Glycogen Synthase Kinase 3β Inhibitiors Blocks The Abormalty Of Neurotransmission Induced By Cocaine In Neucleus Accuembens

As a kind of abuse substance, cocaine acts as an inhibitor of dopamine transporters. By inhibiting the up-taking process of dopamine, cocaine increased the concentration of dopamine in the inter-synaptic cleft, which constitutes to the pharmacological basis for the cocaine addiction. In recent years, the role of glycogen synthase kinase 3-β in the cocaine addiction has been established. GSK3β inhibitors can alleviate the cocaine-induced neuronal hyper-excitability by acting on the medium spiny neurons(MSN) in the nucleus accumbens(Nac). However, the acting details are kept obscure, and the interaction between GSK3β, cocaine and dopamine needs further investigation.In this study, we explored the role and the acting detail that GSK3β plays in the hyper-excitability induced by cocaine by methods of animal behavior, brain slice clamp and the extracellular recording in vivo. Our findings are as follows, the GSK3 inhibitor LiCl(100 mg/kg,i.p.)and the specific GSK3β inhibitor SB216763(2.5 mg/kg,i.p.)can block the hyper-locomotor activity induced by cocaine in rats.SB216763 and LiCl can also reverse the inhibiting action of cocaine on the firing of MSN in the core of Nac. The pre-perfusion of SB216763(5 μM)can ameliorate the inhibiting effect of cocaine(10 μM) on evoked AMPA mediated excitatory post-synaptic current(EPSC) and NMDA mediated EPSC in the Nac Core via the activation of dopamine receptor-1.Cocaine can inhibit the release of glutamate from the pre-synaptic zone of MSN in NAC. SB216763 can alleviate this kind of inhibition. Cocaine can activate the dopamine receptor-2, and lower the excitability of MSN, which can’t be changed by SB216763.The ratio between AMPA mediated EPSC and NMDA mediated EPSC was higher in the cocaine repeated administered(5 days) groups than the saline treated group. The perfusion of GKS3β inhibitor annulled this kind of increase.Our study indicated that cocaine can activate the dopamine recpeor-1 and GSK3β in the pre-synaptic zone, prohibit the release of glutamate from the pre-synaptic zone, inhibit the firing of MSN in Nac, reduce the release of inhibitory neurotransmitter GABA, and consequently promote the pan hyper-excitability of brain. GSK3β can promote the release of glutamate during the use of cocaine, block the inhibiting effect of cocaine on the MSN in Nac, and alleviate the hyper-locomotor activity induced by cocaine in rats. Meanwhile, SB216763 can block the cocaine induced neuro-plasticity, which paves a new way for treating the cocaine addiction.