Effects Of Aerobic Exercise On The Nicotine Addiction Induced Inhibitory Synaptic Plasticity In The Vta

Abstract

PURPOSE: Disinhibition of the ventral tegmental area (VTA) dopamine neurons has been implicated in nicotine addiction. This study aimed to investigate the effect of aerobic exercise on the nicotine addiction behavior in mice, and the effect on GABAergic transmission and dopaminergic activity in the VTA. METHODS: 2 months old male C57BL/6J mice were randomly divided into sedentary + saline group (SS), sedentary + nicotine group (SN), exercise + saline group (ES) and exercise + nicotine group (EN) respectively. The ES and EN groups were made to run on the treadmill for 1 hour per one day, five times a week, for 12 weeks. The exercise workload consisted of running at a speed of 12 m/min for the first 10 min, 15 m/min for the last 50 min, with 0% grade of inclination. The conditioned place preference (CPP) assay was used to evaluate nicotine addiction related behavior. In the CPP assay, SN and EN mice were given an intraperitoneal (i.p.) 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 dopamine neuron excitability and GABAergic transmission in the VTA. Immunofluorescence was used to detect the expression of tyrosine hydroxylase (TH) in the VTA. RESULTS: 8 weeks of treadmill exercise decreased nicotine exposure induced CPP expression (CPP score, SS, -33.69±16.57; SN, 121.51±14.53; ES, -21.72±15.12; EN, 66.34±15.12; SS vs. SN, p<0.001; EN vs. SN, p<0.05, two-way ANOVA). Exercise decreased nicotine CPP induced dopamine neuron hyperexcitability (SS, 3.36±0.45; SN, 6.63±0.56; ES, 3.22±0.48; EN, 4.60±0.18; SS vs. SN, p<0.001; EN vs. SN, p<0.01, two-way ANOVA). Exercise decreased nicotine CPP induced increase of TH expression in the VTA (relative fluorescence intensity, SS 1.00; SN, 2.03±0.15; ES, 1.38±0.06; EN, 1.04±0.07; SS vs. SN, p<0.001; EN vs. SN, p<0.001, two-way ANOVA). Exercise restored nicotine CPP induced impairment of GABA transmission in the VTA (sIPSCs frequency, % as baseline, SS, 154.62±6.86%; SN, 102.19±6.20; ES, 141.36±5.84; EN, 121.82±4.41; SS vs. SN, p<0.001; EN vs. SN, p<0.05, two-way ANOVA). CONCLUSIONS: Aerobic exercise restores nicotine addiction induced VTA dopamine neuron hyperexcitability by enhancing the inhibitory transmission. Supported by the China Postdoctoral Science Foundation (2018M641260, 2019T120067).