Identifying patterns of human polysubstance use to guide development of rodent models

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Project Summary (Supplement) This proposal is for a Diversity Supplement for a PhD student, Javier Mesa. This supplement will allow Javier, who is an underrepresented minority in the biomedical sciences, to work under the parent grant DA045140. During the course of the supplement, Javier will be trained on cutting-edge techniques in neuroscience and expand his conceptual knowledge on translational rodent models of drug seeking. The mentoring team is composed of the MPIs of the parent grant, Drs. Lori Knackstedt and Linda Cottler, and co-I’s Drs. Marek Schwendt and Barry Setlow. Additionally, Dr. Jesse Dallery, a member of Javier’s dissertation committee, will contribute to mentoring. All mentors are current or past NIDA grantees, and have expertise ranging from the use of preclinical rodent models of drug-seeking to uncover neurobiological changes (Drs. Knackstedt, Schwendt and Setlow) to assessing human patterns of drug-taking (Dr. Cottler) and using behavioral strategies to reduce drug seeking (Dr. Dallery). Javier will contribute to data collection for parent grant aims, while also pursuing his own independent aims that he has constructed. The parent grant aims to back-translate human patterns of cocaine-alcohol and cocaine-cannabis polysubstance use (PSU) into rodent models. One such model has been in use in the Knackstedt lab, with two publications finding that sequential self-administration of cocaine and alcohol leads to unique NA core glutamate adaptations differing from that of cocaine self-administration alone. Specifically, we found that during a both a cocaine- and a cue+cocaine-primed reinstatement test, NA core glutamate efflux increases in rats that consumed cocaine alone, but not in those with a history of sequential cocaine and alcohol consumption, despite equivalent levels of cocaine-seeking during the reinstatement test. This glutamate efflux drives the reinstatement of cocaine-seeking, as blockade of NA core glutamate receptors attenuates such reinstatement. We also found that reduced reinstatement-induced Fos expression in the NA core and the PFC occurred in the PSU group relative to the cocaine-only group, consistent with the idea that PFC-NA core pathways do not mediate reinstatement of cocaine seeking in the PSU condition. Conversely, we observed increased Fos expression in the BLA of cocaine-alcohol PSU rats relative to cocaine-only rats. Here, Javier proposes to use this model of sequential cocaine+alcohol consumption to investigate the novel neurocircuitry underlying relapse to cocaine seeking in the PSU model. His aims are designed to test the hypotheses that 1) inactivation of the BLA will suppress the reinstatement of cocaine seeking in rats in PSU rats, possibly to a greater extent than in cocaine-only rats; and 2) inactivation of the PFC-NA core pathway will suppress the reinstatement of cocaine seeking in rats that self-administered only cocaine and not in PSU rats. These aims will provide valuable information regarding the presence of distinct vs. overlapping neurocircuitries mediating cocaine seeking in cocaine monosubstance use vs. cocaine-alcohol polysubstance use.