Voluntary Ethanol Intake Enhances Excitatory Synaptic Strength in the Ventral Tegmental Area

Abstract

BACKGROUND: Addiction has been considered a disorder of motivational control over behavior, and the ventral tegmental area (VTA), in conjunction with other limbic brain structures, is thought to play a critical role in the regulation of a number of motivated behaviors including seeking of addictive drugs such as alcohol. Of particular interest is the ability of prolonged exposure of addictive drugs to enhance the function of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic receptors (AMPAR) in the VTA, as glutamate receptor activation can significantly regulate VTA neuron activity. Here, we examined whether voluntary ethanol intake altered VTA AMPAR function. METHODS: We utilized in vitro electrophysiology to examine glutamatergic function in the VTA neurons 12 to 24 hours after the last self-administration bout, which occurred 35 to 50 days after the initiation of ethanol self-administration under a 2-bottle intermittent access model. RESULTS: Voluntary intermittent ethanol intake in a 2-bottle paradigm enhanced postsynaptic AMPAR function, indicated by an increased ratio of evoked AMPAR to N-methyl-d-aspartic acid receptor currents, and by an increase in the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) measured in the presence of tetrodotoxin to prevent action potential-dependent release. In contrast, ethanol self-administration did not alter evoked presynaptic glutamate release, indicated by no change in the paired-pulse ratio of 2 AMPAR EPSCs evoked 50 ms apart, although spontaneous glutamate release was significantly enhanced, indicated by enhanced mEPSC frequency. CONCLUSIONS: Our results suggest that postsynaptic AMPAR function in VTA neurons was significantly enhanced after ethanol self-administration. As increased VTA AMPAR function can significantly regulate firing and enhance the reinforcing and activating effects of drugs of abuse, the increased AMPAR activity observed here may facilitate the drive to consume ethanol.