Behavioral and Molecular Responses to Ethanol in Mice Expressing Ethanol-Resistant NMDA Receptor

Glutamate activated N-methyl-D-aspartate receptors (NMDARs) play a major role in mediating alcohol action including those associated with intoxication and withdrawal. Alterations in NMDAR function that alter the sensitivity of the receptor to ethanol may contribute to the subjective response of ethanol and underlie individual risk of developing alcoholism. The precise molecular site(s) of action for ethanol on NMDARs remains unknown though recent work has identified a potential site of action on the GluN1 subunit of the NMDAR that when mutated (F639A) decreases the ethanol sensitivity of the receptor. This dissertation first characterizes the functional and behavioral responses of knockin mice that express mutant NMDARs with altered sensitivity to ethanol inhibition. Results from these studies confirm the long-standing hypothesis that NMDARs are key mediators of specific behavioral actions of acute ethanol and supports the hypotheses that the F639 residue in the third transmembrane domain of the GluN1 subunit defines an alcohol sensitive site on the receptor. It provides evidence for NMDARs sensitivity to ethanol in regulating ethanol drinking behavior. This work also examines if the extent of ethanol inhibition of NMDARs alters the neuroadaptations associated with chronic ethanol. These results show that adaptive changes in NMDAR expression following repeated ethanol treatment are influenced by ethanol sensitivity of the receptor and that this underlies behavioral adaptations to ethanol. Together, this work supports the hypothesis that reducing the ethanol inhibition of the receptor alters the effects of ethanol on behavioral intoxication, consummatory behavior, and molecular adaptations