Role of Calcium in Cocaine-Induced Sensitization

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Abuse of psychostimulants such as cocaine has become a medical and social ill in this country, making it necessary to identify the cellular and molecular mechanisms underlying the behavioral effects that result from repeated administration of these drugs. Among the reasons to study these mechanisms is the phenomenon of behavioral sensitization which is a progressive and enduring augmentation of locomotor and stereotyped activity in rats that results from repeated intermittent psychostimulant administration. Furthermore, studies suggest that following repeated drug taking there are changes in neurophysiology that contribute to drug craving. Thus, investigating these underlying neurophysiological alterations can help elucidate mechanisms of neuronal plasticity in general. Evidence indicates that calcium and calcium-mediated second messenger systems play an important role in the effects of psychostimulant-induced plasticity. Systemic injections of L-type calcium channel antagonists have been shown to impair the behavioral activating effects of carmine while infra-VTA administration of an L- type calcium channel agonist can mimic the induction phase of behavioral sensitization to cocaine. The proposed research will expand on these findings by examining the role of calcium signaling molecules in the initiation of cocained-induced sensitization. This will be accomplished in two ways. First, rats will receive infra-VTA or infra- nigral injections of antagonists of either L-type calcium channels, calmodulin, or CaMKII prior to systemic administration of cocaine, and behavior will be monitored. Following a two week withdrawal period all rats will receive a systemic challenge injection of cocaine and their behavior will be monitored to determine the effects of inhibiting calcium influx through L-type channels or inhibiting calcium signaling on sensitization to cocaine. Second, rats will receive either acute or repeated cocaine and relative abundance of either calmodulin or CaMKII will be measured in the VTA and substantia nigra using immunolabeling techniques.