Intravenous nicotine injection induces rapid, experience-dependent sensitization of glutamate release in the ventral tegmental area and nucleus accumbens

摘要

Although numerous data suggest that glutamate (GLU) is involved in mediating the neural effects of nicotine, direct data on nicotine-induced changes in GLU release are still lacking. Here, we used high-speed amperometry with enzyme-based GLU and enzyme-free GLU-null biosensors to examine changes in extracellular GLU levels in the ventral tegmental area (VTA) and nucleus accumbens shell (NAcc) induced by intravenous nicotine in a low, behaviorally active dose (30 μg/kg) in freely moving rats. Using this approach, we found that the initial nicotine injection in drug-naive conditions induces rapid, transient, and relatively small GLU release (~ 90 nM; latency ~ 15 s, duration ~ 60 s) that is correlative in the VTA and NAcc. Following subsequent nicotine injections within the same session, this phasic GLU release was supplemented by stronger tonic increases in GLU levels (100-300 nM) that paralleled increases in drug-induced locomotor activation. GLU responses induced by repeated nicotine injections were more phasic and stronger in the NAcc than in VTA. Therefore, GLU is phasically released within the brain's reinforcement circuit following intravenous nicotine administration. Robust enhancement of nicotine-induced GLU responses following repeated injections suggests this change as an important mediator of sensitized behavioral and neural effects of nicotine. By using high-speed amperometry with glutamate (GLU) biosensors, we show that i.v. nicotine at a low, behaviorally relevant dose induces rapid GLU release in the NAcc and VTA that is enhanced following repeated drug injections. This is the first study reporting second-scale fluctuations in extracellular GLU levels induced by nicotine in two critical structures of the motivation-reinforcement circuit and rapid sensitization of GLU responses coupled with locomotor sensitization. By using high-speed amperometry with glutamate (GLU) biosensors, we show that i.v. nicotine at a low, behaviorally relevant dose induces rapid GLU release in the NAcc and VTA that is enhanced following repeated drug injections. This is the first study reporting second-scale fluctuations in extracellular GLU levels induced by nicotine in two critical structures of the motivation-reinforcement circuit and rapid sensitization of GLU responses coupled with locomotor sensitization.