Journal Article

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

Hodges, Amber B., Wulu, Jacqueline A., Beauvais, Genevieve, Martin, Tracey A., Cadet, Jean Lud, Jayanthi, Subramaniam, Ladenheim, Bruce, Krasnova, Irina N., McCoy, Michael T.

2011

Overview

Rationale Repeated injections of cocaine cause blunted responses to acute cocaine challenge-induced increases in the expression of immediate early genes (IEGs). 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. 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.

• Publisher: Springer-Verlag,Springer,Springer Nature B.V
• Subject: Analysis of Variance / Animals / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Central Nervous System Stimulants - administration & dosage / Corpus Striatum - drug effects / Corpus Striatum - metabolism / CREB-Binding Protein - genetics / CREB-Binding Protein - metabolism / Cytoskeletal Proteins - genetics / Cytoskeletal Proteins - metabolism / Dose-Response Relationship, Drug / Drug addiction / Drug Administration Schedule / Gene expression / Gene Expression Regulation - drug effects / Genes / Immediate-Early Proteins - classification / Immediate-Early Proteins - genetics / Immediate-Early Proteins - metabolism / Male / Medical sciences / Methamphetamine / Methamphetamine - administration & dosage / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neuropharmacology / Neurosciences / Original Investigation / Pharmacology. Drug treatments / Pharmacology/Toxicology / Protein binding / Psychiatry / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) / Psychology. Psychoanalysis. Psychiatry / Psychopharmacology / Rats / Rats, Sprague-Dawley / RNA / RNA, Messenger - metabolism / Rodents