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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.
- Source :
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Psychopharmacology [Psychopharmacology (Berl)] 2011 May; Vol. 215 (2), pp. 353-65. Date of Electronic Publication: 2011 Jan 13. - Publication Year :
- 2011
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Abstract
- Rationale: Repeated injections of cocaine cause blunted responses to acute cocaine challenge-induced increases in the expression of immediate early genes (IEGs).<br />Objectives: 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.<br />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.<br />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.
- Subjects :
- Analysis of Variance
Animals
CREB-Binding Protein genetics
CREB-Binding Protein metabolism
Cytoskeletal Proteins genetics
Cytoskeletal Proteins metabolism
Dose-Response Relationship, Drug
Drug Administration Schedule
Immediate-Early Proteins classification
Immediate-Early Proteins genetics
Male
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Central Nervous System Stimulants administration & dosage
Corpus Striatum drug effects
Corpus Striatum metabolism
Gene Expression Regulation drug effects
Immediate-Early Proteins metabolism
Methamphetamine administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1432-2072
- Volume :
- 215
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Psychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 21229349
- Full Text :
- https://doi.org/10.1007/s00213-010-2146-7