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PO1-1-129

Analysis of the roles of μ receptor subtypes in the regulation of acetylcholine and dopamine efflux in the nucleus accumbens of freely moving rats

[Speaker] Yuri Aono:1
[Co-author] Yuriko Watanabe:2, Tadashi Saigusa:1
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 contains μ receptors on which opioid analgesics could act. Such μ receptors exist as μ 1 and μ 2 subtypes based on sensitivity to the μ 1 receptor antagonist naloxonazine. We have shown that local administration of the putative endogenous μ receptor agonists endomorphin (EM)-1 and EM-2 into NAc increases accumbal dopamine (DA) with and without stimulating μ receptors, respectively. The NAc includes cholinergic interneurons expressing μ receptors that may inhibit neural activity. However, the roles of μ receptors in regulating accumbal neuronal acetylcholine (ACh) release are unknown. Therefore, we analysed the effects of endomorphins on ACh efflux in NAc of freely moving rats using in vivo microdialysis. Perfusates contained a low concentration of the cholinesterase inhibitor physostigmine (50 nM) to reduce enzymatic degradation of extracellular ACh. Since this may affect regulation of accumbal DA efflux by endomorphins, we re-evaluated the effects of μ receptor antagonists on EM-1- and EM-2-induced accumbal DA efflux.
Methods: Male Sprague-Dawley rats were used. ACh and DA levels in accumbal perfusates, taken every 15 and 20 min, were determined by HPLC-ECD. Apart from naloxonazine, which was given intraperitoneally, μ receptor ligands were administered intracerebrally through the dialysis probe. Doses of these compounds indicate total amount (mol) over a 30-min infusion time.
Results: EM-1 and EM-2 (6 and 30 nmol) decreased ACh in a dose-related manner. These EM-1- and EM-2 (30 nmol)-induced reductions in ACh were prevented by co-administration of the μ receptor antagonist CTOP (3 nmol), which failed to alter basal ACh. Both EM-1 (15 nmol) and EM-2 (30 nmol) enhanced DA efflux. EM-1- but not EM-2-induced DA efflux was suppressed by CTOP. Naloxonazine (15 mg/kg), which inhibits EM-1-induced DA efflux, did not alter EM-1- and EM-2-induced reductions in ACh.
Conclusions: The present results show that μ receptors mediate inhibition of accumbal ACh efflux. This study also provides in vivo neurochemical evidence indicating μ 1 receptors play a stimulatory role in regulating accumbal DA efflux and μ 2 receptors play an inhibitory role in regulating accumbal ACh efflux.
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