Exercise Restores The Excitation-inhibition Balance In Vta Dopamine Neurons Disrupted By Nicotine Addiction

Abstract

PURPOSE: The imbalance between excitation and inhibition has been implicated in a variety of neurological disorders including addiction. This study aimed to investigate whether repeated nicotine exposure in vivo altered the excitation-inhibition (E/I) balance of dopamine neurons in the ventral tegmental area (VTA), and if so, whether exercise affects nicotine-induced changes in the E/I balance. METHODS: 2 months old C57BL/6 J mice were randomly divided into sedentary saline group (SS), sedentary nicotine group (SN), exercise saline group (ES) and exercise nicotine group (EN). ES and EN mice were introduced to a treadmill running paradigm (12 m/min for 10 min and 15 m/min for 50 min, 60 min/d, 5 d/w, 8 weeks). The conditioned place preference (CPP) paradigm was used to examine nicotine addiction related behavior. SN and EN mice were given an intraperitoneal injection of nicotine (0.5 mg/kg) while SS and ES mice were given an injection of saline. Patch clamp was used to investigate the excitatory and inhibitory synaptic transmission and E/I ratio in VTA dopamine neurons. RESULTS: Exercise decreased repeated nicotine exposure in vivo induced CPP expression (SS, -27.58 ± 29.72; SN, 123.96 ± 9.74; SE, -21.82 ± 17.23; NE, 65.14 ± 6.58; SS vs. SN, p < 0.001; SN vs. EN, p < 0.001). Exercise restored the reduction of GABAergic inhibition induced by nicotine CPP (IPSC PPR after nicotine acute exposure, SS, 0.53 ± 0.05; SN, 1.23 ± 0.13; SE, 0.71 ± 0.04; NE, 0.81 ± 0.03; SS vs. SN, p < 0.001; SN vs. EN, p < 0.01). Exercise decreases the enhancement of AMPA/NMDA ratio induced by nicotine CPP (SS, 0.58 ± 0.08; SN, 0.96 ± 0.10; SE, 0.62 ± 0.09; NE, 0.59 ± 0.07; SS vs. SN, p < 0.01; SN vs. EN, p < 0.01). Nicotine CPP alters the E/I balance in VTA dopamine neurons, which is reversed by exercise (E/I ratio, SS, 0.74 ± 0.16; SN, 2.09 ± 0.27; SE, 0.86 ± 0.15; NE, 0.96 ± 0.26; SS vs. SN, p < 0.001; SN vs. EN, p < 0.01). CONCLUSIONS: Repeated nicotine exposure in vivo shifts the balance of excitatory and inhibitory synaptic transmission in VTA dopamine neurons. Exercise restores nicotine addiction by reestablishing the balance between excitation and inhibition. Supported by the China Postdoctoral Science Foundation (2018 M641260, 2019 T120067) and the Chinese Universities Scientific Fund (BSU2020038).