Limbic-cortical involvement in drug seeking

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DESCRIPTION (provided by applicant): Drug dependence is considered a chronic disease due to the high incidence of relapse. Incentive motivational effects (e.g., craving) produced by consumption of drug or by exposure to stimuli present during the drug experience (e.g., paraphernalia or the environment) are thought to play a major role in relapse. Despite the importance of these phenomena to relapse, little is known about the neural mechanisms involved. Limbic-cortical circuits, which play a role in emotion, memory, and formation of associations between initially neutral stimuli and rewards, are likely involved in these effects. Furthermore, mounting evidence suggests that dopamine, serotonin (5-HT), and glutamate neurotransmitter systems may play a critical role in these effects as well. The objective of this research is to examine the role of limbic-cortical circuits in the incentive motivational effects produced by cocaine and cocaine-paired environmental stimuli. We hypothesize that the central and basolateral amygdala play predominant roles in the incentive motivational effects of cocaine and cocaine-paired stimuli, respectively, whereas the prelimbic and anterior cingulate cortex play a critical role in the incentive motivational effects of both types of stimuli. We will investigate these hypotheses by examining the effects of excitotoxic lesions of these regions on acquisition, expression, and cocaine reinstatement of cocaine-conditioned place preference (CPP). Expression of CPP is thought to reflect incentive motivational effects of cocaine-paired stimuli, whereas reinstatement of extinguished CPP by cocaine priming injections is thought to reflect the incentive motivational effects of cocaine itself. In addition, we will survey key regions of the brain that are involved in learning, memory, motivation, and sensorimotor processes for neuronal activation in response to exposure to cocaine-paired stimuli or to cocaine priming injections using induction of immediate early genes (IEGs), c-fos and zif/268, as markers. Furthermore, we will characterize the neurons that exhibit IEG induction to determine whether they co-express mRNAs for dopamine D1, D2, or D3 receptors, 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT4 receptors, and glutamate AMPA receptor subunits GluRl, GluR2, and GluR3 using double-labeling in situ hybridization. Subsequently, we will build from these studies by examining the effects of lesions that disrupt acquisition of cocaine-CPP on IEG responses in brain regions interconnected with the lesion site. A disruption of IEG expression in regions interconnected with the lesion site would suggest functional connection between the regions that may be involved in acquisition of cocaine-CPP. These experiments will provide much new information on the role of the amygdala and cortical brain regions in incentive motivation for cocaine and will help elucidate the neural circuitry involved in relapse elicited by cocaine and cocaine-paired stimuli. The findings may be useful for developing behavioral and pharmacological treatments for cocaine dependence.