Mu opioid receptor-gated roles of glutamatergic and GABAergic ventral tegmental area neurons in fentanyl reward and relapse - PROJECT SUMMARY Drug overdose deaths have surged more than fivefold over the last two decades, and more than 75% involve opioids. Both rewarding aspects of drug use as well as the avoidance of aversive withdrawal symptoms contribute to opioid addiction. A key question amidst the opioid epidemic is whether rewarding and aversive aspects of opioid addiction can be leveraged to aid recovery in addicted individuals. Opioid drugs of abuse exert their powerful addictive properties by exploiting the brain’s reward center, the ventral tegmental area (VTA). Canonically, the rewarding effects of opioids arise through activation of μ-opioid receptors on VTA neurons that release the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Opioid binding on these GABAergic neurons leads to increased dopamine release in the nucleus accumbens that is critical for opioid reward and opioid-seeking. Surprisingly, we recently discovered μ-opioid receptor VTA neurons that release the excitatory neurotransmitter glutamate. Contrary to the classically rewarding circuit governed by GABAergic neurons, opioid binding on glutamatergic VTA neurons reduces excitatory drive onto dopamine neurons. My preliminary data indicate that GABA release from μ-opioid receptor VTA neurons supports opioid-induced reward, but glutamate release from μ-opioid receptor VTA neurons does not. Based on these findings, we ask two questions: (1) Do glutamatergic or GABAergic μ-opioid receptor VTA neurons alone modulate nucleus accumbens dopamine? and (2) Do glutamatergic or GABAergic μ-opioid receptor VTA neurons alone drive opioid-seeking? We hypothesize that glutamatergic and GABAergic μ-opioid receptor VTA neurons differ in their modulatory effects on the nucleus accumbens reward system and in their ability to drive opioid-seeking behavior. In Aim 1, I propose to specifically activate μ-opioid receptors on glutamatergic or GABAergic VTA neurons while measuring dopamine release in the nucleus accumbens in mice. In Aim 2, I will determine whether selective μ-opioid receptor activation on glutamatergic or GABAergic VTA neurons drives opioid- seeking in a model of relapse. The completion of these Aims will use cutting-edge techniques such as cell type-specific pharmacology (DART), fiber photometry of dopamine sensors (GRABDA), and a reinstatement/relapse paradigm of intravenous self-administration. The mentoring committee at the University of Colorado Boulder, Colorado State University, and Duke University will provide expert guidance throughout the study. I will receive significant training in intracranial microinjections and the methodology of DART, intravenous self-administration and reinstatement paradigms, and the interpretation of GRABDA dynamics. The findings of this study may redefine the neurobiological underpinnings of opioid-induced reward and relapse, which will prove crucial in the continued struggle with the opioid epidemic.
