The Neuroscience of Cocaine: Mechanisms and Treatment

France

Preface

V.R. Preedy, King’s College London, London, United Kingdom

Cocaine usage has been recorded for several thousand years and in the early part of the 20th century cocaine was included in some proprietary brands of medicines and tonics. However, there have been long-standing concerns about the ill effects that cocaine usage may impose. Cocaine has been used by at least 13 million Europeans and 36 million Americans at least once in their lifetime. In the United States there are about 2 million current cocaine users, with addiction a frequent occurrence. Cocaine is very often associated with other forms of drug addiction or misuse. Cocaine alters neurological and behavioral processes and impacts negatively on nonneurological tissues. It has a defined neuropharmacological profile that is still being explored in order to understand the mechanisms of its effects. Research into the effects of cocaine allows new pharmacological compounds to be derived and paves the way for new therapeutic regimens. In relation to therapies, the cessation of cocaine misuse can lead to adverse withdrawal and abstinence-related conditions that alter the cell at the molecular level as well as the individual at the behavioral level. Due to the adverse profiles of cocaine and cocaine misuse, various strategies have been developed to diagnose cocaine addiction and curtail its use. Such strategies go hand-in-hand with treatment regimens of various kinds. However, the scientific material relating to cocaine, its neurological effects, assessments, and treatments is enormous and interrelated in a complex way. Unraveling such relationships into a single publication has hitherto been difficult, but is addressed in The Neuroscience of Cocaine: Mechanisms and Treatment.

The book is divided into 10 parts as follows:

I. General aspects, features of ill health and setting the scene

II. Molecular effects

III. Cellular effects

IV. Regional, structural, and imaging aspects

V. Behavioral aspects

VI. Receptors, transporters, and neuropharmacology

VII. Withdrawal and abstinence

VIII. Poly-drug use and comorbidities

IX. Assessment and treatment aspects

X. Resources

The Editor recognizes the difficulties in assigning some chapters to different parts. Very often chapters cover different domains so that they can equally fit into one of several parts of the book. However, this is resolved by the excellent indexing system complied by Elsevier.

The Neuroscience of Cocaine: Mechanisms and Treatment transcends multiple disciplinary and intellectual divides as each chapter has:

• Key Facts (focused areas)

• Mini-Dictionary of Terms

• Summary Points

The Neuroscience of Cocaine: Mechanisms and Treatment is designed for research and teaching purposes. It is suitable for neurologists and neuroscientists, drug abuse workers, health scientists, public health workers, doctors, pharmacologists, and research scientists. It is valuable as a personal reference book and also for academic libraries that cover the domains of neurology, health sciences, or addictions. Contributions are from leading national and international experts including those from world-renowned institutions. It is suitable for undergraduates, postgraduates, lecturers, and professors.

Part I

General Aspects, Features of Ill Health and Setting the Scene

Outline

Chapter 1 The Nervous System: A Starter Pack for Beginners

Chapter 2 Sex Differences in the Effects and Actions of Cocaine

Chapter 3 Contribution of Stress to Cocaine Addiction

Chapter 4 Strokes Associated With Cocaine Use

Chapter 5 Concentrations of Cocaine in Blood Samples From Impaired Drivers and Drug-Related Deaths

Chapter 6 Cocaine Postmortem Distribution in Brain

Chapter 7 Cocaine Adulterants and Effects on Monoamine Transporters

Chapter 8 Global Approaches in the Analysis of Cocaine-Induced Gene Expression

Chapter 1

The Nervous System

A Starter Pack for Beginners

R.A. Armstrong,    Aston University, Birmingham, United Kingdom

Abstract

The human nervous system comprises the brain, spinal cord, and peripheral nerves and is composed of several billion nerve cells or neurons. Specific populations of neurons, together with associated fiber tracts, are organized anatomically into pathways involved in sensory, motor, and cognitive function. A significant proportion of the brain carries out a sensory analysis of the world using information supplied from specialized receptors in skin, joints, ear, eye, nose, and tongue. This information is analyzed in primary sensory areas before being integrated into an image of the state of the world. This image is used in cognitive processing resulting in motor action and a behavioral response to incoming sensory data. This chapter provides a guide to the parts of the nervous system, the structure of sensory systems, and describes how this information is used in more complex brain functions.

Keywords

Nervous system; brain; anatomical pathway; neuron; sensory system; cognitive function; motor action

Summary Points

• The nervous system is the most complex body system, comprising a very large number of interconnected neurons.

• In association with white matter fiber tracts, networks of neurons are organized into anatomical pathways which are involved in sensory, motor, and cognitive functions.

• The whole of the nervous system develops from a narrow strip of ectoderm cells located on the surface of the human embryo which extends from the head to the tail of the embryo.

• A large part of the brain is concerned with the reception and analysis of sensory data and in the control of subsequent motor responses.

• The parietal lobe of the brain integrates data from the different senses and provides an image of the state of the world.

• Data concerning the state of the world are used in more complex cognitive processing in the temporal lobe, resulting ultimately in motor action and a change in behavior.

Key Facts

• The general function of the hippocampus is to act as a comparator, memory and spatial function playing important roles as part of this overall system.

• The entorhinal cortex receives information from all sensory systems via the temporal lobe, the latter acting as a data storage region.

• This information is transmitted to the dentate gyrus via the perforant path and also to the subiculum.

• The information circulates around the hippocampal circuit and results in specific items being selected that are important to a particular task.

• The essential function of the system is to compare actual with predicted stimuli and behavior is only controlled under specific conditions.

• For a comparator to function effectively, it must have access to current sensory events (the state of the world) and also to expected events generated by a predictor. Once a prediction has been made, it has to be tested against the world.

• Once tested, the comparator results in four possible outcomes: (1) in a new environment, data are gathered to make subsequent predictions possible; (2) predicted and actual events continue to agree resulting in no change of behavior; (3) a mismatch is detected between actual and predicted events resulting in inhibition of current motor behavior and new data gathering; and (4) discrepancy between actual and predicted events is resolved and control passes back to other systems.

List of Abbreviations

A astrocyte

BBB blood–brain barrier

CA cornu ammonis

CB cerebellum

CC corpus callosum

CG cingulate gyrus

Cl claustrum

CN caudate nucleus

CSF cerebral spinal fluid

DG dentate gyrus

EC external capsule

EnC entorhinal cortex

FL frontal lobe

GCL granule cell layer

HC hippocampus

H/E hematoxylin and eosin

HP hypothalamus

IC internal capsule

ITG inferior temporal gyrus

LF lateral fissure

LGN lateral geniculate nucleus

LHE hematoxylin and eosin/luxol fast blue

Me medulla

Mg microglia

ML molecular layer

MTG middle temporal gyrus

N neuron

OC occipital cortex

OG oligodendrocyte

P pons

PC parietal cortex

PCG precentral gyrus

PHG parahippocampal gyrus

PoCG post central gyrus

PrC Purkinje cell

Put putamen

STG superior temporal gyrus

SUB subiculum

Th thalamus

WM white matter

1.1 Introduction

The nervous system is the most complex of the systems of the human body and comprises the brain, spinal cord, and the cranial and peripheral nerves. It is composed of gray matter comprising many billions of cells or neurons, each with the capability of communicating with a large number of other cells (Nauta & Feirtag, 1986). It is the pattern of connections between these neurons which determines brain function and, ultimately, the intellectual ability and even the personality of an individual. In association with white matter fiber tracts, networks of neurons are organized anatomically into pathways which are involved in sensory, motor, and cognitive function (Diamond, Scheibel, & Elson, 1985; Haines, 1987; Moyer, 1980). This chapter provides an introduction to the anatomy of the nervous system including the sensory systems involved in skin sense, proprioception (position sense), vision, hearing, smell, and taste and also describes how this information is used in cognitive processing resulting in motor action and a behavioral response (Gray & McNaughton, 2000).

1.2 Development of the Brain

The nervous system develops from a narrow strip of ectoderm cells extending the length of the embryo. During development, this strip of cells gradually sinks into the embryo to form the neural groove. As the neural groove sinks further, its upper edges meet and fuse together to form a neural tube. With the exception of the head region, this neural tube develops into the spinal cord. Hence, dorsal neural tube cells develop processes that extend to the periphery of the embryo and will have a sensory function while ventral neural tube cells extending toward the developing muscles have a motor function.

At the head of the embryo the neural tube swells to form three regions, namely the forebrain, midbrain, and hindbrain. Within the swollen portions, the cavity of the neural tube also expands to form larger ventricles which manufacture cerebral spinal fluid (CSF), a liquid which surrounds the brain providing protection against trauma. A pair of lateral swellings originate from the forebrain and develop into the cerebral hemispheres, the most dominant feature of the mature human brain. The neural tube also extends into these developing hemispheres to form the lateral ventricles. At the same time, the midbrain develops a series of small swellings on its dorsal surface which become the inferior and superior colliculi, regions important in hearing and vision, respectively, while the hindbrain differentiates into the pons, medulla, and cerebellum. In the human brain, the cerebral hemispheres continue their massive development. To accommodate the cerebral hemispheres within the limited space of the skull, they become bent forward so that in an individual standing upright, the original neural tube is vertical within the spinal cord but horizontal within the brain.

1.3 The Parts of the Brain

When the upper part of the skull is removed, the brain is seen to be protected by a thick, fibrous layer, the dura matter. Cutting open the dura matter exposes the two cerebral hemispheres with their characteristic folds (gyri) and fissures (sulci). Many important structures of the brain can be seen in two views of the cerebral hemispheres, namely the lateral and medial sagittal surfaces, the latter revealed by separating the two hemispheres and sectioning the midbrain and hindbrain.

1.3.1 The Lateral Surface

First, on the lateral surface (Fig. 1.1), anterior to the precentral gyrus (PCG), there is a large area of frontal lobe concerned with control of complex movement, emotion, and intellectual activity. Second, the PCG itself comprises the motor cortex, and together with supplementary motor areas in adjacent frontal lobe, is concerned with control of bodily movements. Third, behind the PCG is the post central gyrus (PoCG) or somatosensory cortex, which is the region where sensory information from all parts of the surface of the body is processed. Fourth, posterior to the PoCG and anterior to the occipital lobe is the parietal lobe, a region bounded by the primary sensory areas, namely, somatosensory cortex anteriorly, occipital cortex posteriorly, and auditory cortex ventrally, the latter located in the superior temporal gyrus (STG). The parietal lobe is in prime location to begin the integration of information from various senses into an image of the world. Fifth, posterior to the parietal cortex is the occipital lobe which is concerned with the analysis of visual data. Finally, beneath the lateral fissure is the temporal lobe, a complex area of brain involved with the analysis of sound and smell, and with learning, memory, and emotion.

Figure 1.1 The lateral surface of the brain.

The main anatomical features visible on the lateral surface of the brain. FL, frontal lobe; LF, lateral fissure; PL, parietal cortex; PCG, precentral gyrus; PoCG, post central gyrus; OL, occipital cortex; STG, superior temporal gyrus; TL, temporal lobe.

1.3.2 The Sagittal Surface

Many of the remaining anatomical features can be seen in a medial sagittal view of the brain (Fig. 1.2). First, the medial surface of the cerebral cortex is apparent, including a large portion of frontal and occipital lobes, as well as the cingulate gyrus (CG) and medial temporal lobe. Second, a notable feature is the corpus callosum, a large fiber bundle connecting both hemispheres. Third, in the center of the brain is the thalamus, an important relay station for data entering and leaving the brain; beneath which lies the hypothalamus, concerned with many functions including the control of hormonal processes of the body via the pituitary gland. Fourth, a second large fiber bundle, the pons, can be seen which facilitates communication between the cerebral cortex and cerebellum. Fifth, the cerebellum is important in the control of balance and fine movement. Finally, beneath the pons is the medulla, which is concerned with the control of vital functions such as the cardiac cycle and respiration.

Figure 1.2 The sagittal surface of the brain.

The main anatomical features visible on the medial sagittal surface of the brain. CB, cerebellum; CC, corpus callosum; CG, cingulate gyrus; HP, hypothalamus; Me, medulla; P, pons; Th, thalamus.

1.3.3 The Cranial Nerves

An important group of nerves originates from the brain, i.e., the 12 pairs of cranial nerves (Diamond et al., 1985). These nerves either have an exclusively sensory or motor function or have elements of both. The olfactory nerve (I) originates in short, fine fibers of the olfactory mucosae located in the upper part of the nose and transmits smell information to the brain. The optic nerve (II) comprises the axons of the ganglion cells of the retina which convey visual information to the brain. The oculomotor nerve (III) has its origin in the midbrain and together with the trochlear nerve (IV) enters the orbit to supply most of the eye muscles. The trigeminal nerve (V) has three roots, two of which are sensory and supply the face, nose, and mouth, while the remaining branch has a motor function and passes both to the muscles involved in chewing and to a muscle in the middle ear. The abducens nerve (VI) is a motor nerve supplying the one remaining eye muscle. The facial nerve (VII) is a complex nerve supplying the muscles of facial expression, the middle ear, two of the three pairs of salivary glands, the soft palate, and taste buds on the anterior two-thirds of the tongue. The vestibulocochlear nerve (VIII) has two functions: the cochlear division is responsible for hearing while the vestibular division is involved in the control of balance. The glossopharyngeal (IX) nerve supplies the taste buds of the remaining posterior part of the tongue, the parotid salivary gland, and muscles of the pharynx. The vagus (X) nerve has both sensory and motor functions and supplies the pharynx, larynx, and viscera of chest and abdomen. The accessory nerve (XI) has both spinal and cranial divisions supplying the neck muscles, the cranial division being accessory to the vagus nerve. Finally, the hypoglossal nerve (XII) supplies the muscles of the tongue.

1.4 Cells of the Nervous System

There are four main types of cell visible in routinely stained thin sections of brain tissue (Fig. 1.3) (Nauta & Feirtag, 1986). The larger cells, which have a distinct cell body when stained with hematoxylin and eosin (H/E) or a Nissl stain, are neurons. Most typically, they have a cell body with a centrally placed nucleus, a distinctive cytoplasm composed of cell membranes and ribosomes (Nissl substance), and a series of projections radiating from the cell body, which although not unique to neurons are particularly characteristic of them. The shorter branched dendrites receive signals from other neurons while electrical information is transmitted via a longer, thinner axon. Different types of neuron vary in size, number, and complexity of their dendritic systems and in the length of their axons. Hence, pyramidal cells have a collection of branched dendrites and a single axon, dorsal root cells a single axon but no dendrites, granule cells have branched dendrites and a short axon for transmitting information over short distances, and bipolar cells found largely in the retina have a single dendrite and axon. Purkinje cells (PrC) in the cerebellum hemisphere have the most complex dendritic systems of any neuron.

Figure 1.3 Cells of the nervous system.

The cells of the nervous system visible in a thin section stained with hematoxylin and eosin (H/E). A, astrocyte nucleus; N, neuron; OG, oligodendrocyte nucleus; Mg, microglial nucleus, Bar=10 μm.

The larger lighter-staining nuclei (Fig. 1.3) have an irregular cell body and numerous processes that radiate outward and are called astrocytes. These cells form a matrix in which neurons are embedded. In addition, superficial astrocytes send their processes to the surface of the brain where the aggregation of their end feet forms a glial capsule constituting the outer wall of the brain and spinal cord by fusing with the pia mater and forming the pial-glial membrane. Where blood vessels from the surface penetrate brain tissue, the pial-glial membrane also invaginates to follow the course of these vessels, thus constituting a component of the blood–brain barrier (BBB). The second type of glial cell, appearing as small darkly stained round nuclei, is the oligodendrocyte. Oligodendrocytes coat axons in brain and spinal cord with lipid and protein, essentially forming the myelin sheaths and thus facilitating nerve conduction along white matter fiber tracts. The third type of glial cell is the microglia, in which the nucleus is also dark but less regular in shape. Microglia may not originate within the central nervous system but arrive in association with the blood vessels during brain development.

1.5 Sensory Systems of the Brain

Although all parts of the brain are richly interconnected, neurons are collected together into regions which are then organized anatomically in sequence. Hence, each sensory system is associated with an anatomical pathway by which sensory data, initially sensed by special receptors, is conveyed to the brain and subsequently analyzed to provide a specific sense. Sensory systems have a number of features in common. First, there are one or more relays on route to the brain where preliminary processing of signals occurs before being conveyed to a specific area of cerebral cortex. Second, sensory information is transmitted in coded form appropriate to the stimulus and third, sensory information is enhanced on route and random noise reduced by a process of lateral inhibition, the brain receiving a sharper image of the world than exists in reality.

1.5.1 Somatosensory System (Skin Sense)

Sensations received at the surface of the body such as pressure, temperature change, touch, or pain are sensed by special receptors embedded in the skin (Carpenter, 1984). These impulses are transmitted from skin to the spinal cord by unipolar neurons whose cell bodies are clustered in groups in the dorsal root ganglia of the spinal cord. Hence, impulses from special encapsulated endings, such as the Pacinian corpuscle, travel in the spinal cord in two fiber bundles to the gracile and cuneate nuclei located in the medulla. These impulses then ascend via the medial lemniscus to a region of thalamus, before finally terminating in the PoCG. The surface of the body is mapped onto the somatosensory cortex, i.e., information from specific regions of the body is analyzed in particular regions of the PoCG.

1.5.2 Proprioception (Position Sense)

Proprioception is the sense the body has of the position of its various parts and is essential in carrying out complex movements. First, there are special receptors in and around the joints which inform the brain about the position of the limbs in space. Second, striated muscle, which directly controls movement, possesses muscle spindles which react to the degree of tension in the muscle, thus enabling the nervous system to calculate how much force is required to carry out a movement. Third, Golgi tendon organs react to the degree of tension of the tendons attached to muscles and joints. Finally, the position and movement of the head relative to the body is sensed by the semicircular canals of the inner ear. All of this information can then be integrated by the brain in the planning and execution of a specific movement.

1.5.3 Auditory System

Hearing depends on the coding of two aspects of a sound wave, namely, its frequency (pitch) and intensity (loudness). The cochlea of the inner ear, via specialized hair cells embedded within the organ of Corti, makes a frequency analysis of incoming sound waves, deconstructing them into sine waves of different frequency. The pathways by which this information is conveyed to the brain are complex with many relays including the cochlear nucleus, superior olive, inferior colliculus, and medial geniculate body, before arriving in the STG. The different frequency components which make up the sound wave travel in different fibers of the auditory system and are then reassembled in the cortex.

1.5.4 Visual System

The nerve fibers of the retina, which represent the axons of the ganglion cells, collect together at the optic disk and leave the eye as the optic nerve, subsequently passing into the brain through the orbital bones. The optic nerves from each eye meet at the optic chiasm, a structure at the base of the brain where nerve fibers originating from the nasal halves of the retina from each eye cross over. On leaving the optic chiasm, each optic tract contains fibers from the nasal retina of one eye and the temporal retina of the other eye. Optic tract fibers then relay in the lateral geniculate nucleus (LGN), a part of the thalamus. Lateral inhibition occurs in the LGN before a series of radiating nerve fibers, the optic radiation, convey the information to the visual cortex in the occipital lobe. Sight perception ultimately derives from processing within this and adjacent areas of brain.

1.5.5 Smell

Smell is perceived initially by specialized receptors in the upper part of the nose, namely the olfactory epithelium. This information is conveyed by the axons of the olfactory epithelium through the cribriform plate where they are processed initially in the olfactory bulb. Subsequently, this information is conveyed by the olfactory tract to the olfactory cortex located at the medial temporal pole. Hence, smell is the only sense which is not processed by the thalamus or a related nucleus before being sent to the cortex.

1.5.6 Taste

In contrast with the richness of smell, taste only has four modalities, namely salt, sour, bitter, and sweet, all of which are sensed by special receptors, namely, circumvallate and fusiform papillae, on the surface of the tongue. These sensations travel to the somatosensory cortex via the facial and glossopharyngeal cranial nerves.

1.6 More Complex Sensory Processing

Each type of sensory information is conveyed to a unique primary sensory area of cerebral cortex. The cerebral cortex comprises six layers or laminae. In the visual system, e.g., information arrives in the primary visual cortex VI from the LGN in lamina IV (Singer, 1979) and is then conveyed to laminae II and III and to a lesser extent lamina V. The output from area VI to association areas where more complex visual processing takes place is mainly via the large pyramidal neurons in laminae II/III which constitute the feedforward corticocortical projections (De Lacoste & White, 1993; Zeki, 1971). In addition, neurons in the lower cortex provide the output to subcortical visual areas, e.g., from lamina VI to the dorsal and ventral LGN and from lamina V to the superior colliculus and the pretectal area (Parnavelas & McDonald, 1983).

Ultimately, all types of sensory information are combined into an image of the state of the world, a process which begins in the parietal lobe. This conclusion is supported not only by studies of brain lesions in human patients (Luria, 1980) but also by brain imaging studies. Hence, a consequence of a tumor or hemorrhage affecting the parietal lobe is agnosia, i.e., a disorder of higher-level sensory analysis; characterized not by a failure in primary processing but in more complex sensory analysis. Hence, patients may be able to feel and see but have problems in identifying the sensory image they perceive as in tactile or visual agnosia, respectively. In addition, patients exhibit apraxia, i.e., clumsiness in the performance of specific physical tasks and an inability to produce a specific action on command. Finally, patients with parietal lobe lesions, especially if they are located at the junction of parietal and temporal lobes, can exhibit aphasia, most usually manifest as a defect in understanding speech or language (Wernicke’s aphasia).

1.7 Cognitive Processing

Information regarding the state of the world is transferred to many regions of the brain and used in more complex cognitive processing. In particular, the temporal lobe of the brain is involved in a variety of cognitive functions in humans (Brodal, 1981). Gyri adjacent to the STG, including the middle (MTG) and inferior temporal gyri (ITG), are involved in more complex auditory processing including that of speech and language. In addition, the left temporal lobe is involved in comprehension, naming of objects, and in verbal memory. The ventral surface of the temporal lobe, especially the parahippocampal gyrus (PHG), which includes the entorhinal cortex (EnC), is involved in more complex visual processing including facial recognition and analysis of the visual scene. Areas of medial temporal lobe are also involved in the processing of olfactory information and in memory including episodic/declarative memory. The hippocampus (HC) (Fig. 1.4) is a particularly important part of the temporal lobe and is involved in various cognitive systems including transfer of information from short- to long-term memory, spatial memory, and control of behavior (Gray & McNaughton, 2000; O’Keefe & Nadel, 1978).

Figure 1.4 Anatomy of the hippocampus.

A section of the human hippocampus (HC) stained with combination of H/E and luxol fast blue (LHE). CA1–4, sectors of cornu ammonis; DG, dentate gyrus; SUB, subiculum.

There are two main features of interest regarding the functional connections of the HC. First, it makes relatively few contacts with the rest of the brain. Second, it comprises several sectors termed cornu ammonis (CA) 1–4, which are connected in a circuit. Hence, projections from the EnC take the perforant path and terminate in the molecular layer of the dentate gyrus (DG). From the DG, mossy fibers travel to sectors CA3/4, while sector CA3 fibers have collaterals which travel to sector CA1. Sector CA1 axons connect with the subiculum representing the major output pathway of the HC via the fornix. In addition, there are direct projections from the EnC to sectors CA3 and CA1 and a return pathway from sector CA3 to the DG. Within this circuit, sector CA3 is an important nodal point at which many major projections converge.

The EnC and HC receive highly processed information from all of the senses (Stafekhina & Vingradova, 1975; Vinogradova & Bragin, 1975). Based largely on animal research, there have been three major theories concerning the functioning of the HC, namely, the behavioral inhibition theory, the memory theory, and the spatial theory. Although controversial, the behavioral inhibition theory is particularly well developed (Gray & McNaughton, 2000), which states that the HC may act as a comparator (Vinogradova, 2001). Hence, the HC compares current sensory events, obtained from the image of the world, with expected or predicted events generated by a comparator. If an expectation continues to be verified by information derived from the image of the world then no alteration of current behavior results. If, however, a discrepancy is detected, the HC intervenes by initiating appropriate action and directly controlling behavior by active inhibition of current motor activity and initiation of new data gathering.

1.8 Motor Systems

The result of data processing by the HC and adjacent regions is a motor response and, ultimately, a change in behavior. It is the ventral horn cells of the spinal cord which directly connect to the muscles and initiate their movement. Nevertheless, a number of anatomical regions exert a controlling influence on the spinal cord, the most important of which are the cerebellum, basal ganglia, and cerebral cortex.

The cerebellum is a highly folded structure at the base of the brain and is composed of two hemispheres and a central region termed the vermis. In section, the cerebellum is made up of folia lined by PrC (Fig. 1.5). The anatomical connections of the cerebellum have been extensively studied because of their relative simplicity. Hence, each PrC is influenced by two different inputs: (1) the climbing fibers which have their origin in the cortex and which climb up and around the PrC and (2) the mossy fibers which again originate in the cortex and which carry sensory data into the cerebellum. The mossy fibers synapse onto the granule cells and then send parallel fibers across the PrC dendrites. In patients with lesions of the cerebellum, coordination between sensory and motor data is poor, resulting in frequent missing of a target, tremor, and speech problems.

Figure 1.5 Anatomy of the cerebellum.

A section of a folia of the cerebellar hemisphere stained with combination of H/E and luxol fast blue (LHE). GCL, granule cell layer; ML, molecular layer; PrC, Purkinje cell layer; WM, white matter.

One of the most important areas of brain involved in the control of motor activity is the basal ganglia located at the base of the forebrain (Fig. 1.6) (Brodal, 1981). The basal ganglia are connected to many other areas of brain including the cerebral cortex, thalamus, and cerebellum and comprise several regions, most notably the caudate nucleus and putamen, which together constitute the striatum, plus the globus pallidus, substantia nigra, nucleus accumbens, and subthalamic nucleus. The substantia nigra is located in the midbrain and divided into two parts, namely the substantia nigra reticulata (SNr) and substantia nigra compacta (SNc). The SNr in combination with the globus pallidus act to inhibit the thalamus. By contrast, the SNc provides the major dopamine projection to the striatum (striatonigral pathway) and regulates the activity of the striatum.

Figure 1.6 Motor pathways of the brain.

The basal ganglia in coronal section stained with combination of H/E and luxol fast blue (LHE). Cl, claustrum; CN, head of caudate nucleus; EC, external capsule; IC, internal capsule; Put, putamen.

Ultimate control over movement is via the cerebral cortex and especially the PCG and the premotor cortex. In these regions, movement of different parts of the body is controlled by distinct areas of cortex. The surface area of PCG allocated to each movement reflects the importance of the movement, e.g., fingers and mouth have a larger representation corresponding to the complexity of the movements they perform.

The movement of any muscle is under the control of both excitatory and inhibitory influences and hence, there are two anatomical systems which control movement. First, the direct pathway, in which the cerebral cortex projects an excitatory input to the striatum, which in turn provides an inhibitory input to the SNr and globus pallidus and, ultimately, a net reduction of the inhibitory effect of the thalamus. Finally, the thalamus projects an excitatory effect to the cerebral cortex, especially the motor cortex, resulting in an overall stimulatory effect. This effect is then transmitted to the brain stem, lateral corticospinal tract, and ultimately to the muscles of the body. Second, is the indirect pathway, the effect of which is to decrease the degree of stimulation of the motor cortex resulting in reduced muscle activity.

1.9 Higher Brain Functions

It is common human experience that the human brain is capable of more complex functions than sensory analysis and a motor response. First, although motor action may be essentially determined by sensory data, it is whether a particular sensory stimulus is perceived as desirable or undesirable which is also important. Hence, there is a brain system which identifies the needs of the body, namely, the hypothalamus and a cognitive system which has a map of the environment where such needs may be satisfied, namely, the HC. Second, directed behavior manifested as motor action is controlled and influenced by human emotion and generation of an emotion by a need may be important in fulfilling that need. Hence, there are two basic emotional responses: (1) arousal, which results in movement either toward a desirable goal or away from a threat and (2) conservation, i.e., a state of inactivity which results if every possible action is perceived as unpleasant, and which may result in a depressed emotional state. Third, there is the question of the role of conscious awareness in brain processing. This remains one of the most complex and elusive questions confronting neuroscientists as it is not clear what kind of state consciousness is, why the human brain is an organ with a sense of itself, or which brain systems are responsible.

Mini-Dictionary of Terms

• Gray matter. Regions of nervous system which contain the majority of neurons.

• White matter. Regions of nervous system which contain the fiber tracts.

• Neural tube. A structure derived from surface ectoderm during development and which gives rise to the nervous system.

• Ventricle. A chamber within the brain that secretes cerebral spinal fluid.

• Dura matter. The thick fibrous coat which protects the brain in the skull.

• Lateral inhibition. Process by which sensory data are enhanced and noise reduced before analysis in the cerebral cortex.

• Muscle spindle. Striated muscle sense organ which detects the degree of tension in the muscle.

• Agnosia. A disorder of complex sensory analysis.

• Apraxia. Clumsiness in the execution of a movement or difficulty in carrying out an action on demand.

• Agnosia. A defect of speech or language, often the result of a lesion in the posterior parietal lobe.

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Chapter 2

Sex Differences in the Effects and Actions of Cocaine

H.N. Kerver and J.B. Becker,    University of Michigan, Ann Arbor, MI, United States

Abstract

The use of cocaine among women has steadily increased in the last decade, despite overall cocaine use decreasing. Women progress through the landmark stages from initial use to dependence at a faster rate than men do. Females escalate more rapidly to addiction, have greater motivation to obtain and/or use drugs of abuse, and have a greater risk of relapsing following abstinence. Importantly, rats exhibit the same sex differences, demonstrating that fundamental biological processes contribute to sex differences in cocaine addiction. This chapter will attempt to parse out the underlying sex differences in the mechanisms mediating the behavioral effects of cocaine, the role that estradiol plays in the molecular, systemic, and behavioral effects of cocaine, and how this impacts addiction.

Keywords

Sex difference; estradiol; dopamine; addiction; nucleus accumbens; dorsolateral striatum; dorsomedial striatum; motivation

Summary Points

• Females progress through the landmark stages of addiction more rapidly than males.

• Despite males having more D1 DA receptors and higher basal levels of extracellular DA in the striatum, females have greater electrically stimulated release of DA following cocaine exposure.

• Estradiol is capable of altering cocaine-induced DA changes within this reward circuit, along with increasing behavioral sensitization.

• Estradiol enhances cocaine-induced increase in DA in females, but not males.

• It is proposed that females acquire cocaine taking more rapidly and self-administer more cocaine because there is less of an increase in DA in the nucleus accumbens relative to the dorsolateral striatum.

Key Facts

• Sexual differentiation begins before birth and helps shape the brain and behavior into adulthood.

• Sex differences persist in activity or number of DA transporters (DAT), DA release, DA receptor numbers, as well as long-term consequences of cocaine exposure.

• Estradiol affects aspects of the dopaminergic reward system differentially in males and females.

List of Abbreviations

CAST castrated

DA dopamine

DAT dopamine transporter

DLS dorsolateral striatum

DMS dorsomedial striatum

NAc nucleus accumbens

OVX ovariectomized

2.1 Introduction

In an effort to increase the study of both sexes in preclinical research, the US National Institutes of Health (NIH) recently instituted a policy to ensure that research investigators include sex as a biological factor in research funded by the NIH (Consideration of Sex as Biological Variable in NIH Funded Research; NOT-OD-15-102). This means that more investigators are beginning to investigate both females and males in basic pharmacological research. Here we discuss research on sex differences in the acute and chronic responses to cocaine and how this impacts addiction vulnerability.

Sex differences begin during embryogenesis. Sexual differentiation in mammals begins with the genetic sex of an individual that determines whether the bipotential gonads become testes or ovaries. Subsequently, the presence of testicular hormones during development masculinizes the brain. The absence of hormones feminizes the brain during the early period of sexual differentiation. During puberty both testicular and ovarian hormones actively drive development of further sex differences in the brain (Sisk & Zehr, 2005). In adults there are also activational effects of hormones that can result in additional sex differences (McCarthy, 2008). Thus, the presence of genetic, hormonal, and even epigenetic factors all contribute to sex differences in the brain and behavior (McCarthy & Arnold, 2011).

The importance of including both sexes in preclinical studies, as well as studying sex differences that emerge from this research, is emphasized by the prevalence of sex differences in many disease states. From heart disease to neurodegenerative disorders, men and women differ in their susceptibility to illness. Addiction is no exception. Sex differences are seen in almost all facets of use in drugs of abuse. These differences can be attributed to the sex differences in the brain that arise during sexual differentiation as well as the influence of ovarian hormones on the brain regions that mediate reward processing and addiction (Perry, Westenbroek, & Becker, 2013a). Here we will focus on the sex differences seen in addiction, with a specific emphasis on how sex differences in the response to cocaine impact the addiction liability for this drug differently in females and males.

2.2 Dopamine Signaling

2.2.1 Sex Differences in Dopamine Signaling

Cocaine acts by blocking dopamine (DA) reuptake into the presynaptic terminal. Therefore, sex differences in the effects of cocaine could be produced by sex differences in one or more processes, including the activity or number of DA transporters (DAT), sex differences in DA release, sex differences in DA receptors, and/or sex differences in the long-term consequences of cocaine exposure. Sex differences in the organization of the DA projections and/or terminal area may also contribute. Evidence for sex differences in each of these processes will be discussed below.

Males have been shown to have 10% more striatal D1 DA receptors than females, but no sex differences are reported in the density of D2 DA receptors in the adults (Andersen, Rutstein, Benzo, Hostetter, & Teicher, 1997; Hruska, Ludmer, Pitman, De Ryck, & Silbergeld, 1982; Miller, 1983). These studies were done examining DA receptor binding, and did not examine regional variation in D1 or D2 DA receptor localization between the sexes. Basal levels of extracellular DA are also sexually dimorphic in the striatum, with males having higher extracellular DA concentrations than females (Castner, Xiao, & Becker, 1993; Xiao & Becker, 1994).

Studies using fast-scan cyclic voltammetry in the striatum indicate that there is greater electrically stimulated release of DA following cocaine exposure in intact female rats than intact males, and suggest that DA neurotransmission in the female rat is more tightly regulated by the DAT and autoreceptor mechanisms than in males (Walker, Ray, & Kuhn, 2006) (see Fig. 2.1). The greater DAT regulation of DA in females may explain why we find that cocaine-induced increases in DA in dialysate are lower in the striatum from ovariectomized (OVX) females, compared with castrated (CAST) male rats (Fig. 2.2).

Figure 2.1 Sex differences in cocaine-induced DA in the rat striatum in vivo.

Fast cyclic voltammetry was used for recordings before and after cocaine administration (40 mg/kg) in the rat striatum. There is greater electrically stimulated DA release in the rat striatum following cocaine administration, and the DA release is greater in females than males. Open symbols represent baseline data and filled symbols represent data following cocaine administration. Circles and squares represent females and males, respectively. At 50 and 60 Hz frequencies females were significantly greater than males (*p<0.05). Reproduced from Walker, Q. D., Ray, R., & Kuhn, C. M. (2006). Sex differences in neurochemical effects of dopaminergic drugs in rat striatum. Neuropsychopharmacology, 31, 1193–1202 with permission.

Figure 2.2 Estradiol has region- and sex-specific effects on cocaine-induced increases in DA.

Estradiol enhances cocaine-induced DA within the dorsolateral striatum (DLS) of ovariectomized female rats (A; # denotes p<0.05), but not in the DLS of castrated male rats (B). This increase in DA in estradiol-treated females in the DLS is significantly greater than the increase in DA in the nucleus accumbens (NAc) (C; a denotes p<0.05). Cocaine-induced DA is also significantly higher in the NAc of males (D) than in females (C), regardless of treatment (*p<0.05). The arrows represent the time point of cocaine administration (10 mg/kg, i.p.). Estradiol benzoate treatment was 5 μg in 0.1 mL oil, given subcutaneously prior to the first collection time point. Reproduced from Cummings, J. A., Jagannathan, L., Jackson, L. R., and Becker, J. B. (2014). Sex differences in the effects of estradiol in the nucleus accumbens and striatum on the response to cocaine: neurochemistry and behavior. Drug and Alcohol Dependence, 135, 22–28 with permission.

2.2.2 Estradiol’s Effects on Dopamine Signaling

Extracellular DA concentrations in the striatum vary with the estrous cycle in females (Xiao & Becker, 1994). Estradiol enhances psychostimulant-induced increases in DA from the striatum of females, but not males (Castner et al., 1993; Cummings, Jagannathan, Jackson, & Becker, 2014). Estradiol treatment enhances stimulated striatal DA release and striatal DA levels are higher in gonadally intact females compared to OVX female rats (Becker & Beer, 1986; Castner et al., 1993; Cummings et al., 2014). Thus, while basal DA concentrations are lower in females, compared with males, the concentrations of DA in striatum after cocaine or amphetamine are not different or are even greater, making the relative increase enhanced for females (Becker & Hu, 2008).

Estradiol’s ability to enhance the cocaine-induced increase in DA is thought to occur through activation of membrane estradiol receptors on medium spiny neurons in the striatum (Mermelstein, Becker, & Surmeier, 1996), which reduces GABA release (Hu, Watson, Kennedy, & Becker, 2006; Schultz et al., 2009), and thereby disinhibits dopaminergic neuron terminals to increase striatal DA release following stimulation (Becker, 1999; Hu & Becker, 2008). Following amphetamine administration, female rats in the proestrus stage of their estrous cycle, when estradiol is elevated, have a greater percentage of neurons that express the immediate early gene, fos, in the striatum compared to females in diestrus or OVX females (with lower or no circulating estradiol); CAST males and intact males also had lower fos expression than proestrous females (Castner & Becker, 1996).

When OVX female rats are given estradiol, cocaine-induced DA is enhanced within the dorsolateral (DLS) striatum. This effect is not mirrored in CAST males (Cummings et al., 2014) (Fig. 2.2). There is a significantly lower cocaine-induced increase in DA from the nucleus accumbens (NAc) of OVX females compared to CAST males with or without estradiol treatment (Cummings et al., 2014) (Fig. 2.2), and this sex difference in DA response has also been reported for amphetamine in the NAc (Gillies, Virdee, McArthur, & Dalley, 2014; Virdee et al., 2014) and nicotine in the ventral striatum of humans (Cosgrove et al., 2014). Estradiol has no effect on DA in dialysate from the NAc in either sex, although males have higher baseline levels of DA in both the DLS and NAc than females (Cummings et al., 2014).

Estradiol also regulates DA receptor binding in females, but not males. For example, estradiol rapidly downregulates D2 binding in OVX females, with no effect on males (Bazzett & Becker, 1994). In contrast to the effects of acute estradiol, chronic estradiol treatment is capable of increasing D2 binding sites in the striatum and NAc core, in both males and females (Hruska & Silbergeld, 1980; Hruska, 1986; Lévesque & Di Paolo, 1989). Thus, estradiol can affect DA signaling within discrete brain regions involved in reward and addiction, and has opposite effects depending on whether estradiol treatment is acute or chronic.

2.3 Behavioral Effects of Cocaine

2.3.1 Sex Differences in the Behavioral Response to Cocaine

Acute administration of cocaine produces increases in motor behaviors such as horizontal and vertical activity and stereotyped behaviors in both males and females, but the effect is greater in females than males (Walker et al., 2001). Acute administration of amphetamine also produces greater rotational behavior in female rats than males (Becker, Robinson, & Lorenz, 1982). These greater behavioral responses in intact females are likely due to the greater relative increase in DA for females, compared with males, as discussed above.

Chronic psychomotor stimulant administration produces an enhanced behavioral response to the same dose of the drug, a phenomenon known as behavioral sensitization (Robinson & Becker, 1986). Female rats show greater behavioral sensitization to cocaine than do males (Cummings et al., 2014; Hu & Becker, 2003). In other studies increases in cocaine-induced locomotor activity with repeated treatment were seen only in female rats (Van Haaren & Meyer, 1991). Female rats also show a more robust and prolonged behavioral response to both acute and binge patterns of cocaine administration than males (Festa et al., 2003).

2.3.2 Estradiol’s Effects on Behavior

Multiple studies have identified effects of estradiol on the DA system that may contribute to the increased rewarding effects of drugs of abuse in females. The behavioral response to both cocaine and amphetamine is amplified by estradiol, as indicated by greater stereotypy, locomotion, and rotational behavior following treatment with estradiol (Becker, 1999; Becker & Cha, 1989; Becker, Molenda, & Hummer, 2001; Becker et al., 1982; Camp, Becker, & Robinson, 1986; Jackson, Robinson, & Becker, 2006; Robinson, Camp, Jacknow, & Becker, 1982).

Estradiol is capable of altering cocaine-induced DA changes within this reward circuit, along with increasing behavioral sensitization. Pulsatile estradiol treatment enhances sensitization of cocaine-induced rotational behavior, as OVX female rats given estradiol benzoate had significantly greater sensitization of rotational behavior with a faster rate of sensitization than did OVX females, CAST males, or intact males (Hu & Becker, 2003). In other studies estradiol has been shown to enhance stereotypy or rotational behavior induced by amphetamine or cocaine in females, but not males, as well as spontaneous motor performance (Becker & Cha, 1989; Becker & Rudick, 1999; Becker, Snyder, Miller, Westgate, & Jenuwine, 1987, 2001; Castner et al., 1993; Cummings et al., 2014; Schultz et al., 2009). Thus, estradiol has dramatic effects on behaviors mediated by the striatum of female rats. The fact that estradiol does not act the same way in males demonstrates that there are sex differences in the reward system in terms of sensitivity to estradiol, it is not solely that females synthesize more estradiol. Understanding the role that hormones play in the motivation for drugs of abuse will give us better insight into the underlying mechanisms of addiction.

2.4 Motivational Aspects of Cocaine Use

2.4.1 Sex Differences in Motivation: Choice Paradigm

Women progress through the landmark stages of initial drug use to dependence and addiction at a faster rate than men (Bobzean, DeNobrega, & Perrotti, 2014; Perry, Westenbroek, & Becker, 2013b; Van Etten, Neumark, & Anthony, 1999). Numerous preclinical studies show that female rats acquire drug taking more rapidly than male rats, they progress to an addicted phenotype of behavior more rapidly than males, and they are more highly motivated to take cocaine than males (Carroll & Anker, 2010; Cummings et al., 2011; Hu & Becker, 2008; Hu, Crombag, Robinson, & Becker, 2004; Larson, Anker, Gliddon, Fons, & Carroll, 2007; Lynch, 2006; Lynch & Taylor, 2004; Lynch, Roth, Mickelberg, & Carroll, 2001; Perry, Anderson, Nelson, & Carroll, 2007; Perry et al., 2013b). Female rats are also more willing to work to increase their cocaine intake at the expense of other reinforcers. In a novel choice self-administration paradigm (Perry, Westenbroek, Jagannathan, & Becker, 2015a; Perry et al., 2013b), rats were given the choice between cocaine and a sucrose food reward. Initially all animals preferred the pellets, but over a period of 2–7 weeks some rats came to prefer cocaine (Fig. 2.3). This paradigm encompasses several aspects of the clinical criteria for drug abuse/dependence as outlined by the DSM-IV, and cocaine-preferring rats represent an addicted phenotype, consistent with a loss of interest for nondrug rewards, increased motivation for cocaine, and also an increased relapse potential. After 7 weeks of drug taking, over 50% of females preferred cocaine to the tasty pellets, while only 16% of males preferred cocaine (see Fig. 2.3). Additionally, female rats showed this preference for cocaine sooner than the males (Perry et al., 2013b). These findings suggest widespread sex differences in motivation for drug reward.

Figure 2.3 Sex difference in the development of a preference for cocaine.

(A) Females (filled circles) tested in the choice paradigm (Perry et al., 2013b) had significantly more cocaine-preferring rats (50%) between the second and last fixed ratio five tests (*p<0.05), and there were significantly more cocaine-preferring females than males (open circles, 16%) by the end of testing ($p<0.05). (B) Representation of the self-administration pattern of a pellet-preferring animal over 21 days of fixed ratio testing. (C) Representative self-administration behavior in a cocaine-preferring rat, where preference shifted from pellets to cocaine at day 11. Modified from Perry, A. N., Westenbroek, C., and Becker, J. B. (2013b). The development of a preference for cocaine over food identifies individual rats with addiction-like behaviors. PLoS One, 8, e79465.

2.4.2 Estradiol’s Effects on Motivation

Exogenous estradiol treatment alone in OVX rats is sufficient to facilitate acquisition of cocaine self-administration, and this acquisition is reduced following ovariectomy (Hu et al., 2004; Lynch et al., 2001). Castration of male rats produces no effect on acquisition of cocaine self-administration behavior, and exogenous estradiol given to CAST males also has no effect (Jackson et al., 2006).

There are sex differences in motivation to receive an injection of cocaine, when motivation is assessed on a progressive ratio schedule with females exhibiting greater motivation than males (Cummings et al., 2011; Roberts, Bennett, & Vickers, 1989; Westenbroek, Perry, & Becker, 2013). Estradiol also enhances the motivation for cocaine as indicated by how hard a female rat will work for cocaine (Becker & Hu, 2008; Roberts et al., 1989) (Fig. 2.4). Female rats will also choose higher doses of cocaine in estrus compared with female rats in other stages of the estrous cycle or males (Lynch, 2006; Lynch, Arizzi, & Carroll, 2000).

Figure 2.4 Estradiol benzoate increases motivation to obtain cocaine in OVX female rats.

Female rats were trained on a fixed ratio 1 and then 2 schedule of reinforcement with 0.4 mg/kg cocaine infusions. They were then transferred to a 4-h progressive ratio schedule, with a treatment of either vehicle or 5 μg estradiol benzoate (EB) 30 min prior to testing for the first 5 days and then no treatment for 2 days. The first week of progressive ratio testing animals were given cocaine doses of 0.3 mg/kg, followed by 0.4 mg/kg the second week, and 0.5 mg/kg the third week. EB had no effect on the mean number of responses at the 0.3 mg/kg infusion dose, but in the second and third weeks, the females that received EB had significantly more responses for the 0.4 and 0.5 mg/kg infusions of cocaine than animals that received the oil vehicle. Reproduced from Becker, J. B., and Hu, M. (2008). Sex differences in drug abuse. Frontiers in Neuroendocrinology, 29, 36–47 with permission.

One way to assess the relative possibility of relapse in an animal model is to look at responding for cocaine after the drug-taking behavior has been extinguished. Female rats in estrus are more likely to exhibit reinstatement when given a low dose of cocaine than males or females in another stage of the cycle (Kippin et al., 2005). In women, the subjective effects of stimulants are also affected by ovarian hormones, and differ across the menstrual cycle in women, with increases in estradiol potentiating the positive subjective effects (Evans, 2007; Justice & de Wit, 1999, 2000).

2.5 Mechanisms of Addiction

Variability regarding individual differences in sensitivity to addictive drugs is mediated by the dopaminergic reward system across species (Belin & Everitt, 2008; Nader et al., 2006; Volkow et al., 1999). Sex differences exist in humans in the relative size of the various brain regions and connections involved in the reinforcing effects of cocaine (Ingalhalikar et al., 2014).

The NAc and dorsomedial striatum (DMS) are sites of action in the dopaminergic reward system that are important for the acquisition of drug taking, and the DLS is involved in escalated drug taking (Belin-Rauscent, Everitt, & Belin, 2012; Willuhn, Burgeno, Everitt, & Phillips, 2012). Recent work suggests a hierarchy of DA action, such that DA signaling is enhanced in the DLS during the progression to enhanced drug taking (Willuhn et al., 2012) (Fig. 2.5). Neural control is thought to shift from the NAc and DMS during acquisition, to the DLS as avid drug seeking and addiction progresses (Murray, Belin, & Everitt, 2012; Willuhn et al., 2012). We recently proposed that females acquire cocaine taking more rapidly and self-administer more cocaine because there is less of an increase in DA in the NAc relative to the DLS, compared with males (Perry, Westenbroek, & Becker, 2015b). Thus, more cocaine is necessary initially to achieve comparable increases in DA in the NAc. Additionally, the transition to compulsive drug taking in females is proposed to be facilitated by enhanced DA transmission in the DLS relative to the NAc and estradiol exacerbates these effects in females.

Figure 2.5 Drug cue-induced phasic dopamine release in the ventromedial striatum (VMS) and dorsolateral striatum (DLS).

Fast-scan cyclic voltammetry was utilized to characterize DA transmission across 3 weeks of cocaine self-administration using 0.5 mg/kg infusions of cocaine. (A) DA signals in the VMS decreased in amplitude over the course of 3 weeks, while DA signaling in the DLS (B) increased in amplitude in the second and third weeks of testing. *p<0.05, ***p<0.001. Modified from Willuhn, I., Burgeno, L. M., Everitt, B. J., and Phillips, P. E. (2012). Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use. Proceedings of the National Academy of Sciences of the United States of America, 109, 20703–20708 with permission.

2.6 Sex Differences in Cocaine Use in Humans

Among individuals that use cocaine, only around 16–17% actually develop dependence to the drug (Brady & Randall, 1999). There are different behavioral traits among men and women that are associated with the risk for transitioning from recreational use to compulsive drug taking. Men display more impulsivity and risk-taking behaviors and women show more anxiety and depressive-like behaviors prior to the onset of addiction. Men are more likely to begin using drugs for recreation due to impulsivity, while women are more likely to self-medicate for anxiety and depression (Becker & Hu, 2008; Becker, Perry, & Westenbroek, 2012). Women in residential treatment programs are reported to have higher current use and have greater lifetime use of cocaine than their male counterparts even when they have used for shorter periods of time (Lejuez, Bornovalova, Reynolds, Daughters, & Curtin, 2007).

The use of cocaine among women has steadily increased in the last decade, despite overall cocaine use decreasing, according to the National Survey on Drug Use and Health (Substance Abuse & Mental Health Services Administration, 2013). Of chronic cocaine users, women account for 56% of users between ages 12 and 17, 42% of users between 18 and 25, and among those users 26 years and older, 38% are women (Johnston, O’Malley, Bachman, & Schulenberg, 2005; Johnston, O’Malley, Bachman & Schulenberg, 2008). Women begin initial cocaine use at earlier ages than men, and have more severe cocaine use problems than men (Griffin, Weiss, Mirin, & Lange, 1989; Kosten, Gawin, Kosten, & Rounsaville, 1993). Women progress through the landmark phases of drug addiction more rapidly than men, and they have poorer prognosis for addiction recovery, as they escalate drug use more rapidly following relapse (Carroll, Lynch, Roth, Morgan, & Cosgrove, 2004; Paliwal, Hyman, & Sinha, 2008).

While social and cultural factors may contribute, they cannot be the sole explanation for this marked sex difference in addiction-like behavior, as the same findings are mirrored in the rat population, as we have discussed above. There are clearly fundamental biological processes that contribute to sex differences seen in cocaine abuse.

2.7 Summary

There are sex differences in the behavioral and neurochemical effects of cocaine, and these effects are modulated by estradiol. The ability of estradiol to act on the DA system may contribute to the behavioral activation by, as well as the rewarding effects of, cocaine in females. Estradiol’s action may also facilitate the shift in neural control from NAc and DMS to the DLS as addiction develops and progresses, resulting in a more rapid progression to addiction in females. The striking sex differences in the behavioral aspects of addiction and the associated neurobiological correlates suggest specific targets to decrease addiction or enhance rehabilitation for the future. The importance of individualized care and medicine is highlighted, as well as the need for studying both sexes in all research paradigms.

Mini-Dictionary of Terms

• Estradiol. The primary product of the ovaries; also a metabolite of testosterone (one of a class of hormones referred to as estrogens).

• Ovariectomy. Removal of the ovaries, therefore removing naturally circulating estradiol.

• Castration. Removal of the testes, thereby reducing circulating