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

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 48; no. 13; pp. 1889 - 1900
• Main Authors: McGovern, Dillon J, Polter, Abigail M, Prévost, Emily D, Ly, Annie, McNulty, Connor J, Rubinstein, Bodhi, Root, David H
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2023
• Subjects: Analgesics, Opioid - metabolism; Analgesics, Opioid - pharmacology; Animals; Dopamine; Dopamine - metabolism; Dopaminergic Neurons - metabolism; Drug abuse; Drug addiction; gamma-Aminobutyric Acid - metabolism; Glutamatergic transmission; Glutamic Acid - metabolism; Male; Mesolimbic system; Mice; Narcotics; Neurons; Nucleus accumbens; Opioid receptors (type mu); Oxycodone; Oxycodone - metabolism; Receptors, Opioid, mu - metabolism; Reinstatement; Self-administration; Sex differences; Ventral Tegmental Area - metabolism; Ventral tegmentum; γ-Aminobutyric acid
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-023-01637-w

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.