Ventral tegmental area glutamate neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate opioid-seeking behavior

Authors

Dillon J. McGovern, Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA.
Abigail M. Polter, Department of Pharmacology and Physiology, George Washington University, Washington, DC, 20052, USA.
Emily D. Prévost, Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA.
Annie Ly, Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA.
Connor J. McNulty, Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA.
Bodhi Rubinstein, Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA.
David H. Root, Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA. David.Root@Colorado.edu.

Document Type

Journal Article

Publication Date

7-5-2023

Journal

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

DOI

10.1038/s41386-023-01637-w

Abstract

A two-neuron model of ventral tegmental area (VTA) opioid function classically involves VTA GABA neuron regulation of VTA dopamine neurons via a mu-opioid receptor dependent inhibitory circuit. However, this model predates the discovery of a third major type of neuron in the VTA: glutamatergic neurons. We found that about one-quarter of VTA neurons expressing the mu-opioid receptor are glutamate neurons without molecular markers of GABA co-release. Glutamate-Mu opioid receptor neurons are largely distributed in the anterior VTA. The majority of remaining VTA mu-opioid receptor neurons are GABAergic neurons that are mostly within the posterior VTA and do not express molecular markers of glutamate co-release. Optogenetic stimulation of VTA glutamate neurons resulted in excitatory currents recorded from VTA dopamine neurons that were reduced by presynaptic activation of the mu-opioid receptor ex vivo, establishing a local mu-opioid receptor dependent excitatory circuit from VTA glutamate neurons to VTA dopamine neurons. This VTA glutamate to VTA dopamine pathway regulated dopamine release to the nucleus accumbens through mu-opioid receptor activity in vivo. Behaviorally, VTA glutamate calcium-related neuronal activity increased following oral oxycodone consumption during self-administration and response-contingent oxycodone-associated cues during abstinent reinstatement of drug-seeking behavior. Further, chemogenetic inhibition of VTA glutamate neurons reduced abstinent oral oxycodone-seeking behavior in male but not female mice. These results establish 1) a three-neuron model of VTA opioid function involving a mu-opioid receptor gated VTA glutamate neuron pathway to VTA dopamine neurons that controls dopamine release within the nucleus accumbens, and 2) that VTA glutamate neurons participate in opioid-seeking behavior.

APA Citation

McGovern, Dillon J.; Polter, Abigail M.; Prévost, Emily D.; Ly, Annie; McNulty, Connor J.; Rubinstein, Bodhi; and Root, David H., "Ventral tegmental area glutamate neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate opioid-seeking behavior" (2023). GW Authored Works. Paper 3117.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3117

Department

Pharmacology and Physiology