Regulation of System Xc-by the Neuropeptide PACAP: Implications for Glutamate Transmission in Drug Addiction

Drug addiction is a chronic brain disorder characterized by heightened relapse susceptibility. Drug-induced aberrant glutamate signaling in corticostriatal circuitry contributes to behaviors in virtually every preclinical model of drug seeking and correlates with drug craving in human. Here, we propose that glutamate signaling is a product of integrated activity between neurons and astrocytes, such that disruptions within astrocytes can stem from abnormal neuronal signaling (e.g., altered corticostriatal firing) and be the source of additional disruptions in other neuronal circuits. The astrocytic mechanism studied in these experiments is system xc- (Sxc) since drug-induced changes to this non-vesicular glutamate release mechanism contribute to heightened relapse vulnerability in preclinical models of addiction. My first objective was to determine whether neurons or neuronal factors regulate Sxc activity in astrocytes (Chapter II and III) since this would illustrate the degree to which glutamate signaling involves integrated activity of multiple cell types. We found that neurons release a soluble factor that potently increases Sxc activity. Moreover, we discovered that the neuropeptide PACAP (pituitary adenylate cyclase-activating peptide) likely contributes to this effect since it upregulates Sxc activity in astrocytes (Chapters II and III). Next, we focused on the importance of PACAP regulation of Sxc to synaptic transmission in the nucleus accumbens (NAc), since this structure is highly implicated in drug addiction (Chapter IV). PACAP depressed synaptic transmission in NAc neurons projecting to the substantia nigra, an important efferent that encodes motivated behaviors. Interestingly, PACAP-induced control over synaptic transmission required enhanced Sxc activity. Given this, we then determined the behavioral impact of increasing PACAP signaling in the NAc on drug-seeking behavior (Chapter IV). Specifically, we found that microinfusion of PACAP into the NAc attenuated cocaine-primed reinstatement of drug seeking. Lastly, we determined that PACAP is expressed in corticostriatal projections to the NAc, and that endogenous PACAP is an unrecognized factor influencing relapse vulnerability (Chapter IV). Collectively, this dissertation reveals that a novel form of neuron-astrocyte communication, namely PACAP regulation of Sxc, is a critical link integrating the glutamate network that mediates motivated behavior