Presynaptic Mu Opioid Receptors Suppress the Functional Connectivity of Ventral Tegmental Area Dopaminergic Neurons with Aversion-Related Brain Regions

Opioid abuse poses a major healthcare challenge. To meet this challenge, the brain mechanisms underlying opioid abuse need to be more systematically characterized. It is commonly thought that the addictive potential of opioids stems from their ability to enhance the activity of ventral tegmental area (VTA) dopaminergic neurons. Indeed, activation of mu opioid receptors (MORs) disinhibits VTA dopaminergic neurons projecting to the nucleus accumbens, providing a substrate for the rewarding effects of opioids. However, the abuse potential of opioids has also been linked to their ability to suppress pain and aversive states. Although medial VTA dopaminergic neurons are commonly excited by aversive stimuli, the effects of MOR signaling on this circuitry have not been systematically explored. To fill this gap, a combination of anatomical, optogenetic, and electrophysiological approaches were used to study the afferent circuitry of paranigral VTA (pnVTA) dopaminergic neurons and its modulation by MOR signaling in male and female mice. These studies revealed that aversion-linked glutamatergic neurons in the lateral hypothalamus, ventrolateral periaqueductal gray, and lateral habenula innervated a subset of pnVTA dopaminergic neurons and that activation of presynaptic MORs suppressed their ability to drive pnVTA spiking. A distinct set of pnVTA dopaminergic neurons were innervated by lateral hypothalamus GABAergic neurons, which also were subject to MOR modulation. Thus, MORs robustly inhibit the ability of brain circuits coding aversive states to drive the activity of pnVTA dopaminergic neurons, suggesting that the addictive potential of opioids may stem in part from their ability to act as negative reinforcers.