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 NMDA receptor responses in vivo, the interaction of these agents in brain after different routes of administration were investigated by using transcription factor Fos protein expression to follow NMDA receptor activation and EtOH 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 induction, rats received either intraperitoneal (ip) or intragastric (ig) EtOH 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 vehicle.


RESULTS
For the 38 forebrain regions examined, ip and iv NMDA significantly 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 nucleus, anterior lateral septum, and dentate gyrus. For EtOH, prominent Fos-LI induction was found in the central amygdala, dorsolateral bed nucleus of the stria terminalis, Edinger-Westphal nucleus, and paraventricular hypothalamus. Despite ip and ig EtOH induction of Fos-LI in these regions, the major effect of EtOH was to block NMDA-induced Fos-LI in 8 of 13 (ip) and 27 of 32 (ig) of the NMDA-positive regions, respectively, including retrosplenial, 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.
Knapp
D J
DJ
Bowles Center for Alcohol Studies, and Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. djkjas@med.unc.edu
Braun
C J
CJ
Duncan
G E
GE
Qian
Y
Y
Fernandes
A
A
Crews
F T
FT
Breese
G R
GR
D000818:Animals; D001519:Behavior / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry; D002404:Catheterization; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage* / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects; D014018:Tissue Distribution
D016760:Proto-Oncogene Proteins c-fos; D000431:Ethanol; D016202:N-Methylaspartate