Conditioned drug effects are believed to be involved in the relapse which often occurs following cessation of compulsive drug use. While a great deal of research has explored behavioral and neurochemical aspects of drug seeking behavior, there remains a lack of understanding of the fundamental relationship of conditioned drug effects to the neural circuitry affected by repeated drug exposure. Determining this relationship is critical to understanding the mechanisms of drug dependence and for the ultimate treatment of long term drug dependence. Recent studies from this laboratory have demonstrated conditioned cued responding following prolonged extinction from chronic cocaine self-administration in rats. In addition, it appears that the basolateral amygdala plays a key role in mediating conditioned cued effects, since lesions of this nucleus greatly attenuate conditioned cued recovery, without affecting maintenance of cocaine self-administration. The studies proposed here will utilize this model of conditioned drug effects to explore parameters of responding in the presence of conditioned reinforcers following extinction. Further experiments will lesion the dopaminergic inputs to the basolateral amygdala and utilize excitotoxic lesions of nuclei closely associated with the basolateral amygdala in order to determine if loss of these pathways also attenuates conditioned cued responding. Other experiments will attempt to potentiate conditioned responding by direct stimulation of glutamatergic and dopaminergic receptors in the basolateral amygdala. Finally, we will test the hypothesis that the basolateral amygdala is critical to conditioned responding across other classes of abused drugs by testing animals following chronic morphine self-administration. These experiments provide an integrated approach aimed at understanding the neural basis of long lasting conditioning effects produced during contingent drug administration. Information gained from this project will also provide direction for current development of medications aimed at treating craving and preventing relapse. the questions addressed in this proposal can only be answered by utilizing an animal model such as that proposed here.
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