Regional specificity of ethanol and NMDA action in brain revealed with FOS-like immunohistochemistry and differential routes of drug administration

Background: Inhibition of NMDA receptor function in brain is believed to be an important action of ethanol (EtOH). To investigate EtOH inhibition of N MDA receptor responses in vivo, the interaction of these agents in brain af ter different routes of administration were investigated by using transcrip tion factor Fos protein expression to follow NMDA receptor activation and E tOH inhibition of this response. Methods: The induction of Fos-like immunoreactivity (Fos-LI) in 38 regions of the rat brain was measured 2 hr after treatment with NMDA, EtOH, or both . To determine the relative contribution of abdominal drug effects on Fos i nduction, rats received either intraperitoneal (ip) or intragastric (ig) Et OH and ip or intravenous (iv) NMDA. Rats received EtOH (2.5 g/kg ip or 4 g/ kg ig) or vehicle 15 min before NMDA (125 mg/kg ip or 60 mg/kg iv) or vehic le. Results: For the 38 forebrain regions examined, ip and iv NMDA significantl y induced Fos-LI in 13 and 32 regions, respectively. These effects occurred without elicitation of tonic-clonic seizure activity and were strong after iv NMDA in the frontal, prefrontal, and cingulate cortices, supraoptic nuc leus, anterior lateral septum, and dentate gyrus. For EtOH, prominent Fos-L I induction was found in the central amygdala, dorsolateral bed nucleus of the stria terminalis, Edinger-Westphal nucleus, and paraventricular hypotha lamus. Despite ip and ig EtOH induction of Fos-LI in these regions, the maj or effect of EtOH was to block NMDA-induced Fos-LI in 8 of 13 (ip) and 27 o f 32 (ig) of the NMDA-positive regions, respectively, including retrospleni al, cingulate, and medial prefrontal cortices, central amygdala, and taenia tecta. Conclusions: These results provide new evidence for the regionally specific functional interactions of EtOH on NMDA receptors in vivo. Moreover, these results support efforts to identify brain region-specific targets for EtOH and EtOH-induced changes in gene expression.