Differential effects of methamphetamine and SCH23390 on the expression of members of IEG families of transcription factors in the rat striatum.
Methamphetamine (METH) is a psychostimulant that can cause long-lasting neurodegenerative effects in humans and animals. These toxic effects appear to occur, in part, via activation of dopamine (DA) D1 receptors. This paper assessed the possibility that the DA D1 receptor antagonist, SCH23390, might inhibit METH-induced changes in the expression of several members of immediate early genes (IEGs) which are known to control more delayed expression of other genes. We found that injections of METH (4x10 mg/kg, given at 2 h intervals) caused significant increases in c-fos and fra-2 expression which lasted from 30 min to 4 h. Pre-treatment with SCH23390, given 30 min before each METH injection, completely blocked METH-induced expression of c-fos, but only partially inhibited fra-2 mRNA expression. These results were confirmed by Western blot analysis which showed METH-induced changes in c-Fos protein expression that were blocked by pretreatment with SCH23390. There were also delayed METH-induced DA D1 receptor-dependent effects on fosB mRNA expression. Even though fra-1 expression was not affected by pretreatment with METH alone, the repeated injections of SCH23390 caused substantial decreases in fra-1 mRNA expression in both the presence and absence of METH. The repeated injections of METH caused no changes in the mRNAs for c-jun, junB or junD. However, there were significant increases in the phosphorylation of c-Jun protein (ser63). Phosphorylation of c-Jun occurred in a delayed fashion (16 and 24 h after the last METH injections) and was attenuated by SCH23390 pretreatment. Interestingly, SCH23390 given alone caused significant decreases in phospho-c-Jun at all time-points. The METH injections also caused delayed induction in the expression of members of the Egr family of transcription factors in a DA D1 receptor-dependent fashion. Repeated injections of SCH23390 caused substantial suppression of basal striatal egr-1 and egr-2 mRNA expression but not of that of egr-3. Both crem and arc mRNA levels were induced by METH in a SCH23390-sensitive fashion. Moreover, multiple injections of SCH23390 given alone caused marked inhibition of basal arc expression. These results show that multiple injections of METH can differentially affect the expression of several IEGs, some of which occurred in a DA D1 receptor dependent fashion. The SCH23390-mediated suppression of basal fra-1, egr-1, and egr-2 mRNA levels suggests that their basal expression in the striatum might be dependent on tonic stimulation of the DA D1 receptor.
Beauvais
Genevieve
G
Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Jayanthi
Subramaniam
S
McCoy
Michael T
MT
Ladenheim
Bruce
B
Cadet
Jean Lud
JL
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology*; D051765:Early Growth Response Transcription Factors / Q000378:metabolism; D051921:Fos-Related Antigen-2 / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism
D001552:Benzazepines; D000697:Central Nervous System Stimulants; C497412:Crem protein, rat; D003598:Cytoskeletal Proteins; D018492:Dopamine Antagonists; D051765:Early Growth Response Transcription Factors; D051921:Fos-Related Antigen-2; C483820:Fosb protein, rat; C497874:Fosl2 protein, rat; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; C534628:SCH 23390; C092069:activity regulated cytoskeletal-associated protein; D051786:Cyclic AMP Response Element Modulator; D008694:Methamphetamine; D048031:JNK Mitogen-Activated Protein Kinases