Effects of Acamprosate on Alcohol-induced Aberrant Synaptic Plasticity in the PFC

University Of Texas Dallas, Richardson TX

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Abstract

? DESCRIPTION (provided by applicant): Drug addiction is a chronic, relapsing condition characterized by compulsive drug seeking and substance use despite harmful consequences. Evidence suggests that drugs of abuse diminish the ability of the prefrontal cortex (PFC) to exert supervisory control over impulsive behaviors related to drug-seeking and relapse to drug taking. The transition from social drinking where inhibitory control by the PFC is intact, to addiction and dependence where the inhibitory control by the PFC is lost, may reflect fundamental changes in the integrative capacities of the PFC itself. However, a direct test of this theory and an analysis of the cellular mechanisms involved are still forthcoming. Glutamate-mediated excitatory neurotransmission plays an important role in the behavioral effects of acutely administered EtOH, as well as the neuroadaptations associated with prolonged EtOH exposure that underlie EtOH dependence. The NMDA subtype of glutamate receptors is a major target for the effects of alcohol in the brain. We have recently shown that (passive) chronic EtOH exposure selectively upregulates NMDAR function in the PFC, leading to a shift in the NMDA/AMPA current ratio and a dysregulation of long-term synaptic plasticity. The experiments outlined in this proposal expand on these findings to further test the theory that EtOH-induced changes in synaptic plasticity lead to impairments in PFC function, which in turn may lead to further increases in alcohol drinking after a period of abstinence, thus making alterations in glutamatergic plasticity predictive for the propensity for relapse. Specifically, we will study the predicted changes in an operant self-administration model of alcohol addiction and we will correlate changes in behavior (alcohol drinking, and performance in an Attentional Set-Shifting task, respectively) with changes in synaptic plasticity at critical points in the addiction cycle (.e. after prolonged exposure, after withdrawal, and after relapse drinking). Therefore, we perform voltage-clamp recordings (measuring NMDA/AMPA ratios, spontaneous AMPA and GABA currents) in brain slices of adult animals that self- administer EtOH in an operant paradigm in which animals respond for EtOH rewards either under goal- oriented or habit-promoting reinforcement schedules (Aim 1). In Aim 2 we will test the hypothesis that the widely prescribed anti-craving drug acamprosate can normalize the EtOH-induced changes in glutamatergic transmission (i.e. restore the NMDA/AMPA ratio) to restore cognitive flexibility, thus reducing the propensity for relapse. The results of these experiments will inform us how EtOH-induced aberrant glutamatergic plasticity in the PFC contributes to the loss of behavioral flexibility and shift towards sensory-driven compulsive behaviors in alcohol abuse. Moreover, in concert with previous and ongoing experiments in our lab that use a dependence model of alcohol addiction (chronic intermittent ethanol exposure, CIE) these experiments will allow us to study how learning and motivational factors can differentially affect our behavioral and physiological measures of PFC dysfunction.