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First published on September 1, 2006; DOI: 10.1124/mol.106.023051

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Received for publication January 30, 2006.
Revised August 31, 2006.
Accepted for publication September 1, 2006.

METHAMPHETAMINE-INDUCED SENSITIZATION DIFFERENTIALLY ALTERS pCREB AND {Delta}FosB THROUGHOUT THE LIMBIC CIRCUIT OF THE MAMMALIAN BRAIN

John McDaid 1, Martin P. Graham 1, T. Celeste Napier 1*

1 Loyola Univ Chicago Medical Center

* Address correspondence to: E-mail: cnapier{at}lumc.edu

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 2.5mg/kg methamphetamine induced behavioral sensitization that was demonstrated (expressed) three and 14 days later. Using immunoblot procedures, limbic brain regions implicated in behavioral sensitization were assayed for pERK/ERK, (a signal transduction kinase), pCREB/CREB (a constitutively expressed transcriptional regulator) and {Delta}FosB (a long lasting transcription factor). pERK, ERK and CREB levels were not changed for any region assayed. In the ventral tegmental area, pCREB and {Delta}FosB 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 {Delta}FosB 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 drug-induced sensitization.


Key words: MAP Kinase, CREB, Amphetamines


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