ROLE OF NUCLEUS ACCUMBENS CA2+ FLUX IN COCAINE REWARD

Mc Lean Hospital (Belmont, Ma), Belmont MA

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Abstract

DESCRIPTION: (Applicant's Abstract) The purpose of this B/START proposal is to test the hypothesis that calcium (Ca2+) flux in the nucleus accumbens shell (NASh) influences the rewarding and aversive effects of cocaine in rats. Several lines of evidence suggest that changes in Ca2+ flux in the NASh influence brain reward processes. For example, we found that rats self-administer NMDA (glutamate) receptor antagonists (which block Ca2+ flux) directly into the NASh, and that the local rewarding effects of these agents are dopamine-independent. We also found using viral-mediated gene transfer that the Ca2+ permeability of AMPA (glutamate) receptors in the NASh dramatically influences cocaine's subjective effects: cocaine reward is increased when expression of Ca2+-nonpermeable AMPA receptors is high, whereas cocaine aversion is increased when expression of Ca2+-permeable AMPA receptors is high. A common factor among these findings is that decreased Ca2+ flux in the NASh increases reward, regardless of the neural site (NMDA or AMPA receptors) at which it is decreased. In the proposed studies, we will determine if pharmacological manipulations of a third route of Ca2+ flux, L-type channels, within the NASh influence the rewarding and/or aversive effects of cocaine using the place conditioning paradigm. We will precede treatment with a threshold dose of cocaine (1.25 mg/kg, IP) with intra-NASh microinjections of an L-type Ca2+ channel antagonist (diltiazem) or an activator (BAY k 8644) during drug conditioning sessions. Our hypothesis predicts that intra-NASh microinjections of the antagonist will increase time spent in cocaine-associated environments (reward), whereas similar treatment with the activator will decrease time spent in cocaine-associated environments (aversion). Data from these studies will provide a basis of future grant applications in which we will propose to further study the intra-NASh neural events associated with drug reward and aversion using state-of-the-art molecular methods (e.g., viral-mediated gene transfer) to alter Ca2+ channel expression and function in this brain region. Understanding how factors such as intra-NASh Ca2+ flux are involved in cocaine's subjective effects will help to identify neural targets toward which potential treatments for cocaine addiction and craving could be directed.