Chronic morphine differentially impacts glutamatergic synaptic plasticity in the ventral tegmental area of adult versus adolescent mice

Opioids mediate the majority of drug overdose-related deaths in the United States. Opioid-induces addictive behaviors in part via manipulation of excitatory synaptic plasticity of ventral tegmental area (VTA) dopamine cells by targeting presynaptic mu opioid receptors (MORs). Recent data demonstrate VTA GABAergic cells also exhibit excitatory long-term depression (LTD) plasticity that is cannabis susceptible. Here we identify expression of presynaptic MORs at excitatory inputs to VTA GABA cells of male/female adolescent and adult mice using electrophysiology, motivating further examination of morphine impact on synaptic plasticity of these understudied cells. Long-term (7-10 days) intraperitoneal injection of morphine eliminated both LTD and MOR agonist-induced synaptic depression in adolescent mice. Surprisingly, in adult mice chronic morphine eliminated LTD in only ∼50% of VTA GABA cells. Seven-day withdrawal following morphine treatment reversed LTD elimination in all adolescents GABA cells, but not in adults. Next, as LTD is cannabinoid receptor 1 (CB1)-dependent and endogenous opioid and cannabinoid systems have signaling overlap, we examined MOR influence on LTD. While MOR antagonist naloxone did not block LTD, pre-exposure of MOR agonist DAMGO occluded LTD, suggesting CB1 and MOR crosstalk. Collectively, this demonstrates morphine alteration of VTA GABA cell function and plasticity that potentially correlates to dependence and withdrawal, as well as age-dependent morphine impact. Further examination of opioid dependence mediated by the inhibitory reward circuit that considers age-dependence will be essential when considering targets for therapeutic interventions aimed at mitigating opioid addiction.