NMDA RECEPTOR-BINDING IN ADULT-RAT BRAIN AFTER SEVERAL CHRONIC ETHANOL TREATMENT PROTOCOLS

The amino acid L-glutamate is a major excitatory neurotransmitter that is involved in many CNS functions, including learning, memory, long-t erm potentiation, and synaptic plasticity. Acute exposures to ethanol (50 to 200 mM) have been shown to inhibit NMDA receptor responses, whe reas chronic exposure to ethanol leads to adaptive supersensitivity th ought to be involved in ethanol dependence and tolerance. To investiga te the effects of chronic ethanol exposure on glutamate receptor densi ty, we examined the binding of both NMDA and non-NMDA ligands in rat b rain after several chronic ethanol treatment protocols using a number of different rat strains. No increases in the binding of [H-3]MK-801, [H-3]CGP 39653, or the polyamine specific competitive antagonist, [H-3 ]ifenprodil, were seen after two well-used chronic ethanol treatments. These included the 2-week liquid diet developed by Frye et al. (J. Ph armacol. Exp. Ther. 216:306-314, 1981) and the 4-day binge treatment d eveloped by Majchrowicz (Psychopharmacologia 43:245-254, 1975). Howeve r, small increases in the binding of both the NMDA noncompetitive anta gonist [H-3]MK-801, as well as the competitive NMDA antagonist [H-3]CG P 39653, were seen in select frontal brain regions after 3 weeks of th e Walker-Freund chronic ethanol liquid diet. When this chronic liquid diet treatment was extended to a period of 6 weeks, these increases in receptor binding were diminished to nonsignificant levels. The bindin g of the non-NMDA ligands [H-3]AMPA and [H-3]kainate were not signific antly affected by either length of Walker-Freund liquid diet exposure. When rats were treated chronically with ethanol for 30 days using the paradigm developed by Tsukamoto et al. (Hepatology 5:224-232, 1985), small, but significant, increases in the binding of [H-3]MK-801 were s een in the CA1 and dentate gyrus regions of the hippocampus. These stu dies indicate that robust increases in NMDA receptor binding do not oc cur with several chronic ethanol treatment protocols, and suggests tha t NMDA receptor supersensitivity during the development of tolerance a nd dependence to ethanol may not simply be due to changes in the densi ty of NMDA receptors, but may involve other mechanisms.