Activation of accumbal GABAB receptors inhibits δ1 and δ2 receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats

[Speaker] Tadashi Saigusa:1
[Co-author] Yuri Aono:1, Yuriko Watanabe:2
1:Department of Pharmacology, Nihon University School of Dentistry at Matsudo, Japan, 2:Department of Oral Surgery, Nihon University School of Dentistry at Matsudo, Japan

Background: The nucleus accumbens (NAc) is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area (VTA). Opioids, which include potent analgesics in clinical use, are thought to enhance dopaminergic neural activity in NAc by activating opioid receptors, namely δ and μ receptors in the VTA. δ receptor agonists increase accumbal extracellular dopamine (DA) levels in freely moving rats when they are infused into NAc. The NAc contains δ receptors that may decrease GABAergic inhibitory neurotransmission. Reduction in GABAB receptor-mediated inhibition of accumbal DA release due to δ receptor stimulation should be suppressed by activating accumbal GABAB receptors. As δ receptors are subdivided into δ1 and δ2 subtypes, we analysed the effects of the GABAB receptor agonist baclofen on δ1 receptor agonist DPDPE- and δ2 receptor agonist deltorphin II-induced accumbal DA efflux in freely moving rats using in vivo microdialysis.
Methods: Male Sprague-Dawley rats were used. DA levels in accumbal perfusates, taken every 5 min, were determined by HPLC-ECD. Drugs were applied intracerebrally into NAc through the dialysis probe. Doses of compounds show total amount administered (mol) during 25-50 min infusions.
Results: The δ1 receptor antagonist BNTX (150.0 pmol) and δ2 receptor antagonist naltriben (1.5 nmol) suppressed DPDPE (5.0 nmol)- and deltorphin II (25.0 nmol)-induced increases in DA efflux, respectively. Baclofen (2.5 and 5.0 nmol), which did not alter basal DA levels, inhibited DPDPE-induced DA efflux. Baclofen (2.5 and 5.0 nmol) also inhibited deltorphin II-induced DA efflux. A low dose of the GABAB receptor antagonist 2-hydroxysaclofen (100.0 nmol), which did not alter basal DA levels, counteracted the inhibitory effects of baclofen on DPDPE- and deltorphin II-induced DA efflux.
Conclusions: These results indicate that reduction in accumbal GABAB receptor-mediated inhibition of dopaminergic activity is necessary to facilitate δ1 and δ2 receptor-induced increases in accumbal DA efflux. This study also suggests that activation of δ1 and δ2 receptors on the cell bodies and/or terminals of accumbal GABAergic interneurons inhibits GABA release and, accordingly, decreases GABAB receptor-mediated inhibition of dopaminergic terminals, resulting in enhanced accumbal DA efflux.

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