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Cocaine and the Changing Brain


Nancy S. Pilotte, Ph.D.
National Institute on Drug Abuse
National Institutes of Health
Rockville, MD

Recent research coupling the neurobiology of reward with the neurochemical sequelae of repeated cocaine administration indicates that adaptations within the dopamine system occur but do not alone underlie the enduring aspects of drug abuse. This symposium was organized to document these changes and had three objectives. The first was to summarize the neural remodeling (anatomical or neurochemical) that occurs within the mesolimbic dopamine system, after repeated exposure to and withdrawal from cocaine, and to link these neuroadaptations to their functional consequences. As the modification of one system often leads to compensatory changes in other systems, the second objective was to identify and describe the functional changes that occur in nondopaminergic neurons at various times after the cessation of cocaine administration. The third goal of this symposium was to aid in identifying enduring changes in one or more brain systems, to suggest possible neurochemical targets for developing therapeutic interventions for the medical treatment of drug abuse.

The presentations encompassed the macroscopic visions and the microscopic details of the brain after cocaine use. Data were presented detailing where cocaine itself bound in the human and the nonhuman primate brains. In addition to the expected labeling of dopamine transporter sites in areas rich in dopamine terminals, there was appreciable binding in the orbitofrontal cortex, the hippocampus, the amygdala, and the thalamus. Within these areas, the cocaine binding was not entirely displaced when various monoaminergic transport inhibitors were used as competitors.

Using imaging techniques to help define functional changes that occur subsequent to repeated drug use and withdrawal, data were presented that pointed to a profound dopamine D2 receptor deficiency in the mesostriatal dopaminergic neurons. This deficiency was accompanied by marked reductions in glucose utilization in the orbitofrontal cortex, an area sparse in dopaminergic innervation, where cocaine is thought to bind to nondopaminergic targets. Neurons from the prefrontal cortex project to striatal targets, where they may serve as cognitive pattern generators in a manner analogous to the well-known functions of the motor pattern generators of the brainstem. In this role, cortical inputs may evaluate the cognitive aspects of stimulation, including the environmental context, reinforcement, and learning, and may eventually activate or even downregulate other brain circuits that work in concert with the ventral striatum to produce behavioral activation. An acute cocaine challenge given to animals after a period of repeated cocaine treatment plus an intervening withdrawal period produces patterns of neural activation (marked by induction of immediate early gene expression) that are different from those observed after acute administration, representing yet another example of cocaine-induced neuroplasticity.

Repeated administration of cocaine has functional consequences on both dopaminergic and nondopaminergic neurons that persist after the exposures are terminated. For example, dopamine is removed from the extracellular space by uptake processes more slowly in the nucleus accumbens than in the dorsal striatum because there are fewer transporters in the accumbens than in the striatum. In behaviorally sensitized animals, uptake of dopamine by the dopamine transporter in the nucleus accumbens is even more inefficient, and a challenge injection of cocaine results in supranormal concentrations of dopamine in the synaptic space of brain areas known to be critical in mediating the reinforcing properties of drugs of abuse. This neurochemical sensitization accompanies the behavioral sensitization.

Other data suggest that the rate of uptake may be regulated by changes in the membrane potential, and depolarization decreases the rate of uptake by the dopamine transporter. Furthermore, repeated exposure to cocaine can alter the mechanisms underlying transmitter release in response to a depolarizing agent and decreases the efficiency of sodium and calcium channels in the plasma membrane. Acutely, the cocaine-induced inhibition of monoamine uptake increases synaptic transmission and blocks the inhibitory function of serotonergic autoreceptors by prolonging the residence time of the neurotransmitter in the synaptic space. At the same time, heterosynaptic modulation (by serotonin and dopamine) of transmitters such as GABA is also enhanced. Intermittent exposures to cocaine ultimately enhance the dopamine-D1 stimulation of cAMP. One of the metabolic products of cAMP is adenosine, which has transmitter activities of its own and decreases GABA release. It seems, then, that chronic cocaine use can alter the dynamic balance between different neurotransmitter systems and can lead to enduring changes in neural control. This observation is also noticed at the systems level, where withdrawal from cocaine can alter basal neural tone such that basal extracellular dopamine and serotonin concentrations fall below the limits of detection over a long period of time.

The final area of research discussed by the participants of this symposium is that of peptides and genes regulated by cocaine. One of these, corticotropin-releasing factor or CRF, is the well-known mediator of the "stress response," by which hypothalamic CRF induces the release of ACTH from the anterior pituitary gland, which in turn elicits the output of glucocorticoids from the adrenal gland (to dampen the initiating stimulation by CRF). This peptide is also found in brain regions that have not been directly linked with the peripheral stress response, such as the locus coeruleus, and nuclei within the amygdala. Acutely, the injection of cocaine increases the extracellular concentration of CRF in the central nucleus of the amygdala; cocaine withdrawal similarly activates neurons within this region. Another family of peptides, the cocaine- and amphetamine-regulated transcription factors or CART, is found in brain regions that are implicated in the rewarding properties of drugs of abuse, as well as in centers that control other behaviors associated with satiety. Finally, cocaine administration directly induces the expression of a gene, the NAC-1, within the nucleus accumbens; animals in which antisense has been used to knock out this gene do not develop behavioral sensitization to cocaine.

The variety of targets identified through these presentations are at once encouraging and daunting. They clearly point out that cocaine produces enduring neural adaptations, not only in dopaminergic systems but also in nondopaminergic systems. The recognition of the potential interactions between these systems (and those that surely exist but have not yet been identified) suggests that neuroadaptations occur at many different levels. Each level is a potential target for the development of medical interventions, with the possibilities of preventing further use and abuse and reversing adaptations induced by cocaine. An appreciation of the intricacies and interrelationships among these factors is crucial for each of us who works in this field.

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