title: Chronic methamphetamine exposure suppresses the striatal expression of members of multiple families of immediate early genes (IEGs) in the rat: normalization by an acute methamphetamine injection.
abstract: BACKGROUND
  Repeated injections of cocaine cause blunted responses to acute cocaine challenge-induced increases in the expression of immediate early genes (IEGs).
  
  
  OBJECTIVE
  The aim of this study was to test if chronic methamphetamine (METH) exposure might cause similar blunting of acute METH-induced increases in IEG expression.
  
  
  RESULTS
  Repeated saline or METH injections were given to rats over 14 days. After 1 day of withdrawal, they received a single injection of saline or METH (5 mg/kg). Acute injection of METH increased c-fos, fosB, fra2, junB, Egr1-3, Nr4a1 (Nur77), and Nr4a3 (Nor-1) mRNA levels in the striatum of saline-pretreated rats. Chronic METH treatment alone reduced the expression of AP1, Erg1-3, and Nr4a1 transcription factors below control levels. Acute METH challenge normalized these values in METH-pretreated rats. Unexpectedly, acute METH challenge to METH-pretreated animals caused further decreases in Nr4a2 (Nurr1) mRNA levels. In contrast, the METH challenge caused significant but blunted increases in Nr4a3 and Arc expression in METH-pretreated rats. There were also chronic METH-associated decreases in the expression of cAMP responsive element binding protein (CREB) which modulates IEG expression via activation of the cAMP/PKA/CREB signal transduction pathway. Chronic METH exposure also caused significant decreases in preprotachykinin, but not in prodynorphin, mRNA levels.
  
  
  CONCLUSIONS
  These results support the accumulated evidence that chronic administration of psychostimulants is associated with blunting of their acute stimulatory effects on IEG expression. The METH-induced renormalization of the expression of several IEGs in rats chronically exposed to METH hints to a potential molecular explanation for the recurrent self-administration of the drug by human addicts.
authors.affiliation: Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, NIDA/NIH, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: McCoy
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Jayanthi
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Wulu
authors.forename: Genevieve
authors.initials: G
authors.lastname: Beauvais
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Martin
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krasnova
authors.forename: Amber B
authors.initials: AB
authors.lastname: Hodges
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects*; D017874:Immediate-Early Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D003598:Cytoskeletal Proteins; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C092069:activity regulated cytoskeletal-associated protein; D008694:Methamphetamine; D050882:CREB-Binding Protein