African green v e r v e t m o n k e y s (Cer~optte~us aethtop~) has also been demonstrated recently [71a] Our data led us to e x a m i n e the possibility that the DS effects o f L S D and L H M might be sufficiently &fferent to allow rats to discriminate b e t w e e n them Because rats can learn to discriminate q u a n t l t a n v e differences m drug effects [14], three groups o f rats were trained to discriminate b e t w e e n L S D and L H M at three different potency ratios (0 02, 0 04 or 0 08 mg/kg of L H M vs 0 08 mg/kg of LSD), chosen on the basis of the previous experiments Otherwise, the methods were the same as those described previously e x c e p t that an F R 16 schedule was used Each o f the three groups readily learned to discriminate L S D from L H M The results of substitution tests with saline, L S D , L H M , the D A agonist a p o m o r p h l n e (APO), and the 5-HT agonist quipazlne (QPZ) are shown in Fig 3 In the 0 08 mg/kg L H M group, the discrimination s e e m e d to be based on the quantitative difference of amount of drug effect, i e , at equivalent doses, L H M is much more potent than L S D , thus, during tests with a relatively high dose of any drug, responding o c c u r r e d primarily on the L H M a p p r o p n a t e lever whereas during tests with low drug doses,

370

WHITE

002

LSO vS Saline

008

LSO vs Saline

032

LSD vs Saline

i
n,-

,_1

4o

P
no 20 o i i I I I l I I t i i i

0 0 2 LHM vs SIIIml

0 08 LHM vs Saline

~/~'-'~

0 32 LHM vs Saline

ao

-r

2o

I i OOOO5 ooot

0.005 001

0,05

0.1

05

10

i ~OOl
Dose

I I ooos OOl
of Drug

i oos [mg/kg]

I ol

i o~

10

001

OOS

01

0.5

10

FIG 2 Results of substitution tests w~th LSD and LHM m groups of rats trained to d~scnmmate one of three doses (0 02, 0 08 or 0 32 mg/kg) of either LSD (top panel) or LHM (lower panel) from sahne Asterisks represent slgmficant substitutions Reprinted from [102] w~th permission (Copynght by the AAAS )

most responding o c c u r r e d on the L S D - a p p r o p r l a t e l e v e r In contrast, in the o t h e r groups, the discriminations w e r e based on quahtattve dtfferences b e t w e e n the effects of L S D and L H M , I e , during saline tests and tests with low doses of L S D , choice b e h a v i o r was not under stimulus control As the dose of L S D increased, the percentage of L S D lever responding increased to a b o v e chance levels Discrimination o f all doses of L H M was near perfect As the dose of Q P Z increased, rats r e s p o n d e d as though they had r e c e i v e d L S D , as the dose of A P O increased, they r e s p o n d e d as though they had r e c e i v e d L H M Thus, the effects of L S D and L H M w e r e sufficiently different to enable rats to discriminate b e t w e e n them Observations that the 5-HT agonlst QPZ elicits L S D - a p p r o p r l a t e responding w h e r e a s the D A agonlst A P O elicits L H M appropriate responding suggest that the DS effects of L S D are m e d m t e d primarily by 5-HT receptors w h e r e a s the DS effects of L H M are mediated primarily by D A receptors This interpretation is supported by our findings that (1) 5 - H T agonlsts substitute completely for L S D but only partlally for L H M , (2) 5-HT antagonists block the L S D cue but not the L H M cue, (3) D A agonlsts substitute c o m p l e t e l y for L H M but not at all for L S D , and (4) D A antagonists block the L H M cue but not the L S D cue (see Table 2) This is not meant to imply that L S D and L H M act only at 5-HT and D A receptors, respectively, but that the DS effects of these

drugs are mediated pr;mardy by actions on one or the other of these neuronal systems These data present striking evidence that previously reported quantitative differences between the neuronal actions of L S D and L H M can result in qualitative differences in the discriminable " s t a t e s " p r o d u c e d by these ergots Thus, our results parallel those seen in humans in that L H M exerts m u c h greater potency as a D A agonlst (antl-Parklnsonlan effects) and does not produce L S D - h k e hallucinogenic reactions [45] With respect to the possible i n v o l v e m e n t of N E neuronal systems m the L S D and L H M cues, previous studies have d e m o n s t r a t e d that N E is not involved in the L S D cue since it is neither blocked nor mimicked by either a-adrenerglc (phentolamlne) or fl-adrenerglc (propranolol) antagonists [66] N e v e r t h e l e s s , biochemical m e a s u r e s indicate effects of both L S D and L H M on N E turnover, m o r e o v e r , L H M exerts other effects which are consistent with both c~- and fl-adrenerglc a n t a g o n i s m [15, 27, 62] To investigate this possibility more directly the effects of selective c~1 and ~_, agents w e r e studied in rats trained to discriminate either L S D (0 08 mg/kg) or L H M (0 04 mg/kg) from saline as d e s c r i b e d a b o v e In substitution tests, the c~, b l o c k e r yohlmblne p r o d u c e d a dose-related increase in both L S D and L H M l e v e r responding which was considerably more e v i d e n t in the L H M trained rats (Table 3) N e i t h e r the c~ antagonist p r a z o s l n nor the /3 antagonist propranolol

LSD, L I S U R I D E A N D H A L L U C I N O S I S elicited significant L H M or L S D lever responding (Table 3) Thus, these results suggest that c~,-adrenoceptor antagonism may play a role in the DS effects of L H M , but is less likely to be involved m the LSD cue
A u n l m a t v o/ B e h a v t o r a l S t u d w

371

tOO

IIo
40

In contrast to the available biochemical data, behavioral research with direct LSD vs L H M comparisons is more extensive and thorough It is evident from the available studies that LS D and L H M exert strikingly similar effects on " 5 - H T - r e l a t e d " behaviors but that L H M is a much more potent elicitor of " D A - d e p e n d e n t " behaviors In fact, upon review of the available data, there is little compelling behavioral evidence that LSD acts as a DA agonlst when administered at reasonable doses in intact (l e , unlesloned) animals We have recently found that relatively low doses of LS D partially mimic the DS properties of apomorphine, indicating that DA agonlst effects of low L S D doses can be detected when rats are trained to attend to such a neuronal action, 1 e , are trained to discriminate a direct DA agonlst [53] Interestlngly, we also found that this effect of LSD was blocked to a greater extent by 5-HT antagonists than by DA antagonists, suggesting that the effect may be secondary to 5-HT receptor activation [10,53] With respect to distinguishlng specific LSD induced behaviors and underlying mechanisms, the DD paradigm has been most successful in identifying differences between LSD and L H M , thus. it is obvious that the DS effects of LSD rely primarily on direct postsynaptlc 5-HT receptor activation (above) whereas the DS effects of LHM rely primarily on its actions as a direct DA receptor agonlst Among the other interesting behavioral comparisons of LSD and L H M is the finding that the FR-40 disruption caused by these ergots is blocked only by 5-HT antagonists [71] To date, this seems to be the only effect of LH M (at least at reasonable doses) that is not blocked by DA antagonists, suggesting that the particular pattern of disruption caused by LSD, L H M and various hallucinogenic drugs (pausing) may be a specific reflection of 5-HT receptor activation Thus, additional studies should attempt to identify the specific types and locations of the 5-HT receptors involved in LS D and L H M induced FR disruption ELECTROPHYSIOLOGICALSTUDIES
5 - H T Sv~tem~

004

LHM vs 0.08 LSD

|
O,

loo

J.
C

g
o I 008
1oo

I LHM vs 0 0 8 LSD

eo

6o

\
I I I o~ I

20

soooos ooo1

0Ol of Test

oos Drug

olo [mglkg]

oso

lo

60

Dose

FIG 3 Results of substitution tests with LSD, LHM, qmpazme (QPZ) and apomorphme (APO) m rats trained to discriminate 0 08 mg/kg LSD from either 0 02 mg/kg LHM (top panel), 0 04 mg/kg LHM (middle panel) or 0 08 mg/kg LHM (bottom panel) Note that zero percent LSD responses is equivalent to 100 percent LHM responses Asterisks represent slgmficant subsutuuon of QPZ for the LSD cue, or s~gmficant substitution of APO for the LHM cue (p<0 05, t-test for correlated measures) Reprinted from [102] with permission (Copyright by the AAAS )

Perhaps the most thoroughly characterized physiological effect of LSD is the ability of very low doses to reduce the firing rate of 5-HT containing neurons in the mldbraln dorsal raphe nucleus [4] These predominantly inhibitory neurons fire m a slow regular rhythm and thus keep the majority of their postsynaptlc target cells under tonic inhibition [1,6] LSD, when applied systemically (IV) in small doses (0 01-002 mg/kg) or when applied dtrectly onto the raphe soma by mlcrolontophoresls, produces an abrupt inhibition of the firlng rate of these cells [4-6] This in turn causes an increase in activity of the postsynaptlc target cells due to the release of inhibition Psychoactive congeners of LSD, other hallucinogenic drugs and agents which increase synaptlc availability of 5-HT (uptake inhlbitors, precursors, monoamlne oxldase mhlbltors) inhibit these raphe cells, potency of the hallucinogens in this regard is similar to their behavioral potency [6] Aghajanlan and colleagues [5] have also shown that the postsynaptic - t a r g e t " cells of the raphe nuclei, located in various brain regions (lateral geniculate nucleus, amygdala),

are much less responsive to LSD than are the raphe cells Therefore, they have proposed that the hallucinogenic effects of LSD may result from this preferential agonlstic effect at 5-HT autoreceptors located in the somatodendrltlC regions of the 5-HT containing raphe neurons [5], reasoning that the preferential inhibition of 5-HT cells causes dislnhlbltlon of postsynaptic target cells In contrast, non-hallucinogenic compounds which suppress 5-HT cells (5-HT, 5-HTP) also potently Inhibit the postsynaptic neurons thereby preventing "dIslnhlbltIon " Like LSD, L H M produces an abrupt, dose-dependent suppression of serotonerglc neurons In the dorsal raphe [81,100] In fact, In a comparative study, L H M was found to be 5-10 times more potent than LSD in selectively inhibiting the firing rate of these cells [81], both intravenous and mlcroaontophoretlcally applied L H M were potent in this regard On the basis of the molar intravenous dose required to completely inhibit cellular activity in the raphe, L H M is the most

372 TABLE 3 RESULTS OF SUBSTITUTION TESTS WITH ADRENERGIC AGENTS IN RATS TRAINED TO DISCRIMINATE LSD (0 08 mg/kg) OR LHM (0 04 mglkg) FROM SALINE* Dose (mg/kg) 0 08 0 04 -50 100 200 50
100

WHITE

Test Drug LSD LHM Sahne Propranolol

LSD-Rats 98 -1 4 6 15 8
6

n/Nt 8/8 -8/8 8/8 8/8 4/8 8/8

6/8

LHM-Rats -99 2

n/N~ -8/8 8/8 8/8 6/8 3/8 8/8 6/8 8/8 8/8 7/8 4/8 8/8 8/8 8/8 7/8

2 1 2 3 8 3
2

1 I

3 1 12 5 9 6 4 +
10

Phentolamme Prazosm

2
4

10 20 40 80 10 20 40 80

2 3 12 21

1 1 4 6

8/8 8/8 7/8 5/8 8/8 8/8 7/8 6/8

4 14 31 24 20 46 67 79

2 6 12 12 6 9 12 8

Yohlmbme

0 14 8 56 12 31 14

*All data are presented as the percentage of responses on the drug-lever tn/N refers to the number of rats responding out of those tested

p o t e n t d r u g d e s c n b e d to date [81] T h e s e r e s u l t s p r o v i d e a d d i t i o n a l e w d e n c e l n c o n s t s t e n t wtth t h e 5 - H T a u t o r e c e p t o r hypothests of hallucinogenic drug action However, unhke L S D , L H M ts q m t e p o t e n t at l n h t b l t m g t h e firing of a m y g dala n e u r o n s w h t c h r e c e w e a d e n s e 5-HT m n e r v a t l o n ( W a n g a n d A g h a j a m a n , u n p u b h s h e d results), a finding w h i c h ts in a c c o r d w t t h t h e p r e f e r e n t t a l a u t o r e c e p t o r h y p o t h e s i s o f hall u c m o g e n t c activity M o r e d a m a g i n g e v i d e n c e for the a u t o r e c e p t o r hypothes~s of hallucmogenlc drug actmn has been provided by a recent series o f e x p e r i m e n t s in w h i c h d o r s a l r a p h e activity a n d behavtoral measures were simultaneously monitored m awake, freely m o v i n g cats [94] T h e s e e x p e r i m e n t s r e v e a l e d t h a t the t t m e c o u r s e o f t h e b e h a v t o r a l effects o f L S D ( L F / A G , see a b o v e ) d o e s n o t c o r r e l a t e with m h t b l t o r y effects o f L S D m t h e d o r s a l r a p h e . In a d d i t i o n , a l t h o u g h the b e h a v i o r a l effects of LSD exhlbtted tolerance followmg repeated admlmstratlon, s u c h w a s n o t the c a s e for l n h t b m o n o f dorsal r a p h e a c t t v l t y [94] A l t h o u g h t h e s e r e s u l t s a r g u e a g a i n s t a c t m n s at t h e d o r s a l r a p h e as t h e p n m a r y m e c h a m s m of L S D - m d u c e d h a l l u c l n o s t s , o n e m u s t t a k e m t o a c c o u n t t h e p o s s t b l e lack of a p p r o p n a t e n e s s o f the L F / A G cat m o d e l as a n m d l c a t o r of h a l l u c m o g e m c efficacy ( a b o v e ) P e r h a p s equally d a m a g i n g to the a u t o r e c e p t o r h y p o t h e s i s is the r e c e n t f i n d m g t h a t the 5 - H T a g o m s t q m p a z m e , w h t c h is a p p a r e n t l y n o n h a l l u c m o g e m c [72,105] p o s s e s s e s a p o s t / p r e s y n a p t l c efficacy ratio (for l n h l b l t m g 5 - H T n e u r o n s a n d n e u r o n s in the lateral g e n l c u l a t e n u c l e u s , r e s p e c t t v e l y ) t h a t is s~mllar to t h a t o f L S D [18]. In v i e w o f the a b o v e p r o b l e m s w i t h the p r e s y n a p t l c 5 - H T receptor hypothesis of LSD's hallucmogemc potency, and t h e b e h a v m r a l e v i d e n c e s u p p o r t m g an i m p o r t a n t role of

p o s t s y n a p t l c 5 - H T r e c e p t o r s in h a l l u c m o g e m c acttvlty [ 102], electrophyslologlsts have turned their attention to p o s t s y n a p t l c 5 - H T r e c e p t o r s as p o t e n t i a l sites o f specific hall u c m o g e m c a c t i o n s In a n e l e g a n t series o f e x p e r i m e n t s , M c C a l l a n d A g h a j a n l a n [69] h a v e s h o w n t h a t L S D and o t h e r h a i l u c m o g e n s , b u t n o t L H M , c a n p o t e n t i a t e the exo t o m o d u l a t o r y effects of 5 - H T o n g l u t a m t c a o d - m d u c e d e x c i t a t i o n s in t h e rat facial m o t o r n u c l e u s (see [68a] for detailed s u m m a r y a n d r e f e r e n c e s ) M o r e o v e r , this is an effect t h a t is b l o c k e d b y 5 - H T a n t a g o n i s t s , a findmg w h t c h is m c o n c e r t with t h e b e h a v t o r a l e v i d e n c e d i s c u s s e d a b o v e It ~s difficult to e n v i s i o n h o w a c t i o n s o f L S D o n m o t o r n e u r o n s c o u l d b e I n v o l v e d m the c o m p l e x h a l l u c i n a t o r y e p i s o d e s i n d u c e d b y L S D H o w e v e r , If s u c h actions o f L S D o c c u r m o r e g e n e r a l l y at o t h e r b r a i n sites, p e r h a p s in llmblc, visual o r corttcal a r e a s , t h e y would take on c o n s i d e r a b l e a d d e d i m p o r t a n c e T o e x p l o r e thts possibility, e x t r a c e l l u l a r single cell r e c o r d i n g s were r e c e n t l y o b t a i n e d from the rat n u c l e u s a c c u m b e n s ( N A c ) , a f o r e b r a m h m b l c s t r u c t u r e often p o s t u l a t e d to be i n v o l v e d in m a n y o f the c o g n m v e a n d emotional d i s t u r b a n c e s o f s c h l z o p h r e m a [68, 91, 111] Prelimin a r y studies l n d t c a t e at least t w o different effects o f L S D m thts s t r u c t u r e (1) a p r e d o m i n a n t i n h i b i t o r y effect as previo u s l y d e m o n s t r a t e d m o t h e r f o r e b r m n s t r u c t u r e s [5,6], a n d (2) a p o t e n t t a t m g effect o n t h e e x c i t a t o r y ( m o d u l a t o r y ~) action o f 5 - H T w h t c h w a s e v i d e n t on a small s u b s e t o f n e u r o n s , i n t e r e s t i n g l y , this p o t e n t i a t i n g effect o f L S D on 5H T - l n d u c e d rate i n c r e a s e s o c c u r r e d o n a s p o n t a n e o u s l y active n e u r o n , b u t not w h e n g l u t a m l c actd was iont o p h o r e s e d to a c t i v a t e a q u i e s c e n t N A c (Fig 4) T h i s is m c o n t r a s t to the f a o a l m o t o r n u c l e u s w h e r e L S D p o t e n t i a t e d the a b d l t y o f 5-HT to d e c r e a s e the a m o u n t of glutamlc acid

LSD, LISURIDE AND HALLUCINOSIS

373

5-HT

20

LSD 40 GLUT 10

110 LLI 1OO I--

5O

8o

(D t::) Z 0 0 Iii O0 0 .rUJ 0.

25

zo

_z6o .a ~ so
B
S-HT

lO 20

40

LSO

,o

5 m

7 LU ~ 0 y 2O W ~0

==~J

=t==~

1 0

10

50

1OO

500

5 MIN F I G 4 Effects ofm=cromntophoretmally admlmstered 5-HT (0 3 M )

CUMULATIVE DOSE

(ug/kg)

and LSD (0 01 M) on the act=v=ty of two nucleus accumbens (NAc) neurons A Both 5-HT and LSD inhibited the abd~ty of glutamate (GLUT, 0 01 M) to activate the finng of this qmescent NAc neuron B 5-HT increased the actlwty of this spontaneously active NAc neuron m a current dependent manner Intravenous LSD (0 02 mg/kg at arrow) exerted no effect itself but apparently potentmted the abdlty of low 5-HT currents to increase firing Numbers represent mntophoret~c current m nanoamperes and hnes represent duration of mntophoret~c apphcatmn

FIG 5 Cumulative log dose response curves of the effects produced by increasing IV doses of LHM or LSD on the finng rates of A10 DA neurons Data points for LSD represent the mean of 13 rats except for the last data point (n=8) Data points for LHM represent the mean of 17 rats except for the last two data points (n=14 and 12, respectively) Vertical bars represent standard errors of the mean Reprinted from [110] w]th permlssmn (Copyright by Pergamon Press )

necessary to activate q u i e s c e n t cells Perhaps In the N A c . the ability of 5 - H T to increase the activity of s o m e neurons reflects an e n d o g e n o u s m o d u l a t o r y facilitation o f 5 - H T on glutamlc acid terminals [2] H o w e v e r , this is speculation based only on preliminary e v i d e n c e (n=3 N A c neurons) It should also be noted that intravenous administration of the 5-HT antagonist plzotIfen, but not the D A antagonist haloperidol, blocked this rate-enhancing effect of 5-HT in the N A c M o r e o v e r , the inhibitory effects of L S D and 5-HT on N A c neurons were not blocked by haloperldol but w e r e partially blocked by plzotlfen Thus far, only inhibitory effects of L H M have been o b s e r v e d in the N A c (n= 12 cells) and these effects were mediated by DA receptors since they w e r e p r e v e n t e d by haloperldol, but not pizotlfen Thus, L H M and L S D differ markedly with respect to their effects in the N A c , suggesting a possible important role for this llmblc nucleus in the bmbehavloral actions of L S D

DA Systema
L S D (0 025-0 05 mg/kg) has been shown to d e c r e a s e the firing rate of s o m e A9 DA neurons in the z o n a c o m p a c t a of the substantla nlgra [23,100], an effect characteristic of D A agomsts which is mediated by DA a u t o r e c e p t o r s in the somatodendrltm regton [3] H o w e v e r , it should be noted that c o m p a r e d to apomorphIne, L S D is very w e a k m this regard [100] M o r e o v e r , after chronic treatment with D A agonlsts, L S D increases the finng rate of A9 D A neurons [24], a findlng consistent with the hypothesis that L S D acts as a mixed agonlst-antagonlst at presynaptic D A receptors [31,98] We have recently c o n d u c t e d a series of e x p e r i m e n t s designed to c o m p a r e and contrast the effects of L S D and L H M

on A10 D A neurons in the rat ventral tegmental area [110] T h e s e A l 0 D A neurons are the primary cells o f origin of the m e s o h m b l c and mesocorttcal D A systems which have been ]mphcated in various cognitive and affectlve aspects of behavior [88] and, therefore, could possibly be involved m certain cognitive and affectlve (psychotomlmetlc) c o m p o n e n t s of the L S D experaence These e x p e r i m e n t s d e m o n s t r a t e d that L H M potently suppressed the firing rates of A10 D A cells, but faded to consistently alter the firing rates of n o n - D A neurons in the V T A The IDa. for L H M suppression of A10 D A cells (0 021 mg/kg, see Fig 5) was similar to that reported for L H M on A9 D A cells [100] As previously d e m o n s t r a t e d on A9 DA cells [100], h a l o p e n d o l was ineffective in reversing the L H M - l n d u c e d suppression but was capable of preventing the effect (Fig 6), suggesting that L H M acted as a noncompetitive or irreversible D A agonlst, as was recently demonstrated for another ergot derivative, bromocrlptine [12] This interpretation is supported further by the fact that, following partial suppression of an A10 or A9 D A neuron by L H M , a p o m o r p h l n e was unable to suppress further the firing rate of the cell (Fig 6) Unlike L S D (see below), L H M did not exert a typical D A antagonist effect because L H M faded to reverse a p o m o r p h l n e ' s rate-depressant effects on A10 DA cells In contrast to L H M , L S D exerted mixed effects on A10 DA cells, partially suppressing the firing of some cells, accelerating the flnng of s o m e cells and exerting no effects on others (Fig 7) Interestingly, our results suggested that A I 0 D A cells with firing rates a b o v e 3 0 H z were m o r e likely to be suppressed by L S D than A10 D A cells with finng rates below 3 0 H z This relationship b e t w e e n the effects of L S D

374

WHITE

LHM

HAL = o 0
n. tit 0.

LSD

HAL

HAL

LHM
v,

B 4o~
o

LSD

APO

LSD

O.uJrr'tuU~ 50~
a. u~

~" 0

5 MIN

LHM

APO

FIG 7 Effects of LSD on the finng rates of A10 DA neurons A Partml suppression of the finng rate of an A 10 DA neuron produced by increasing IV doses of LSD (0 001-0 128 mg/kg, total dose, 0 511 mg/kg IV) B Increases m the finng rate of an AI0 DA neuron produced by increasing IV doses of LSD (0 001-0 256 mg/kg, total dose, 0 511 mg/kg), the subsequent pamal suppression of the finng rate of the cell by increasing IV doses of apomorphme (APO, 0 001-0 032 mg/kg, total dose, 0 063 mg/kg) and the reversal of APO's effect by LSD (0 05 and 0 1 mg/kg IV) Repnnted from [110] with perm=ssmn (Copynght by Pergamon Press )

5MIN

FIG 6 Effects of LHM on the firing rates of A10 DA neurons A Typical suppression of the firing rate of an A 10 DA neuron produced by increasing IV doses of LHM (0 001-0 016 mg/kg, total dose, 0 031 mg/kg) and the inability of haloperidol (HAL) (0 05-0 4 mg/kg IV, total dose, 0 75 mg/kg) to reverse the suppression B Prevennon of the rate-suppressant effects of increasing IV doses of LHM (0 001-0 512 mg/kg, total dose, 1 023 mg/kg) on an A10 DA neuron by pretreatment w~th HAL (0 005-0 04 mg/kg, total dose, 0 075 mg/kg IV) C Partml suppression of the finng rate of an A10 DA neuron produced by increasing IV doses of LHM (0 001-0 032 mg/kg, total dose, 0 063 mg/kg) and the fadure of apomorphme (APO, 0 001-0 032 mg/kg, total dose, 0 063 mg/kg IV) to further suppress the finng rate of the cell Reprinted from [110] with permlSSlOU (Copyright by Pergamon Press )

a n d b a s a l a c t i v i t y is e x a c t l y t h e o p p o s i t e of t h a t r e p o r t e d for the D A a g o n l s t s a p o m o r p h m e , a m p h e t a m i n e , p e r g o h d e , a n d L H M [109] T h e p o t e n c y with w h i c h t h e s e a g o m s t s Inhibit A 1 0 D A n e u r o n s is indirectly r e l a t e d to b a s a l activity s u c h t h a t a g o n l s t - m d u c e d rate s u p p r e s s i o n is m o r e p r o n o u n c e d o n s l o w e r firing D A n e u r o n s [109] T h e r e a s o n s for t h e u n u s u a l n a t u r e o f L S D ' s l n t e r a c n o n s with individual D A n e u r o n s are u n k n o w n b u t t h e s e d a t a s u g g e s t t h a t t h e i n h i b i t o r y effects o f L S D o n A10 D A n e u r o n s are m e d i a t e d vla s o m e w h a t different mechanisms than those of more potent DA agomsts P e r h a p s L S D e x e r t s i n h i b i t o r y effects only o n a p a r t i c u l a r s u b s e t of A10 p r o j e c t i o n n e u r o n s t e r m i n a t i n g in s o m e specific f o r e b r a m a r e a F u r t h e r e x p e r i m e n t a t i o n utilizing sitespecific a n t l d r o m l c s t i m u l a t i o n t e c h n i q u e s will b e r e q u i r e d to i n v e s t i g a t e this posslbtllty T h e h a l o p e n d o l - r e v e r s l b l e partial s u p p r e s s i o n of A l 0 n e u r o n a l a c t i v i t y b y L S D suggests t h a t L S D is only a w e a k D A agonlst m vii, o , a c o n c l u s i o n t h a t is s u p p o r t e d b y previous b i o c h e m i c a l [63] a n d b e h a v i o r a l [53] studies As previo u s l y d e m o n s t r a t e d o n A9 D A n e u r o n s [24], L S D also e x e r t e d w h a t a p p e a r s to be a n a n t a g o n i s t a c t i o n o n A10 D A

n e u r o n s , r e v e r s i n g the r a t e - d e p r e s s a n t effect o f a p o m o r p h m e This r e v e r s a l a p p a r e n t l y was not due to a 5 - H T a g o m s t a c t i o n of L S D b e c a u s e , unlike the 5-HT a g o m s t 5 - M e O D M T , L S D was n o t able to a c c e l e r a t e the activity o f L H M - s u p p r e s s e d A10 D A cells T h u s , o u r results s e e m to be c o n s i s t e n t with m a n y p r e v i o u s r e p o r t s t h a t L S D is a w e a k D A agonlst w h i c h also e x e r t s partial D A antagonist-like act i o n s [23, 24, 63, 98, 100] D A - a n t a g o m s t p r o p e r t i e s of L S D m a y also b e r e s p o n s i b l e for t h e i n c r e a s e d f i n n g rate of s o m e A10 D A cells s e e n following L S D a d m i n i s t r a t i o n b e c a u s e D A a n t a g o n i s t s typically a c c e l e r a t e the firing o f A I 0 DA cells (Fig 6B) A d d i t i o n a l r e s e a r c h IS n e e d e d to identify the p r o j e c t i o n a r e a s o f t h o s e DA n e u r o n s w h i c h are a c n v a t e d by LSD T o d i s c e r n w h e t h e r t h e s e d r u g - i n d u c e d a l t e r a t i o n s in the activity o f A10 D A n e u r o n s were d i r e c t effects on the A10 cells or w e r e possibly m e d i a t e d t r a n s y n a p t l c a l l y , experim e n t s u s i n g direct m l c r o l o n t o p h o r e t l c a p p l i c a t i o n o f L S D a n d L H M o n t o A I 0 DA cells were p e r f o r m e d L H M , like DA, inhibited the activity o f A10 D A n e u r o n s (Fig 8A, [108]), a n effect t h a t was p r e v e n t e d , but n o t r e v e r s e d b y the D A a n t a g o m s t , t r l f l u o p e r a z l n e T h e s e results indicate that the n o n c o m p e U t l v e a c t i o n of L H M o n A10 D A n e u r o n s occurs directly on D A a u t o r e c e p t o r s w h i c h are of the D-2 rec e p t o r s u b t y p e [ 112] M l c r o l o n t o p h o r e t l c a p p l i c a t i o n o f L S D o n t o A10 D A n e u r o n s r e s u l t e d in b o t h a w e a k rate s u p p r e s s a n t effect a n d a partial r e v e r s a l of D A ' s rate s u p p r e s s a n t a c t i o n (Fig 8B) T h u s , it a p p e a r s t h a t L S D e x e r t s m i x e d D A a g o n i s t / a n t a g o n l s t a c t i o n s on D A a u t o r e c e p t o r s
NE System

In c o n t r a s t to its d e p r e s s a n t effects o n r a p h e a n d nigral cells, i n t r a v e n o u s L H M , in h i g h e r d o s e s (0 025-0 05 mg/kg), c a u s e s a n i n c r e a s e in the cellular activity of s o m e N E n e u r o n s o n t h e locus c o e r u l e u s [81], L S D h a s a similar, b u t

LSD, LISUR1DE A N D H A L L U C I N O S I S less pronounced effect [92] This activation of N E neurons ts consistent w~th reports of a-adrenoceptor antagonist effects of both L H M and LSD and the typical finding that L H M is more potent than LSD in this action (above)
CONCLUSIONS

375

DA

LHM

TFP

10

20

...... 10

20

50

B
0 uJ o9
DA LSD

10 10 2 0 20 10 20

20 2~ 50

It is readily obvious that the spectrum of L H M ' s potent neuropharmacologlcal and blobehavloral actions has played havoc with the major current hypotheses regardmg the neuronal mechanisms through which LSD exerts its powerful hallucinogenic properties Discovering the shortcomings of such hypotheses appears, at least m hindsight, to have been inevitable since it is unlikely that any simple theory of hallucinogenic mechanisms could ever account for the multlfaceted components of so striking an experience as that induced by hallucinogens As cogently argued by Freedman and colleagues [39], the necessary orientation for future research is toward essential component parts (both in temporal and dosage parameters) of the L S D experience and their correlation with biochemical and electrophyslologlcal events in the nervous system The problem in this respect IS the paucity of reliable and rephcable pharmacologic parameters in humans from which to deduce such correlations For this reason, the following discussion will attempt to correlate biochemical and electrophyslologlcal findings with data gathered from various behavioral assays in animals, making the admittedly large assumption that such behaviors are, in fact, reliable predictors or analogues of human behavior The original proposal that L S D ' s hallucinogenic effects were due to a decrease in 5-HT turnover failed to account for many of the key biochemical events occurring in the first sixty minutes of LSD administration [39] The fact that L H M produces strikingly similar biochemical changes with respect to 5-HT turnover prompted some researchers to dismiss this action of LSD as an "eplphenomenon unrelated to halluclnosis" [74] We have argued elsewhere [102] that these common effects of LSD and L H M indicate that effects on 5-HT turnover are not alone sufficient for inferring hallucinogenic efficacy The available evidence linking 5-HT neuronal events to L S D ' s actions are certainly far too compelling to be dismissed outright As pointed out above, conslderably more research must be conducted on LSD and LHM with respect to membrane and subcellular events involved in 5-HT (and CA) storage and release mechanisms The popular hypothesis that hallucinogenic efficacy is related to the ability of such drugs to inhibit the activity of 5-HT neurons [5,6] has also been called into question by the greater potency of L H M than LSD at inhibiting raphe neurons [81] Yet the fact that L H M is also more potent than LSD on postsynaptlc 5-HT receptors (Wang and Aghajanlan, unpublished results) is compatible with the presynaptlc selectivity hypothesis of hallucinogenic potency Nevertheless, several other lines of evidence argue against a simple "lnhlbltlon-dlsinhlbmon" mechanism (see Electrophyslologlcal Studies, above) This is not meant to imply that inhibition of dorsal raphe 5-HT neurons is not involved in hallucinogenic efficacy but rather, to suggest that such an effect is not a sufficient condition for the overall composite characteristic of the psychedelic experience Given the minute doses of LS D which inhibit raphe neurons and the rapid onset of this event, it seems at least possible that raphe inhibition may be required to initiate other neuronal events which then propagate and sustain hallucinatory-related consequences However, it is clearly not the case that these

LU R" U)

C
DA

10

APO

20

5 1 0

TFP

20

5 MIN

FIG 8 Comparison of the effects of mlcromntophoretlcally administered LHM (0 01 M), LSD (0 01 M), DA (0 1 M) and apomorphme (APO, 0 01 M) on AI0 DA neurons m the rat A DA readily suppressed the act~wty of th~s cell and the effect was rapidly reversed upon current termmauon In contrast, LHM caused a prolonged suppression of actw|ty which was not reversed by tNfluoperazlne (TFP, 0 05 M) However, after the cell recovered to basal levels, LHM was no longer capable of suppressing the cell B LSD caused a slight suppress]on of th~s cell's basal finng and both partially reversed and partmlly prevented the rate-suppressant effect of DA C Like LHM, APO caused a prolonged rate suppression of this cell but unhke LHM, TFP readily reversed the effect of APO TFP also prevented further rate-suppressant efficacy of both APO and DA Numbers indicate ~ontophoreuc currents m nanoamperes and hnes represent the duration of ~ontophoreUc appllcahon

subsequent events depend upon a potent direct DA agonIst action as previously proposed [94] since LH M is considerably more potent than LSD at DA receptors (see above) In addition to causing scientists to view these previous hypotheses of halluclnosls with a skeptical eye, the discovery of L H M ' s neuroblologlcal activities has generated the search for new potential sites of specific hallucinogenic actions, the most promising of which are postsynaptlc 5-HT receptors At about the same time that we were obtaining behavioral evidence indicating that the discriminable (subjective) states elicited by LSD and LHM were distinguishable primarily because of the greater specificity of L S D ' s interaction with postsynaptlc 5-HT receptors [102], McCall and Aghajanlan [69] discovered that the ability of LSD (and other hallucinogens) to potentiate 5-HT's excitomodulatory action in the facial motor nucleus was not shared by L H M More recently, Jacobs and co-workers [50,58] have also reached the conclusion that postsynaptlc 5-HT receptors may be the most important sites of hallucinogenic activity Among the important questions now at hand are (1) which postsynapttc 5-HT receptors are likely to be involved in LSD-induced halluclnosls, (2) in what way are they involved, and (3) what other neuronal actions may result from activation of these 5-HT receptors9 Several investigators have postulated the existence of two or more types of 5-HT receptors in the CNS [2,73] Clearly, one criterion for accepting or rejecting a particular 5-HT receptor as accountable for hallucinatory phenomena is that LHM should not mimic the effects of LSD on that receptor

376 or, at the very least, L H M should exhibit considerably less potency A second criterion for acceptance of certain 5-HT receptors as mediators of halluclnosis might be derived from the behavioral studies reviewed above Noticeable in almost all cases is the fact that 5-HT antagonists attenuate the behavioral effects of LSD in animals If we generalize this fact to the human experience, one might expect 5-HT antagonists would also attenuate at least some components of the hallucinogemc experience Unfortunately there are, at present, no pubhshed data either to support or reject th~s possiblhty H o w e v e r , if we accept the validity of the behavioral models reviewed herein, then selective antagonism of L S D ' s effects by 5-HT antagonists would be a second criterion to apply to 5-HT receptor candidacy Based on these criteria, only two 5-HT receptors thus far recognized would qualify as potential mediators of hallucinogenic action One such receptor would be those at which 5-HT exerts an e x o t a t o r y (or excitomodulatory) action since the effects of 5-HT and, presumably, LSD are blocked by 5-HT antagomsts Such receptors have been identified in the facml motor nucleus [69] and, in preliminary experiments, in the N A c (above) The search for such receptors in other brain areas ~s an important horizon for future research A second 5-HT receptor which meets the above criteria also appears to be located m the N A c since both 5-HT and LSD inhibit neuronal activity at th~s site and these effects are partially blocked by the 5-HT antagonist plzotlfen Although L H M also inhibits N A c neurons, its effects are blocked only by DA antagonists These are intriguing preliminary results worthy of extensive continued investigation With respect to the first 5-HT receptor o t e d above ( "ex citatory"), ~t should be noted that other "excitatory'" responses to 5-HT have been reported in the cortex and reticular formation However, LSD appears to be an antagomst at these sites [19,80], thus making reconcihatlon of these findings with the 5-HT antagonist-induced reduction of L S D ' s behavioral effects difficult Perhaps some components of L S D ' s actions are due to 5-HT receptor antagonism in the CNS which could explain why some behaworal effects of LSD are partially mimicked by some 5-HT blockers [25,59] Unfortunately, the effects of L H M have not been evaluated on these " e x c i t a t o r y " 5-HT receptors The above d~scussion ~s not designed to exclude completely those 5-HT receptors which are not blocked by antagonists from a potentml role m hallucinatory events G~ven the lack of human clinical data, such exclusion is certainly premature Obviously needed are detaded chmcal

WHITE studies of a variety of 5-HT antagonists with emphasis on parhcular aspects of L S D ' s spectrum of effects, w~th such Information it would then be possible to correlate specific neuronal effects with specific components of the LSD experience Thus far, the majority of antagonist data acquired from human studies Utdlzed DA blockers which were reported m some cases to reduce the intensity of the LSD reaction [56] These results are often cited as supporting a DA agonist action of LSD [31, 74, 75] However, as argued convincingly by Freedman et a! [39], there is no sufficiently compelling evidence that DA antagonists specifically block LSD effects as opposed to merely causing sedation Until more detailed, controlled and nonanecdotal climcal findings are forthcommg (which is unhkely gwen current constralnts), we must continue to rely on animal models and, therefore, the criteria suggested above are offered as a working hypothesis on which to base future research In conclusion then, it ~s certainly true that the effects of LSD reported m the hterature are multlfaceted and d~vergent, lmphcatmg a variety of different but probably interrelated neuronal mechanisms as potentially accountable for the various components of the LS D experience The discovery of the nonhalluclnogenlc compound L H M which bears such close structural and pharmacological similarity to LSD provldes a powerful tool to the hallucinogen researchers w~th which to unmask those neuropharmacologlcal mechanisms unique to the hallucinogens The studies thus far completed continue to emphasize the dominant role of 5-HT neuronal systems but now have led us to explore m greater detad the p r e o s e sites at which L S D ' s lnterachons w~th this system are discrepant from those of LHM. Much work is left to be done, not only along the avenues traveled thus far, but also down new paths through unexplored t em t o r i es Gwen the recent growth of our knowledge of neuropeptide systems, a potential area for future research ~s the possible mterplay between hallucinogens, 5-HT systems and specific peptlde neuromodulators (see [32a]) Continued endeavors in this and other quests wdl hopefully shed new light into the unique neuroblological events which unfold to produce the psychedehc experience ACKNOWLEDGEMENTS I thank Maggie Klevorn and Lmda Russell for manuscript preparatlon and the scientific staff at Schering AG (Berhn) for prowding generous supplies of hsunde used in my experiments Preparahon of this manuscript was supported m part by National Research Service Award MH-08886 from the NIMH

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30 Dahlstrom, A and K Fuxe Evidence for the existence of monoamlne containing neurons In the central nervous system A~ta Phystol S~and 62: 1-55, 1965 31 DaPrada, M , A Saner, W P Burkard, G Barthohnl and A Pletscher Lyserglc a o d dlethylamlde Evidence for stimulation of cerebral dopamme receptors Brmn Re~ 94: 67-73, 1975 32 Dixon, A K Evidence of catecholamlne mediation of the "aberrant" behavior induced by lyserglc acid dtethylamlde (LSD) in the rat Expertentta 15: 743-747, 1968 32aDomlno, E F Oplold-halluclnogen mterachons Pharma~ol Bto~hem Behav 24" 401-405, 1986 33 Dwoskln, L P and S B Sparber Behaviorally inactive doses of mlanserln antagonize the suppressant effect of lyserglc acid dlethylamlde on a fixed ratio operant J Phatma~ ol E~p 7her 225: 77-84, 1983 34 Ernst, A M Mode of action of apomorpblne and dexamphetamlne on gnawing compulsion In rats Ps'vchopharrnatologta 10: 316-323, 1967 35 Fog, R Stereotyped and non-stereotyped behavlour in rats induced by various stimulant drugs Pvvt hopharrnat o[ogta 14: 299-304, 1969 36 Fredrlckson, P A and E Rlchelson Hallucinogens antagonize histamine H-1 receptors of cultured mouse neuroblastoma cells Eur J Pharma~ol 56: 261-264, 1979 37 Freedman, D X Effects of LSD-25 on brain serotonln J Pharma~ol Exp Ther 134: 160-166, 1961 38 Freedman, D X Psychotomlmetlc drugs and brain blogenlc amines Am J P s w htatry 119: 843-850, 1963 39 Freedman, D X and W O Boggan Biochemical pharmacology of psychotomlmetlcs In Handbool, oJ Experimental Pharmacoh~gv, vol 55/III, edited by F Hoffmelster and G Stllle Berhn Spnnger-Verlag, 1981, pp 57-88 40 Freedman, D X, R Gottheb and R A Lovell PsychotomlmetJc drugs and brain 5-hydroxytryptamlne metabohsm Btot hem Pharmat ol 19: 1181-1188, 1970 41 Fujlta, N , K Salto, N Yonehara and H Yoshlda Lisurlde inhibits ~H-splropendol binding to membranes isolated from strlatum Neuropharma~ologv 17: 108%1091, 1978 42 Fuxe, K , B B Fredholm, S Ogren, L F Agnatl, T Hokfelt and J Gustafsson Ergot drugs and central monoammerglc m e c h a m s m s A hlstochemlcal, biochemical and behavioral analysis Fed Prot 37: 2181-2191, 1978 43 Gaddum, J H Antagonism between lyserglc a o d dlethylamlde and 5-hydroxytryptamlne 1 Phvstol 121" 15-21, 1953 44 Glennon, R A , J A Rosecrans and R Young Drug-induced discrimination A description of the paradigm and a review ot its specific apphcatlon to the study of hallucinogenic agents Med Res Re~ 3: 289-340, 1983 45 Goplnathan, G , H Teravalmen, J M Dambrosla, C D Ward, J N Sanes, W K Stuart, E Y Evarts and D B Calne Llsunde m parklnsomsm Neurologx 31. 371-376, 1981 46 Grahame-Smlth, D C Studies m ~tvo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamlne oxldase Inhibitor and l-tryptophan J Neuro~hem 18" 1053-1066, 1971 47 Green, J P , C L Johnson, H Wemsteln and S Maayam Antagonism of histamine-activated adenylate cyclase in brain by d-lyserglc acid dlethylamlde Proc Natl At ad ,St t UAA 74. 5697-5701, 1977 48 Herrmann, W M , R Horowskl, K Dannehl, V Kramer and K Luratl Chnlcal effectiveness of llsunde hydrogen maleate A double-bhnd trml versus methyserglde Heada~ he 17 54-60, 1977 49 Hetey, L , R Schwztzkowsky and W Oelssner Influence of psychotomlmetlcs and hsunde on synaptosomal dopamlne release m the nucleus accumbens of rats Lur J Pharma(ol 93 213-220, 1983 50 Heym, J , K Rasmussen and B L Jacobs Some behavioral effects of hallucinogens are mediated by a postsynaptlc serotonerglc action evidence from single unit studies m freelv moving cats Eur 1 Pharmat ol 101: 57-68, 1984

378

WHITE

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71 Mokler D J , R L C o m m i s s a r l s , M R Warner and R H Rech Blockage of the behavioral effects of lysergic acid dlethylamlde, 2 , 5 - d i m e t h o x y - 4 - m e t h y l a m p h e t a m m e , qulpazme and h s u n d e by 5-hydroxytryptamlne antagonists J Pharma ol Eap Thel 227: 557-562. 1983 7 1 a N l e l s e n , E B D l s c n m m a t l v e stimulus properties of lyserglc acid dlethylamlde i n the m o n k e y I Pharma ol k~rp Ther 234" 244-249, 1985 72 Paran, E A . P Zanardi, D Cocchl, T C a r a c e m and E E Muller N e u r o e n d o c r m e effects of q m p a z m e in m a n in health state or with neurological disorders I Neural 7run~ 47: 273297, 1980 73 Peroutka, S J and S H Snyder Multiple s e r o t o n m receptors Differential binding of (~H) 5 - h y d r o x y t r y p t a m m e , (~H) lyserglc acid dlethylamlde and (~H) spiropendol Mol Pharmaol 16. 687-699, 1979 74 Plerl, L . H H Keller, W Burkard and M DaPrada Effects of h s u n d e and L S D on cerebral m o n o a m m e s y s t e m s and hallucmosls Nature 272. 278--280. 1978 75 Plen, L . M Plerl and W Haefely L S D as an agomst of d o p a m m e receptors in the s t n a t u m Nature 252: 586-588, 1974 76 Pleri, M , R Schaffner, L Plen, M DaPrada and W Haefely Turning in MFB-lesioned rats and antagonism of neurolepticinduced catalepsy after hsurlde and LSD Life ~ t 22 16151622. 1978 77 Pycock. C and G Anlezark L S D and dopamlne receptors N a t m e 257: 6%70, 1975 78 Randrup, A and I M u n k v a d Role of catecholamlnes in the a m p h e t a m i n e excitatory response N a t m e 211. 540-541. 1966 79 Rech, R H and R L C o m m i s s a r l s N e u r o t r a n s m i t t e r b a s l s of the behavioral effects of hallucinogens N e u r o ~ I Biobehav Re~ 6 521-527. 1982 80 Roberts, M H T and D W Straughn Excitation and depression of cortical n e u r o n s by 5 - h y d r o x y t r y p t a m m e I PIn~u,l 193" 26%294, 1967 81 Rogawski, M A and G K A g h a j a m a n R e s p o n s e of central m o n o a m m e r g l c neurons to h s u n d e C o m p a r i s o n w~th LSD Lt[e Set 24: 128%1298, 1979 82 R o s e c r a n s , J A and R A G l e n n o n Drug-reduced cues m studying m e c h a n i s m s of drug action Neuropharma~ olo~,~ 18: 981-989, 1979 83 R o s e c r a n s , J A , R A L o v e l l a n d D X F r e e d m a n Effects of lyserglc acid dlethylamide on the metabolism of brain 5 - h y d r o x y t r y p t a m m e Bto~ hem Pharma ol 16: 2011-2021, 1967 84 Rosenfeld, M and M H M a k m a n The interaction of hsuride, an ergot derivative, with serotonergic and d o p a m m e r g l c receptors i n rabbit brain I Phu~maol L r p 7heJ 216: 526-531. 1981 85 Saiam, L , M Trabucchl, G C T o n o n and P F Spano Bromocrlptme and h s u n d e stimulate the accumulation ot cychc A M P m intact slices but not in h o m o g e n a t e s of the n e o s t n a t u m Neurost Lett 14 31-36, 1979 86 S c h l e m m e r , R F and J M Davis A comparison of three p s y c h o t o m l m e t l c - m d u c e d models of p s y c h o s i s m n o n h u m a n primate social colonies In kdhopharma ologx Prm:ate Model~ of Neuropsv htatH Disorders, edited by K MIczek New York Alan R Llss Press, 1983, pp 33-78 86a S c h l e m m e r , R F , Jr and J M Davis A primate model for the s t u d y of hallucinogens Pharmaol Btochem Behu~ 24 381-392, 1986 87 Sdbergeld, E K and R E H r u s k a Llsuride and LSD D o p a m m e r g l c and serotonerglc interactions m the " s e r o t o n m s y n d r o m e " P ~ h o p h a r m m olo~.,v (Berhn) 65. 233-237. 1979 88 Simon, H . B Scatton, and M LeMoal Dopamlnergic A10 n e u r o n s are involved in cognitive f u n c t m n s Nature 286" 150151, 1980 89 Sloviter, R S , E G Drust and J D Connor Specificity of a rat behavioral model for s e r o t o n m receptor actwatlon I Phurmac ol E t p Ther 206: 33%347. 1979

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89a Sparber, S B , L P D w o s k l n and M S K l e v e n Studies on the specificity of neurochemlcal and behaworal effects of LSD-25 Pharmat ol Blot hem Beha* 24. 341-345, 1986 90 Stevens, J R An a n a t o m y of schizophrenia9 Arch Gen Psvc htatrv 29:117-189, 1973 91 S v e n n s o n . T H , B S B u n n e y and G K Aghajanlan Inhlbntlon of both noradrenerglc and serotonerglc n e u r o n s nn the brain by the alpha-adrenerglc agonlst clomdlne Brain Res 92" 291-306. 1975 92 Tlssarl, A H , L Atzorl and M T Galdlerl Inhibition of dopamlne s y n t h e s i s in strlatal s y n a p t o s o m e s by h s u n d e StereospeclfiC reversal by ( - ) sulplrlde N a u n w l S(htntedebere~ Art h Pharma~ ol 322: 8%91, 1983 92a Trulson, M E Dissociations between the effects of hallucinogens on behavior and raphe u m t activity in behaving cats Phat ma~ ol Btoc hem Beha~ 24" 351-357 1986 93 Trulson, M E and B L Jacobs Dissociations between the effects of L S D on behavior and raphe unit activity in freely moving cats Science 205: 515-518, 1979 94 Trulson, M E , C A Ross and B L Jacobs Behavioral evidence for the stimulation of C N S serotonln receptors by high d o s e s of L S D Psv~ hopharma~ ol ( o m m H n 2: 149-164, 1976 95 Ungerstedt, U and G W Arbuthnott Quantitative recording of rotational behavior in rats after 6 - h y d r o x y d o p a m m e lesions of the nlgrostnatal d o p a m m e s y s t e m Brain Re~ 24" 485-493, 1970 96 Ungerstedt, U , T Ljundberg, B Hoffer and G Slgglns Dopammerglc supersens~t~wty m the striatum Adl N e u t o l 9. 57-65, 1975 97 Von H u n g e n , K . S Roberts and D F Hill Interactions between lysergnc acid &ethylamnde and dopamnne-sensntnve adenylate cyclase s y s t e m s in rat brain Brain Res 94: 57-66. 1975 98 Wachtel. H Inhibition of locomotor activity in rats by low d o s e s of different dopamtne (DAt receptor a g o m s t s Nattnxn Ac hmtedebergs At~ h Pttarmac ol 302" 236, 1979 99 Waiters, J R , M D Baring and J M Lakoski Effects of ergohnes on dopamlnergic and serotonerglc single unit activity In l)opammergtc Ergot Derlvattles and Motor Function, edited by K Fuxe and D B Calne N e w York Pergamon Press, 1979, pp 207-221 100 White F J and J B Appel A neuropharmacological analysis of the &scrlmmatnve stimulus properties of f e n f l u r a m m e Ps~hopharma~ olog~ (Berhn) 73" 110-115, 1981

101 White, F J and J B Appel LSD and hsurlde Differentiation of their neuropharmacologlcal actions 5~tent e 216. 535-537, 1982 102 White, F J and J B Appel The role o f d o p a m l n e and serotonln in the discriminative stimulus effects of hsurlde I Pharmac ol Iz~p Ther 221: 421-427, 1982 103 White. F J and J B Appel Training dose as a factor m L S D - s a h n e dlscrlmmatnon P s ~ c h o p h a r m a ~ o / o g v (Berhn) 76: 20--25, 1982 104 White, F J , J B Appel and D M K u h n Discriminative stimulus properties of qulpazlne Direct serotonerglc mediatlon Neuropharmatolog~ 18" 143-151, 1978 105 White, F J , A M Holohean and J B Appel L a c k of specificity of an animal behavior model for hallucinogenic drug action Pharma~ ol Bto~ hem Behav 14. 339--343, 1981 106 White, F J , A M H o l o h e a n a n d J B Appel A n t a g o m s m o f a behavioral effect of L S D and h s u n d e in the cat Psvt hopharma~ olog~ (Berhn) 80. 83-84, 1983 107 White, F J . M A S i m m o n s , K B West, A M H o l o h e a n a n d J B Appel The effect of serotonln depletion on the dlscrlmlnablllty of L S D Pharma~ ol Bloc hem Behav 13" 56%574, 1980 108 Whnte, F J and R Y W a n g A l 0 d o p a m l n e n e u r o n s Role of autoreceptors in determining f l n n g rate and sensitivity to dopamlne a g o m s t s Lt[e Act 34 1161-1170, 1984 109 White, F J and R Y W a n g C o m p a r i s o n of the effects of LSD and hsurlde on A10 dopamlne n e u r o n s in the rat Neuropharma~ oloev 22 66%676, 1983 110 White, F J and R Y Wang Differential effects of classical and atypical antipsychotlc drugs on A9 and AI0 d o p a m m e n e u r o n s 5Cletlce 221 1054-105% 1983 111 White, F J and R Y Wang Pharmacological characterization of dopamlne autoreceptors in the rat ventral tegmental area Mlcrolontophoretnc studies J P h a r m a ( o l E~p Thel 23" 275280, 1984 112 Winter, J C Stimulus properties o f p h e n e t h y l a m n n e hallucinogens and lysergnc acid dnethylamlde The role of 5 - h y d r o x y t r y p t a m m e I Phartnaol E~p Ther 204 416-423, 1978 113 Woolley, D W and E A Shaw A biochemical and pharmacological suggestion about certain mental disorders Pro~ Natl A~ad 5~t USA 40" 228-231. 1954