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Integrative opioid-GABAergic neuronal mechanisms regulating dopamine efflux in the nucleus accumbens of freely moving animals

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Abstract

The nucleus accumbens (NAc) is a terminal region of mesocorticolimbic dopamine (DA) neuronal projections from the ventral tegmental area. Accumbal DA release is integrated by afferents from other brain regions and by interneurons, which involve a diversity of neurotransmitters and neuropeptides. These integrative processes, implicated in the pathobiology of neuropsychiatric disorders, are mediated via receptor subtypes whose relative roles in the regulation of accumbal DA release are poorly understood. Such complex interactions are exemplified by how selective activation of opioid receptor subtypes enhances accumbal DA efflux in a manner that is modulated by changes in neural activity through GABA receptor subtypes. This review delineates the roles of GABAA and GABAB receptors in GABAergic neural mechanisms in NAc that participate in delta- and mu-opioid receptor-mediated increases in accumbal DA efflux in freely moving rats, focusing on studies using in vivo brain microdialysis. First, we consider how endogenous GABA exerts inhibition of accumbal DA efflux through GABA receptor subtypes. We also consider possible intra-neuronal source of the endogenous GABA that inhibits accumbal DA efflux. As NAc contains GABAergic neurons that express delta- or mu-opioid receptors, inhibition of accumbal GABAergic neurons is a candidate for mediating delta- or mu-opioid receptor-mediated increases in accumbal DA efflux. Therefore, we provide a detailed analysis of the effects of GABA receptor subtype ligands on delta- and mu-opioid receptor-mediated accumbal DA efflux. Finally, we present an integrative model to explain the mechanisms of interaction among delta- and mu-opioid receptors, GABAergic neurons and DAergic neurons in NAc.

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Abbreviations

Allylglycine:

l-allylglycine

DA:

Dopamine

GAD:

Glutamic acid decarboxylase

NAc:

Nucleus accumbens

VTA:

Ventral tegmental area

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Funding

This study was supported by Grant-in-Aid for Scientific Research (C) (#17K11858 to TS; #18K09777 to YA) from the Ministry of Education, Culture, Sports, Science and Technology, Japan; The Private University Research Branding Project from MEXT, Japan; Nihon University President's Grant for Specified Interdisciplinary Research: Grant from The Nakatomi Foundation, Japan (TS, JLW); Grants from Suzuki Fund, Nihon University School of Dentistry at Matsudo; Grants from Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo (TS, YA).

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Authors and Affiliations

  1. Department of Pharmacology, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakaecho-Nishi, Matsudo, Chiba, 271-8587, Japan

    Tadashi Saigusa & Yuri Aono

  2. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, St. Stephen’s Green, Dublin 2, Ireland

    John L. Waddington

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  1. Tadashi Saigusa
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  2. Yuri Aono
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  3. John L. Waddington
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TS and JLW reviewed the recent literature and drafted the review. TS, YA and JLW were involved in many of the microdialysis studies that are included in the review. All authors contributed to and approved the final manuscript for submission.

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Correspondence to Tadashi Saigusa.

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Saigusa, T., Aono, Y. & Waddington, J.L. Integrative opioid-GABAergic neuronal mechanisms regulating dopamine efflux in the nucleus accumbens of freely moving animals. Pharmacol. Rep 73, 971–983 (2021). https://doi.org/10.1007/s43440-021-00249-9

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