Dopaminergic Mechanisms of Kappa Opioid Receptor-Induced Potentiation of Cocaine

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DESCRIPTION (provided by applicant): Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of dysphoria, and KOR activation by agonists or by stress-evoked dynorphin release in rodents produces aversion. These dysphoric/aversive effects of KOR activation have been shown to increase the rewarding effects of cocaine, increase drug self-administration, and reinstate extinguished drug seeking behaviors. The cellular and molecular mechanisms responsible for KOR-dependent aversion and potentiation of cocaine reward are not fully understood, but a better understanding may suggest new therapeutic approaches to the treatment and prevention of stress-related diseases including some forms of drug addiction. Evidence strongly supports a role for KOR-dependent inhibition of dopamine (DA) release in the nucleus accumbens (NAc) and KOR-induced activation of p38 mitogen-activated protein kinase (MAPK). We propose to understand how KOR activation and KOR-induced activation of p38 MAPK, either by stress-induced dynorphin release in the ventral tegmental area (VTA) and NAc or by systemic administration of a selective KOR agonist, results in potentiation of the rewarding effects of cocaine. To accomplish these aims we propose 1) to compare the signal transduction pathways underlying KOR-induced potentiation of cocaine-conditioned place preference (cocaine-CPP) to the effects of KOR activation and subsequent administration of cocaine on stimulated DA release in the NAc using fast-scan cyclic voltammetry (FSCV) and 2) to measure KOR-induced potentiation of cocaine-CPP and KOR- mediated interactions with cocaine-induced alterations of DA release using FSCV in animals in which functional KOR activity has been selectively restored to the VTA of KOR knockout (KO) animals.