Research indicates that central 5-hydroxytryptamine(3) (5-HT3: serotonin) receptors regulate: (1) dopamine (DA) mediated behaviors, (2) mesocorticolimbic DA release, and (3) the withdrawal syndrome associated with drugs of abuse. The present application proposes to examine the role of 5-HT3 receptors in regulating the behavioral and neurochemical changes engendered by the continuous infusion of cocaine via an osmotic minipump. The continuous infusion of cocaine is an animal model of compulsive, binge-like, high-dose cocaine abuse. The proposal hypothesizes that continuous cocaine administration produces a decreased ability of 5-HT3 receptors to regulate DA neurotransmission and DA-mediated behaviors. This decreased regulatory capacity will be examined at several different levels of analyses to obtain an integrated picture of the changes in these receptors. Specifically, the present application will examine changes in the ability of 5-HT3 receptor agonists and antagonists to regulate DA release in brain slices from the striatum, nucleus accumbens, and prefrontal cortex, and changes in the ability of 5-HT3 receptor agonists and antagonists to regulate behavior. The present experiments will not only further elucidate the role of 5-HT3 receptors in cocaine abuse, but may also result in a fuller understanding of their functional significance for other psychiatric conditions. Cocaine abuse results in anxiety/mood disorders and depression, and psychosis. Central 5-HT have been implicated in all of these conditions. Thus, a fuller understanding of the behavioral neuropharmacology of 5-HT3 systems may not only aid in our understanding of other psychiatric conditions, but may also result in improved pharmacotherapies for a variety of psychiatric conditions.
