ACUTE AND CHRONIC COCAINE-INDUCED CCK RELEASE

Tufts University Boston, Boston MA

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Abstract

Midbrain dopamine neurons normally shape behavior by reinforcing biologically rewarding events. Psychostimulants such as amphetamine and cocaine reinforce their self-administration by acting on the same mesolimbic dopamine system. Cholecystokinin (CCK) is co-localized with dopamine in this system. Many studies have documented the complex interaction between dopamine and CCK and demonstrated that CCK modulates dopamine release, turnover and receptor binding. In turn, dopamine alters CCK release. A number of behavioral studies suggest that CCK released in response to amphetamine or cocaine, acting on CCK A receptors in the shell of the NAC is involved in the acquisition of dopamine- mediated behaviors and in the expression of enhanced behavioral response to amphetamine in amphetamine-sensitized animals. In drug discrimination assays, CCK A antagonists decrease the subjective effects of cocain in rats and rhesus monkeys. CCK may play a modulatory role in reinforcement by altering dopamine neurotransmission in the NAC. It is also possible that CCK released in response to psychostimulants may have additional effects of reward which are independent of dopamine. Another important feature of the response to chronic cocaine administration is the development of behavioral sensitization. Sensitization is a very complex phenomenon involving multiple brain regions and multiple neurotransmitters. It involves (in part), activation of the dopamine system and activation of glutamate neurotransmission in the vetral tegmental area (VTA) and NAC, including up regulation of GluR1 and NMDAR1 glutamate subtypes. Nothing in known about CCK relase from the NAC in freely moving rats in response to acute and chronic administration of cocaine. Whether CCK release is different in rats sensitized to cocaine than in rats responding to an acute cocaine challenge is unknown. The research in this proposal tests the following hypotheses: 1). Releasae of CCK from the NAC as measured by microdialysis and CCK RIA is greater in rats treated with a challenge dose of cocaine than in rats treated with vehicle. 2). CCK release in response to a cocaine challenge in rats that are behaviorally sensitized differs from non-sensitized rats. This small grant proposes the following specific aims: 1. The ability of single peripheral injections of cocain to produce a dose-dependent increase in CCK release in the shell of NAC in freely moving rats will be determined. 2. Simultaneous measurement of CCK release and locomotor behavior will be used to examine whether CCK release is different in rats that are behaviorally sensitized to cocaine than in rats treated with a single injection of the drug.