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

Neuropsychopharmacology volume 48, pages 1889–1900 (2023)Cite this article

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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.

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Fig. 1: VTA mu-opioid receptor expression is cell-type and location specific.
Fig. 2: Distribution of mu-opioid receptor-expressing and mu-opioid receptor-lacking cell-types in the anterior or posterior VTA.
Fig. 3: VTA VGluT2+ neurons establish a mu-opioid receptor regulated microcircuit to VTA dopamine neurons.
Fig. 4: Dopamine release in the NAcc elicited by VTA VGluT2 neurons is reduced following oxycodone administration.
Fig. 5: VTA VGluT2 neurons signal opioid self-administration-related behaviors.
Fig. 6: VTA VGluT2 chemogenetic inhibition blocks oxycodone reinstatement in male but not female mice.

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Acknowledgements

We thank Alysabeth Phillips and Declan Mulcahy for technical assistance.

Funding

This research was supported by the Webb-Waring Biomedical Research Award from the Boettcher Foundation (DHR), R01 DA047443 (DHR), F31 MH125569 (DJM), F31 MH132322 (AL), a 2020 NARSAD Young Investigator grant from the Brain and Behavior Research Foundation (DHR). Further support was provided by NIH Grants R00MH106757 and R01MH122712, a grant from the Margaret Q. Landenberger Foundation, and a 2019 NARSAD Young Investigator grant (to AMP). Some of the imaging work was performed at the BioFrontiers Institute Advanced Light Microscopy Core (RRID: SCR_018302). Laser scanning confocal microscopy was also performed on a Nikon A1R microscope supported by NIST-CU Cooperative Agreement award number 70NANB15H226. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Prism and Biorender were used to make figures and schematics.

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  1. Department of Psychology and Neuroscience, University of Colorado Boulder, 2860 Wilderness Pl, Boulder, CO, 80301, USA

    Dillon J. McGovern, Emily D. Prévost, Annie Ly, Connor J. McNulty, Bodhi Rubinstein & David H. Root

  2. Department of Pharmacology and Physiology, George Washington University, Washington, DC, 20052, USA

    Abigail M. Polter

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DJM, AMP, and DHR conceived and performed experiments, wrote the manuscript, and secured funding. CM, AL, EDP, BR performed experiments and contributed to the writing of the manuscript.

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McGovern, D.J., Polter, A.M., Prévost, E.D. et al. Ventral tegmental area glutamate neurons establish a mu-opioid receptor gated circuit to mesolimbic dopamine neurons and regulate opioid-seeking behavior. Neuropsychopharmacol. 48, 1889–1900 (2023). https://doi.org/10.1038/s41386-023-01637-w

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