Effects of protracted nicotine exposure and withdrawal on the expression and phosphorylation of the CREB gene transcription factor in rat brain

Addiction to nicotine may result in molecular adaptations in the neurocircu itry of specific brain structures via changes in the cyclic AMP-responsive element binding protein (CREB)-dependent gene transcription program. We the refore investigated the effects of chronic nicotine exposure and its withdr awal on CREB and phosphorylated CREB (p-CREB) protein levels in the rat bra in. We report here that chronic nicotine exposure (l-h withdrawal) had no e ffect on the expression of CREB and p-CREB in the rat cortex and amygdala. On the other hand, decreases in the expression of CREB protein and phosphor ylation of CREB occur in the cingulate gyrus, and in the parietal and the p iriform but not in the frontal cortex during nicotine withdrawal (18 h) aft er nicotine exposure. It was also observed that CREB and p-CREB protein lev els were significantly decreased in the medial and basolateral, but not in the central amygdala during nicotine withdrawal (18 h) after chronic nicoti ne exposure. Furthermore, it was found that nicotine withdrawal (18 h) afte r chronic nicotine exposure leads to decreased CRE-DNA binding without modu lating cAMP-dependent protein kinase A activity in the cortex and the amygd ala of rats. In addition, chronic nicotine treatment produced anxiolytic ef fects whereas nicotine withdrawal (18 h) produced anxiety in rats as measur ed by the elevated plus-maze test. These results provide the first evidence that decreased CREB activity and/or expression in specific cortical and am ygdaloid brain structures may be involved in the underlying molecular mecha nisms of nicotine dependence.