NMDA ANTAGONISTS AND CLONIDINE BLOCK C-FOS EXPRESSION DURING MORPHINE-WITHDRAWAL

The c-fos gene is expressed in the central nervous system (CNS) in res ponse to neuronal stimuli. Induction of c-fos in certain CNS regions o ccurs following naltrexone precipitated withdrawal in morphine depende nt rats. Non-competitive (MK801) and competitive (LY274614) NMDA recep tor antagonists and clonidine, an alpha, partial agonist, attenuate th e intensity of naltrexone precipitated withdrawal. Sire determined the levels of c-fos mRNA by solution hybridization in several brain regio ns in control and morphine dependent rats following pretreatment with saline, MK801 (1 mg/kg, s.c.), LY274614 (100 mg/kg, i.p.), or clonidin e (1.5 mg/kg, i.p.). Morphine treatment increased c-fos mRNA levels in striatum (STR) and amygdala (AMY). Naltrexone did not alter c-fos mRN A levels in placebo-treated rats. However, naltrexone increased c-fos mRNA levels in morphine dependent rats in the nucleus accumbens (NA), frontal cortex (FC), AMY, and hippocampus (HIP) but not in STR or spin al cord. Pretreatment with MK801 blocked this effect of naltrexone in AMY but not in NA, FC, or HIP, while pretreatment with LY274614 or clo nidine blocked this effect of naltrexone in AMY and NA but not in FC o r HIP. These results further delineate both the neuroanatomical pathwa ys involved in morphine withdrawal and the locus of action of compound s that reduce morphine-withdrawal symptoms. (C) 1995 Wiley-Liss, Inc.