Exploration of the unique neurobehavioral profile of sequential opioid-stimulant polysubstance use disorders - Among drug users, polysubstance use is much more common than single substance use. One of the deadliest combinations of substances used in America today is concurrent opioid and stimulant usage, with co-use of these drugs becoming increasingly responsible for overdose deaths. Out of the 2.1 million Americans which had an opioid use disorder (OUD) as of 2017, 11% also had a methamphetamine use disorder. First-time methamphetamine use is more likely after past-month opioid use. Additional research into the neurobiology of polysubstance use is essential for the development of targeted, effective treatments for polysubstance addiction. Addiction behaviors arise from neuroplasticity within the neural circuits responsible for decision - making, motivation, and reward processing. Individually, stimulants and opioids have different actions within these circuits, each targeting distinct regions, receptors, and neurotransmitter systems. Because of this, many of the cellular and molecular adaptations induced by these two drug classes are unique. Yet, it is unclear how the interaction of these compounds within the nervous system produces changes in drug-seeking and taking behavior. The proposed study will explore the neurobehavioral effects of dual opioid and methamphetamine use disorders. The following Aims will guide the proposed study. AIM 1 is to define the behavioral profile of dual opioid-methamphetamine use disorders in a rodent model of addiction. Despite its rising popularity, the underlying behavioral patterns and motivations of polysubstance addiction are not well characterized. Therefore, the first aim will compare and contrast polysubstance and mono substance addiction behavioral patterns (i.e. drug-seeking, drug-taking, and reward valuation) using a reverse-translational rodent self-administration model. AIM 2 is to map neural activation patterns within the cortico-basal ganglia-thalamic (C-BG-T) circuit in response to opioid and methamphetamine self-administration. Alterations in the C-BG-T networks contribute to addiction behaviors, as well as the persistence of individual substance use disorders for both opioids and stimulants. Yet, it is still unclear how chronic, sequential polysubstance use alters neurocircuit activity. Therefore, the proposed study will map neurocircuit activation patterns with a novel viral- mediated gene transfer approach for post-mortem tissue analysis, whole brain lightsheet microscopy, in order to identify differences in C-BG-T network activity between animals with a history of chronic polysubstance or single substance use. We hypothesize that opioid-stimulant polysubstance use will have a unique, synergistic effect on addiction-related behaviors and neural circuit recruitment that is not present when either drug is used alone.
