title: GSK-3β inhibitors reverse cocaine-induced synaptic transmission dysfunction in the nucleus accumbens.
abstract: Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats. By employing single-unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine-inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N-methyl-D-aspartic acid receptor (NMDAR)-mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor-mediate excitatory postsynaptic current (EPSC) were mimicked by the D1 -like receptor agonist SKF 38393 and blocked by the D1 -like receptor antagonist SCH 23390, whereas D2 -like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor-mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D1 -like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D1 receptor-GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine-induced hyperlocomotion.
authors.affiliation: Jiangsu Key laboratory for Translational Research and Therapy for Neuropsychiatric disorders & The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu Province, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Jiangsu Key laboratory for Translational Research and Therapy for Neuropsychiatric disorders & The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu Province, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Jiangsu Key laboratory for Translational Research and Therapy for Neuropsychiatric disorders & The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu Province, China.
authors.forename: Zhaoxiang
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Tianjin Medical University School of Biomedical Engineering, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Jiangsu Key laboratory for Translational Research and Therapy for Neuropsychiatric disorders & The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu Province, China. zhenxuechu@suda.edu.cn.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D001552:Benzazepines; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C417521:SB 216763; C534628:SCH 23390; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride; D003042:Cocaine
keywords: D1 receptor; GSK3β; NAc; cocaine