The experiments proposed here address potential mechanisms of cocaine action in the central nervous system, with a particular emphasis on some of the brain regions which appear to be implicated in the reinforcing effects of cocaine (e.g. nucleus acumbens (NAS), frontal cortex (FC)). The basic hypothesis on which these studies are based is that the action of cocaine are not entirely explicable in terms of its ability to inhibit the neuronal re-uptake of dopamiine (DA) and norepinephrine (NE), since other drugs with greater potencies in inhibiting DA and NE re-uptake in corpus striatum do not appear to share the reinforcing properties of cocaine. One possibility is that there are significant differences between the drug sensitivities of the DA re-uptake systems in the brain regions mediating cocaine reinforcement and those of the corpus striatum. Possible alternative mechanisms of action include direct stimulation of DA release in NAS and FC, indirect stimulation of DA release by inhibition of the action of presynaptic regulators of DA release such as DA itself or cholescystokinin (CCK-8S) which is co-localized with DA in rat NAS, or modulation of the postsynaptic actions of DA. We, therefore, propose to characterize DA uptake systems in brain preparations from NAS, FC and CS from bovine and rat with respect to drug sensitivity in each brain region, and to attempt the solubilization and purification of cocaine binding proteins from these regions of bovine brain for use in the development of tools for the further study of the uptake systems. We will also evaluate the ability of cocaine to stimulate DA release in NAS and FC slice and synaptosome preparations. Finally, the possibility that postsynaptic actions of DA might be affected by cocaine, either acting directly or by affecting a regulatory function of CCK-8S will be studied. The effects of cocaine and CCK-8S on DA binding to D2 and D1 type binding sites, and on DA regulation of adenylate cyclase in these tissues will be studied.
