Glutamate transmission in the prelimbic cortex and nucleus accumbens shell is involved in ethanol reinforcement and drinking in rats

Introduction: Research has implicated mesocorticolimbic glutamate transmission in alcohol use. The current study focused on glutamate transmission within two key sub-regions, i.e., prelimbic (PL) cortex and nucleus accumbens (NAc) shell, in mediating ethanol reinforcement and drinking in rats. Methods: Intracranial self-administration (ICSA) was conducted to examine effects of inhibition of local glutamate transmission on ethanol ICSA into these sub-regions. Protein levels were determined with Western blot in both sub-regions of alcohol-preferring P and Wistar rats on key glutamate-related proteins that can regulate extracellular glutamate levels. Quantitative microdialysis was performed to measure basal extracellular glutamate concentrations and clearance in the PL cortex following chronic ethanol drinking. An additional study tested effects of centrally administered LDN-212320, a glutamate transporter 1 (GLT-1) activator, on ethanol drinking. Results: Co-infusion of the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268 with ethanol inhibited ethanol ICSA into these sub-regions. Expression of mGluR3, but not GLT-1, was lower in P than Wistar rats in both sub-regions. Ethanol drinking enhanced basal extracellular glutamate concentrations and reduced glutamate clearance. Intra-ventricular microinjection of LDN-212320 decreased ethanol drinking. Discussion: These results suggest that (a) activation of local glutamate transmission is critical to ethanol reinforcement within the PL cortex and NAc shell, (b) strain difference exists in mGluR3 protein expression between P and Wistar rats, (c) chronic ethanol induces neuro-adaptations characterized by enhanced basal extracellular glutamate transmission, and (d) up-regulation of GLT-1 attenuates ethanol drinking. Taken together, these results further support the importance of glutamate transmission within the PL cortex and NAc shell in mediating ethanol effects.