Induction of cyclooxygenase-2 in brain during acute and chronic ethanol treatment and ethanol withdrawal.
Prostaglandins play an important role in the regulation of nervous system function including thermoregulation, autonomic nervous system function, hypothalamic regulation of pituitary function, and neuronal excitation. Prostaglandin synthesis is catalyzed by cyclooxygenase (COX; prostaglandin synthase) which occurs as two isozymes, COX-1 and COX-2. COX-1 and COX-2 are constitutively expressed in brain whereas COX-2 type is also inducible in brain by excitatory neurotransmission. Ethanol intoxication and the hyperexcitability of ethanol withdrawal may be influenced by inducible proteins, thus we investigated COX-2 in the rat brain during acute and chronic ethanol treatment, ethanol withdrawal, and after peripheral administration of excitatory amino acids. Kainic acid or NMDA treatment increased COX-2 immunoreactivity in the cortex, hippocampus, and amygdala. An acute dose of ethanol (5 g/kg, intragastric-i.g.) increased COX-2, particularly in the CA4 region of the hippocampus and agranular insular cortex. Chronic ethanol treatment (4 days-intragastric) robustly induced COX-2 in limbic cortex, isocortex, and amygdala. Particularly dense immunocytochemical staining was found in perirhinal and piriform cortices, dentate gyrus, and tenia tecta. During ethanol withdrawal, COX-2 expression increased further in some regions, peaking in most areas 16 hr after the last dose of ethanol. These results indicate that COX-2 immunoreactivity is: 1) increased in the brain during acute ethanol exposure that increases further during chronic treatment; 2) sensitive to excitatory amino acid receptor stimulation; and 3) dramatically increased during ethanol withdrawal. These studies suggest that COX-2 induction may be involved in the acute and chronic effects of ethanol.
Knapp
D J
DJ
Center for Alcohol Studies and Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7178, USA. djkjas@unc.med.edu
Crews
F T
FT
D000435:Alcoholic Intoxication / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D010544:Peroxidases / Q000096:biosynthesis / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
D007527:Isoenzymes; D000431:Ethanol; D016202:N-Methylaspartate; D010544:Peroxidases; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007608:Kainic Acid