During the previous funding period, individual memory systems were evaluated for their role in regulating associative learning processes studied in an eight-arm radial maze as well as in regulating behavior studied in a self-administration maintenance/reinstatement model in rats. The results generated specific hypotheses to suggest (1) that the rostral and caudal subregions of basolateral amygdala are functionally heterogeneous and may therefore have a differential sensitivity to dopamine agonists and antagonists for modifying drug-seeking under maintenance and reinstatement conditions; (2) that the lateral dorsal striatum may regulate the dose-related effects of self-administered cocaine; (3) that the hippocampal subicular subregions may regulate drug-seeking behavior during the contextual encoding (acquisition) stage, but not after contextual information is consolidated; and (4) that within session changes in DA neurotransmission in the lateral prefrontal cortex may regulate the within session changes in the pattern of drug-seeking behavior normally observed.
Specific aim 1 will test these four hypotheses.
For specific aim 2, the interactions between memory systems that are interconnected within two parallel corticostriatalpallidothalamic circuits as well as within the corticostriatalpallido-subthalamic circuit (interface between the basal ganglia and limbic system) will be explored. Specific hypotheses to be tested will be guided by conducting simulations with our newly developed neurocomputational model of drug-seeking behavior. In in vivo experiments, Fos protein expression in the nucleus accumbens at different phases of the cocaine addiction process will be measured in conjunction with the asymmetric GABA agonist inactivation technique to help elucidate if components of these different circuits work cooperatively, competitively or independently in regulating addiction-related behavior. The completion of these aims will advance our understanding of how neurocognitive substrates may regulate drug use and relapse. By studying memory system functions and their interactions during different phases of the cocaine addiction process, insight into the complex challenges that face successful treatment of cocaine-addicted individuals will surface and perhaps guide medications development.
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