Date of Award
Doctor of Philosophy (PhD)
Opioid use disorder (OUD) is associated with enduring psychological withdrawal symptoms believed to contribute to drug abuse. Amongst these are shifts in motivational states, wherein pursuit of drug consumption exceeds that of non-drug rewards, reinforcing escalated opioid use and relapse vulnerability. A critical regulator of behavioral reinforcement, the mesoaccumbal dopamine system is thought to be both necessary and sufficient for opioid motivation. However, previous research into its involvement in opioid withdrawal has been limited to acute rather than protracted timepoints, global neuroadaptations rather than those in subcircuits, and overwhelmingly focused on males over females. Using a rodent model of self-administration to address these constraints, I show that following 14 days of morphine withdrawal, previously dependent male and female mice exhibit elevations in morphine seeking, intake, and motivation compared to non-dependent counterparts. Escalation of intake was paralleled by a male-exclusive reduction in motivation for the non-drug reward, sucrose. Combining retrograde labeling and whole-cell slice recordings, I demonstrate that withdrawal-associated behavioral shifts in males align with reduced neuronal excitability and increased inhibitory (GABAAR-dependent) synaptic transmission in lateral ventral tegmental area (VTA) dopamine neurons projecting to the lateral nucleus accumbens shell (latVTA-latShell) that is not observed in medial dopamine projections to the medial shell (medVTA-medShell). Subsequent studies show that increased inhibitory signaling reflects, in part, an upregulation of GABA release probability arising from the rostromedial tegmental area nucleus – an aversion-associated inhibitory input to VTA dopamine cells. Finally, using a viral-mediated chemogenetic approach to control neural activity, I demonstrate that inhibition of latVTA-latShell dopamine neurons significantly reduces motivation for sucrose. This suggests that enduring reductions in motivation for non-drug reward during protracted withdrawal are driven by a hypoactive state in a latVTA-latShell dopamine neurons driven in part by their increased inhibition. These insights may be useful in development of therapies that temper withdrawal-associated psychological states predisposed towards relapse, a major treatment goal for OUD patients.