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  • Title: CREB involvement in the regulation of striatal prodynorphin by nicotine.
    Author: McCarthy MJ, Duchemin AM, Neff NH, Hadjiconstantinou M.
    Journal: Psychopharmacology (Berl); 2012 May; 221(1):143-53. PubMed ID: 22086359.
    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.
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