title: Acute effects of resveratrol to enhance cocaine-induced dopamine neurotransmission in the striatum.
abstract: Resveratrol is known as an activator of SIRT1, which leads to the deacetylation of histone and non-histone protein substrates, but also has other pharmacological profiles such as the inhibition of monoamine oxidase (MAO)-A and MAO-B. Resveratrol was previously demonstrated to potentiate the rewarding effects of chronic cocaine via activation of SIRT1. However, the role of resveratrol in cocaine responses in the acute phase remains unexplored. Therefore, we investigated the acute effects of resveratrol on cocaine-stimulated dopamine neurotransmission by analyzing protein phosphorylation in neostriatal slices. Treatment with resveratrol (50μM for 30min) enhanced cocaine-induced increases in the phosphorylation of DARPP-32 at Thr34 and GluA1 at Ser845, postsynaptic substrates for dopamine/D1 receptor/PKA signaling, and a cocaine-induced decrease in the phosphorylation of tyrosine hydroxylase at Ser40, a presynaptic substrate for dopamine/D2 receptor signaling. The inhibition of both MAO-A and MAO-B by clorgyline and pargyline, respectively, enhanced the effects of cocaine on DARPP-32 phosphorylation. The acute effect of resveratrol on cocaine-induced DARPP-32 phosphorylation was occluded with inhibition of MAO-A and MAO-B. In behavioral studies, resveratrol (40mg/kg, s.c.) enhanced the increase in locomotor activity induced by acute cocaine administration (10mg/kg, i.p.). Thus, this study provides pharmacological evidence that acute resveratrol enhances cocaine-induced dopamine neurotransmission and behavioral responses, presumably via mechanisms involving the inhibition of dopamine catabolism by MAO-A and MAO-B. Resveratrol may be useful to treat dysregulated dopamine neurotransmission, but it may enhance the risk of developing drug addiction.
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Shuto
authors.forename: Mahomi
authors.initials: M
authors.lastname: Kuroiwa
authors.forename: Yuki
authors.initials: Y
authors.lastname: Koga
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kawahara
authors.forename: Naoki
authors.initials: N
authors.lastname: Sotogaku
authors.forename: Koji
authors.initials: K
authors.lastname: Toyomasu
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; C497929:Ppp1r1b protein, mouse; D013267:Stilbenes; D008995:Monoamine Oxidase; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine; D000077185:Resveratrol; D004298:Dopamine