College of Psychiatric and Neurologic Pharmacists

Abstract
Rationale  The transcription factor cAMP response element binding (CREB) protein plays a pivotal role in drug-dependent neuronal plasticity.
CREB phosphorylation at Ser133 is enhanced by drugs of abuse, including nicotine. Dynorphin (Dyn) contributes to the addictive
process and its precursor gene prodynorphin (PD) is regulated by CREB. PD mRNA and Dyn synthesis were enhanced in the striatum
following acute nicotine, suggesting genomic regulation.

Objective  These studies investigated PD transcription in mice acutely treated with nicotine, determined the role of CREB, and characterized
the receptors involved.

Results  Acute nicotine increased adenylyl cyclase activity, cAMP, and pCREB Ser133 levels in striatum and enhanced CREB binding to
CRE elements (DynCREs) of the PD promoter, preferentially DynCRE3. DynCRE3 binding was dose dependent with 1 mg of nicotine
giving a maximal response. Additionally, DynCRE binding was time dependent, rising by 15 min, reaching a maximum at 1 h, and
returning to control by 3 h, a temporal pattern similar to that of cAMP and pCREB. Supershift experiments showed that CREB
and pCREB Ser133 were the major contributors to DynCRE3 binding complex. The nAChR antagonist mecamylamine and the dopamine
D1-like receptor antagonist SCH 23390 prevented the nicotine-induced increase of pCREB and nuclear protein binding to DynCRE3.

Conclusions  Our findings suggest that nicotine regulates PD expression in striatum at the transcriptional level and CREB is involved.
Dopamine D1 receptor stimulation by nAChR-released dopamine appears to be an underlying mechanism. Altered Dyn synthesis might
be relevant for the behavioral actions of nicotine and especially its aversive properties.

• Content Type Journal Article
• Category Original Investigation
• Pages 1-11
• DOI 10.1007/s00213-011-2559-y
• Authors
  • Michael J. McCarthy, Department of Psychiatry, The Ohio State University College of Medicine, Columbus, OH 43210, USA
  • Anne-Marie Duchemin, Department of Psychiatry, The Ohio State University College of Medicine, Columbus, OH 43210, USA
  • Norton H. Neff, Department of Psychiatry, The Ohio State University College of Medicine, Columbus, OH 43210, USA
  • Maria Hadjiconstantinou, Department of Psychiatry, The Ohio State University College of Medicine, Columbus, OH 43210, USA

• Journal Psychopharmacology
• Online ISSN 1432-2072
• Print ISSN 0033-3158

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