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October 1, 1997

Nancy S. Pilotte, Ph.D.
NIDA/Division of Basic Research and Medications Development Division, 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 them 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 non-dopaminergic 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 so as to suggest possible neurochemical targets for the development of therapeutic interventions for the medical treatment of drug abuse.

The presentations encompassed the macroscopic visions and the microscopic details of the brain after cocaine. Data were presented detailing where cocaine itself bound in the human and the non-human 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 binding of the cocaine was not entirely displaced when a variety of 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 was accompanied by marked reductions in glucose utilization in the orbitofrontal cortex, an area sparse in dopaminergic innervation, and where cocaine is thought to bind to non-dopaminergic targets. Neurons from the prefrontal cortex project to striatal targets, where they may act 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 reinforcement, learning, and eventually activate or even down-regulate 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 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, and represents yet another example of cocaine-induced neuroplasticity.

The repeated administration of cocaine has functional consequences on both dopaminergic and non-dopaminergic neurons that persist even when the intermittent exposures are terminated. For example, dopamine is cleared 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. However, uptake of dopamine by the dopamine transporter in the nucleus accumbens is even more inefficient in animals subjected to daily repeated injections of cocaine, and results in supranormal concentrations of dopamine in the synaptic space of brain areas known to be critical mediators of the reinforcing properties of drugs of abuse. Such a biochemical sensitization may also predict behavioral sensitization. Other data suggest that the rate of uptake may be regulated by changes in the membrane potential and depolarization has been shown to decrease the velocity 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 can alter the dynamic balance between different neurotransmitter systems, and can leads to enduring changes in neural control. This is also observed 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 the that of peptides and genes that are regulated by cocaine. One of these, corticotrophin-releasing factor, or CRH, is the well-known mediator of the Òstress response,Ó 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 transcripts, 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 within the nucleus accumbens, the NAC-1; 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 dopaminergic systems, but in non-dopaminergic systems as well. The recognition of the potential interactions between these systems (and those which surely exist, but have not yet been identified) suggests that neuroadaptations occur at many different levels. Each of the levels has the potential to be a 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 inter-relationships between these factors is crucial for each of us who work in this field. And this is only the beginning.