Abstract
Enhancements in behavior that accompany repeated, intermittent administration of abused drugs (sensitization) endure long after drug administration has ceased. Such persistence reflects changes in intracellular signaling cascades and associated gene transcription factors in brain regions that are engaged by abused drugs. This process is not characterized for the most potent psychomotor stimulant, methamphetamine. Using motor behavior as an index of brain state in rats, we verified that five once-daily injections of 2.5 mg/kg methamphetamine induced behavioral sensitization that was demonstrated (expressed) 3 and 14 days later. Using immunoblot procedures, limbic brain regions implicated in behavioral sensitization were assayed for extracellular signal-regulated kinase and its phosphorylated form (pERK/ERK, a signal transduction kinase), cAMP response element binding protein and its phosphorylated form (pCREB/CREB, a constitutively expressed transcriptional regulator), and ΔFosB (a long-lasting transcription factor). pERK, ERK, and CREB levels were not changed for any region assayed. In the ventral tegmental area, pCREB and ΔFosB also were not changed. pCREB (activated CREB) was elevated in the frontal cortex at 3 days withdrawal, but not at 14 days. pCREB levels were decreased at 14 days withdrawal in the nucleus accumbens and ventral pallidum. Accumbal and pallidal levels of ΔFosB were increased at 3 days withdrawal, and this increase persisted to 14 days in the pallidum. Thus, only the ventral pallidum showed changes in molecular processes that consistently correlated with motor sensitization, revealing that this region may be associated with this enduring behavioral phenotype initiated by methamphetamine. The present findings expand our understanding of the neuroanatomical and molecular substrates that may play a role in the persistence of druginduced sensitization.
Footnotes
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Research was supported by the Ralph and Marian Falk Medical Research Trust (to J.M. and T.C.N.) and the Irene Whitney Foundation (to T.C.N.) through the Neuroscience and Aging Institute at Loyola University Chicago Medical Center, and a United States Public Health Service grant DA503195 (to T.C.N.).
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ABBREVIATIONS: VTA, ventral tegmental area; FCtx, frontal cortex; NAc, nucleus accumbens; VP, ventral pallidum; ERK, extracellular signalregulated kinase; CREB, cAMP response element-binding protein; pERK, phosphorylated (activated) form of ERK; Cdk5, cyclin-dependent kinase 5; PKA, protein kinase A; ANOVA, analysis of variance; rmANOVA, repeated-measures analysis of variance; pCREB, phosphorylated (activated) form of CREB; mANOVA, multiple analysis of variance; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
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↵1 Current affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois.
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↵2 Current affiliation: Department of Pharmacology, Rush University Medical Center, Chicago, Illinois.
- Received January 29, 2006.
- Accepted September 1, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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