Changes in glutamate receptors, c-fos mRNA expression and activator protein-1 (AP-1) DNA binding activity in the brain of phenobarbital-dependent and -withdrawn rats.
We studied changes in glutamate receptors, expression of immediate early genes, and AP-1 DNA binding activity in the brains of phenobarbital (PB)-dependent and -withdrawn rats to investigate the possible involvement of activation of glutamate receptors in PB withdrawal syndrome. PB-dependent rats were prepared by feeding drug-admixed food for 5 weeks. Autoradiographic analysis showed that binding of [3H(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin e (MK-801), an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, increased significantly in the cerebral cortices of PB-dependent and 24-h-withdrawn rats. However, [3H]MK-801 binding in the hippocampus and [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]kainic acid binding in the hippocampus and cerebral cortex were essentially unchanged in both groups. PB withdrawal seizures were followed by increased expression of c-fos mRNA in the hippocampus and cerebral cortex and of c-jun mRNA in the cerebral cortex. The induction of c-fos and c-jun mRNA was suppressed by administration of MK-801. Furthermore, PB withdrawal enhanced AP-1 DNA binding activity in the brain. The present findings suggest functional enhancement of glutamatergic neurotransmission during the development of PB withdrawal syndrome.
Tanaka
S
S
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan.
Kiuchi
Y
Y
Numazawa
S
S
Oguchi
K
K
Yoshida
T
T
Kuroiwa
Y
Y
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism; D018757:GABA Modulators / Q000009:adverse effects*; D006651:Histocytochemistry; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000009:adverse effects*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology; D019966:Substance-Related Disorders / Q000378:metabolism / Q000523:psychology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018757:GABA Modulators; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017470:Receptors, Glutamate; D018808:Transcription Factor AP-1; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007608:Kainic Acid; D010634:Phenobarbital