Alcohol Self-administration and Relapse-like Behavior: A Functional Role for Enhanced Activity at AMPA Receptors

Mechanisms underlying excessive alcohol drinking behavior and relapse are not fully understood and are critical for mapping the pathological course of alcohol use disorders (AUD). Long-term ethanol consumption results in strengthened excitatory neurotransmission and increased AMPA receptor signaling in animal models. However, the mechanistic role of enhanced AMPA receptor activity in ethanol-reinforcement and alcohol-seeking behavior remains unclear. Thus, the experiments in this dissertation sought to elucidate the behavioral and molecular mechanisms that underlie AMPA receptor-mediated ethanol reinforcement processes and relapse to ethanol-seeking behavior using a preclinical model of high alcohol preference, the alcohol-preferring (P-) rat. Enhancement of AMPA receptor signaling by systemically administered aniracetam (AMPA receptor positive allosteric modulator) significantly increased ethanol self-administration in a reinforcer-specific manner. Moreover, aniracetam potentiated cue-induced reinstatement in P-rats, which suggest that enhanced activity at AMPA receptors promotes reinforcement and ethanol-seeking behavior. Experiments further characterized enhanced AMPA receptor signaling in modulating operant self-administration and relapse-like behavior by examining neuroanatomical contributions to AMPA receptor-mediated alterations in ethanol reinforcement. Since AMPA receptor activity is potentiated by post-translational modification (e.g. phosphorylation of GluA1subunits), immunohistochemistry was used to examine neuroadaptive changes in pGluA1 in limbic brain regions after a history of ethanol self-administration. Increased pGluA1 immunoreactivity was observed in sub-nuclei of the amygdala and nucleus accumbens of ethanol self-administering P-rats relative to the sucrose controls. Guided by immunohistochemistry results, the effects of aniracetam on ethanol self-administration were examined via site-specific microinjections in the amygdala and nucleus accumbens. Intra-amygdala, but not intra-accumbens, aniracetam increased ethanol self-administration in a reinforcer-specific manner. Furthermore, coadministration of intra-amygdala aniracetam and myristolated AIP (CaMKII peptide inhibitor) blocked aniracetam-induced increased ethanol self-administration; which demonstrates a critical role for amygdala CaMKII activity in AMPA receptor-mediated potentiation of ethanol reinforcement. These data suggest that enhanced amygdala AMPA receptor activity promotes drinking and ultimately could contribute to alcohol use disorders. In contrast, intra-amygdala aniracetam did not significantly alter cue-induced reinstatement; which suggest that enhanced AMPA receptor activity in this region may not significantly contribute to promoting cue-induced ethanol-seeking. Collectively, key experimental results provide novel insight into AMPA receptor-related mechanisms in excessive alcohol drinking behavior and vulnerability to relapse.