Glutamate Transmission to Ventral Tegmental Area GABA Neurons Is Altered by Acute and Chronic Ethanol

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2018-11, Vol.42 (11), p.2186-2195
• Main Authors: Williams, Stephanie B., Yorgason, Jordan T., Nelson, Ashley C., Lewis, Natalie, Nufer, Teresa M., Edwards, Jeff G., Steffensen, Scott C.
• Format: Article
• Language: English
• Subjects: Adaptation; Alcohol; Alcohol withdrawal; Alcohols; Animal behavior; Dopamine; Drug abuse; Ethanol; Excitability; Excitatory postsynaptic potentials; Exposure; GABA; Glutamate; Injection; Mesolimbic system; N-Methyl-D-aspartic acid; Neurons; Reinforcement; Rodents; Synaptic transmission; Transgenic mice; Ventral Tegmental Area; Ventral tegmentum; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.13883

Background Ventral tegmental area (VTA) GABA neurons have been heavily implicated in alcohol reinforcement and reward. In animals that self‐administer alcohol, VTA GABA neurons exhibit increased excitability that may contribute to alcohol's rewarding effects. The present study investigated the effects of acute and chronic ethanol exposure on glutamate (GLU) synaptic transmission to VTA GABA neurons. Methods Whole‐cell recordings of evoked, spontaneous, and miniature excitatory postsynaptic currents (eEPSCs, sEPSCs, and mEPSCs, respectively) were performed on identified GABA neurons in the VTA of GAD67‐GFP+ transgenic mice. Three ethanol exposure paradigms were used: acute ethanol superfusion; a single ethanol injection; and chronic vapor exposure. Results Acute ethanol superfusion increased the frequency of EPSCs but inhibited mEPSC frequency and amplitude. During withdrawal from a single injection of ethanol, the frequency of sEPSCs was lower than saline controls. There was no difference in α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/N‐methyl‐d‐aspartate (NMDA) ratio between neurons following withdrawal from a single exposure to ethanol. However, following withdrawal from chronic ethanol, sEPSCs and mEPSCs had a greater frequency than air controls. There was no difference in AMPA/NMDA ratio following chronic ethanol. Conclusions These results suggest that presynaptic mechanisms involving local circuit GLU neurons, and not GLU receptors, contribute to adaptations in VTA GABA neuron excitability that accrue to ethanol exposure, which may contribute to the rewarding properties of alcohol via their regulation of mesolimbic dopamine transmission. GABA neurons in the ventral tegmental area (VTA) of the midbrain implicated in natural and drug reward exhibit increased excitability following withdrawal from alcohol. The objective of this study was to determine if glutamate synaptic transmission to these neurons adapts to chronic ethanol. This figure shows that following withdrawal from chronic ethanol, spontaneous and mini excitatory postsynaptic potentials on VTA GABA neurons had a greater frequency than controls, providing some evidence supporting this hypothesis.