Opioid-induced changes to cannabinergic regulation of dopamine and motivation during protracted withdrawal

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PROJECT SUMMARY Opioid abuse remains a costly epidemic in the US, prompting research into new and effective interventions to curb addiction-like behavior. Amongst the therapeutic characteristics of opioids, their associated withdrawal effects are substantial and recognized to contribute to development of abuse and relapse. While acute somatic withdrawal symptoms are relatively well characterized, their prolonged affective counterparts are less understood. Regulating a broad array of affective behaviors, the mesolimbic dopamine (DA) system has been demonstrated as both necessary and sufficient for reward-related behavior towards opioids and withdrawal- related negative affect, with a canonical hypodopaminergic state following opioid dependence at least partially responsible for drug craving and relapse vulnerability. Despite this, limitations of previous studies concerning heterogeneity of mesolimbic circuitry and a shortage of assessments of opioid-induced long-term changes to motivated behavior and subsequent drug intake following dependence have stifled clear demonstrations of protracted motivational dysfunction and detection of underlying mechanism for the associated hypodopaminergic state. Growing evidence indicates that cannabinoid (CB) signaling is highly influential in regulating mesoaccumbal dopamine and opioid systems, including dopamine and opioid control of reinforcement, and that CB-based therapies may hold efficacy in treating negative affective states during acute/somatic withdrawal and perhaps opioid intake. Despite these promising data, data regarding how CB signaling is altered during opioid withdrawal and whether CB-therapies are efficacious in countering dependence-related changes in motivation for and intake of opioids with more protracted withdrawal are almost non-existent. This proposal builds off my research to date demonstrating that 1) morphine dependence promotes a long-lasting elevation in GABAA- mediated inhibitory tone specific to DA neurons in the lateral ventral tegmental area projecting to the lateral nucleus accumbens shell (latVTA-latShell), 2) prior dependence increases motivation for and intake of morphine, and 3) elevations in GABA signaling align with an apparent tolerance to CB1-induced disinhibition of lateral VTA DA firing. In Aim2/Exp1, I will utilize ex vivo slice electrophysiology to assess alterations in synaptic strength and CB-dependent regulation of GABAergic afferents from the rostromedial tegmental nucleus (RMTg) to latVTA- latShell DA cells. Behavior studies in Aim2/Exp2 will extend upon data demonstrating increased effort-based motivated responding for morphine under protracted withdrawal conditions by measuring cannabinoid-induced alteration of this effect. Completing these experiments will support my research development by adding technical skills in more sophisticated electrophysiology and behavioral approaches. Further, results will fill critical unknowns regarding mechanisms underlying ostensibly important changes in DA function and behavior that drive OUD and characterize the longer-lasting benefits and limitations of CB-based interventions.