Assessing the role of corticostriatal circuitry in polysubstance use of fentanyl and methamphetamine using rat self-administration models

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Project Summary Co-use of opioids (fentanyl, heroin) and methamphetamine is now highly prevalent across the U.S., and is associated with severe health risks, including HIV infection and overdose, and poorer treatment outcomes. Yet, the neural circuit alterations and accompanying behavioral changes associated with this polysubstance use are poorly defined, as are the similarities/differences between distinct patterns of opioid/methamphetamine co-use. Notably, the patterning of drug use can have enormous impacts on both circuit-wide brain adaptations and the development of addiction behaviors. Accordingly, delineating whether the outcomes that occur following distinct patterns of polysubstance use reflect the summation of each drug or are synergistic or distinct is particularly important, and likely critical for designing appropriate and long-lasting therapeutic interventions. To address this, we will use rat self-administration models of sequential (use of each substance on separate occasions) and simultaneous (use of both substances at the same time) polysubstance use of fentanyl and methamphetamine that mimic patterns of human consumption. Comparisons will also be made to groups that undergo self- administration of each substance singly. We will combine behavioral analysis with in vivo fiber photometry, ex vivo slice electrophysiology and targeted chemogenetic cellular manipulations to comprehensively map how striatal circuit activity is associated with addiction behaviors following different patterns of fentanyl and/or methamphetamine use. Striatal circuits (i.e., the NAc and its glutamate afferents from the PFC and its dopamine afferents from the VTA) will be examined as they are a key node of the cortico-basal ganglia-thalamic circuit that is well-established to regulate addiction-related behaviors of both opioids and stimulants. The overarching hypothesis of this work is that neural alterations in striatal circuitry will differ between sequential and simultaneous patterns of fentanyl and methamphetamine polysubstance use. In addition, we hypothesize that polysubstance use will produce synergistic and/or distinct circuit changes rather than summative changes compared to single substance use. Collectively, these results would support the idea that the patterning of substance use is particularly important for conferring the development of addiction-related behaviors. This work is significant as polysubstance use of opioids and methamphetamine is common and riskier, but vastly understudied. Our studies will help to address this gap and will provide an important and necessary foundation for ultimately understanding why polysubstance use drives continued drug use, and what neural cells and adaptations may be particularly relevant targets for therapies aimed at addressing polysubstance use.