The proposed research will provide the first intensive examination of the effects of repeated exposure to drugs abuse on the cognitive function and neurochemistry of the ventromedial frontal, i.e. prelimbic cortex, in the non-human primate. We have exciting new data in monkeys which suggests that repeated administration of phencyclidine (PCP) induces a long-term dopamine (DA) deficiency in the prelimbic cortex. This DA deficiency is manifest as, and correlated with, behavioral disinhibition and increased impulsivity, functions known to be dependent on this cortical region. We observed deficits after cessation of chronic exposure so changes in the neural circuitry associated with impulsivity appear to be long-lasting. In addition, we have behavioral and biochemical data in the rodent that suggest parallel functional changes in the cortex after chronic PCP or cannabinoid (THC) administration. Impulsivity following DA dysfunction in the prelimbic cortex may be concomitant with, and indeed enhance, the progressive augmentation of mesolimbic DA transmission induced by chronic drug exposure, effects postulated to subserve the sensitization of the rewarding effects of drugs of abuse. The prelimbic cortex densely innervates the nucleus accumbens (NAc) and therefore dysfunction of this corticolimbic circuit may subserve increased impulsivity and drug-mediated reinforcement. Using in vivo and ex vivo techniques in rats and monkeys, this project will examine the hypothesis that neurobiological changes induced by repeated administration of such drugs of abuse as cocaine, THC and PCP will result in common adaptations and cognitive dysfunctions associated with the prelimbic cortex. The research plan will investigate the following hypotheses: (1) Repeated exposure to drugs of abuse induces analogous changes in prelimbic cortical DA and cognitive function that are long-term and can be characterized by increases in impulsivity. (2) Dysfunction of the prelimbic DA innervation results in an inability to gate or modulate changes in reward motivated behaviors that are dependent on NAc. Thus, repeated drug exposures result in changes in the neural circuitry associated with cognition and reward, both of which are known to be critically dependent on DA innervation of the prelimbic cortex and NAc. The overall goal of these studies is to elucidate neurobiological alterations in the neural substrates associated with impulsivity and reward. Novel therapeutic agents that target DA dysfunction in the prelimbic cortex may provide new avenues for the development of therapies to ameliorate impulsivity associated with drug craving.
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