REGULATION OF CREB EXPRESSION - IN-VIVO EVIDENCE FOR A FUNCTIONAL-ROLE IN MORPHINE ACTION IN THE NUCLEUS-ACCUMBENS

Previous work has shown that chronic opiate administration regulates p rotein components of the cAMP signaling pathway, specifically in the n ucleus accumbens (NAc), a brain region implicated in the reinforcing p roperties of opiates, and that such adaptations may contribute to chan ges in reinforcement mechanisms that characterize opiate addiction. In the present study, we examined a possible role for the transcription factor cAMP response element-binding protein (CREB) in mediating these long-term effects of opiates in the NAc. Chronic, but not acute, morp hine administration was found to decrease levels of CREB immunoreactiv ity in the NAc, an effect not seen in other brain regions studied. The functional significance of this CREB down-regulation was then investi gated by the use of an antisense oligonucleotide strategy that produce s a specific and sustained decrease in CREB levels in the NAc, without detectable toxicity. It was found that the antisense oligonucleotide- induced reduction in CREB levels mimicked the effect of morphine on ce rtain, but not all, cANIP pathway proteins in this brain region, where as a large number of other signal transduction proteins tested were un affected by this treatment. Our results support a role for CREB in aut oregulation of the cAMP pathway in the nervous system, as well as in m ediating some of the effects of morphine on this signaling pathway in the NAc.