Regulation of CREB,cAMP response element binding protein, by morphine and the cAMP system [electronic resource] : in vivo and in vitro studies.

1995

1 online resource (132 p.)

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Chronic morphine administration has been shown to up-regulate many components of the cAMP signal transduction system in rat locus coeruleus (LC), a brain region implicated in physical aspects of addiction. One of these proteins, cAMP-dependent protein kinase, was observed to be regulated at both the protein and message levels, raising the possibility that morphine might regulate gene expression in LC neurons. Consistent with this possibility, chronic morphine was shown to up-regulate the transcription factor cAMP-response element-binding protein (CREB) in the LC, an effect not seen in brain regions in which the cAMP pathway is not regulated by morphine. In order to characterize CREB regulation more completely, studies were performed in an LC-like (CATH.a) cell line. Perturbations of the cAMP system by forskolin and VIP were demonstrated to regulate CREB mRNA and protein levels. In contrast, the CREB-like protein, activating transcription factor-1 (ATF-1), is not regulated by forskolin in CATH.a cells. The observed down-regulation of CREB message by forskolin in CATH.a cells appears to be mediated by a decrease in the rate of CREB transcription, and not message stability. These types of mechanistic studies that are possible in vitro are difficult to perform in vivo. However, in vivo studies are needed to allow a relevant assessment of the functional significance of CREB regulation. For this purpose, studies were performed in the nucleus accumbens (NAc), wherein chronic morphine has been shown to exert many of the same effects as in the rat LC. The NAc, which is implicated in the reinforcing aspects of drug addiction, is more readily adapted to biochemical and molecular studies than the LC due to its larger size. In contrast to the LC, chronic morphine administration resulted in a decrease in CREB protein levels in the NAc. Results obtained from CREB antisense studies support the hypothesis that CREB down-regulation may mediate some, but not all, of the morphine-induced alterations in cAMP-dependent signal transduction proteins in the NAc.

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English

July 12, 2011

Thesis (Ph.D.)--Yale University, 1995.

Yale University.