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.Doctor of Philosoph
