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

Abstract

Addiction to nicotine may result in molecular adaptations in the neurocircuitry of speci®c brain structures via changes in the cyclic AMP-responsive element binding protein (CREB)-dependent gene transcription program. We therefore investigated the effects of chronic nicotine exposure and its withdrawal on CREB and phosphorylated CREB (p-CREB) protein levels in the rat brain. We report here that chronic nicotine exposure (1-h withdrawal) had no effect 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 phosphorylation of CREB occur in the cingulate gyrus, and in the parietal and the piriform but not in the frontal cortex during nicotine withdrawal (18 h) after nicotine exposure. It was also observed that CREB and p-CREB protein levels were signi®cantly decreased in the medial and basolateral, but not in the central amygdala during nicotine withdrawal (18 h) after chronic nicotine exposure. Furthermore, it was found that nicotine withdrawal (18 h) after chronic nicotine exposure leads to decreased CRE-DNA binding without modulating cAMP-dependent protein kinase A activity in the cortex and the amygdala of rats. In addition, chronic nicotine treatment produced anxiolytic effects whereas nicotine withdrawal (18 h) produced anxiety in rats as measured by the elevated plus-maze test. These results provide the ®rst evidence that decreased CREB activity and/or expression in speci®c cortical and amygdaloid brain structures may be involved in the underlying molecular mechanisms of nicotine dependence.

Withdrawal from chronic nicotine in adolescent and adult rats

“…Irvine et al, 2001;Bhattacharya et al, 1995;Pandey et al, 2001). Adolescent rats, however failed to display a nicotine withdrawal-induced increase in anxiety-like behaviors.…”

“…withdrawal-induced anxiety) has been hypothesized to be an important factor contributing to smoking maintenance in humans (Koob et al, 1993;Watkins et al, 2000a), and has been successfully modeled in rats using the elevated plus maze (EPM) test. When assessed 18-24 hours following nicotine withdrawal, animals chronically treated with nicotine demonstrated an increase in anxiety-like behavior, as indexed by a decrease in time spent in the open arms of the EPM, when compared with saline-exposed control animals (Bhattacharya et al, 1995;Pandey et al, 2001). The acoustic startle response has been used to model altered sensorimotor reactivity during withdrawal, and has proven to be a sensitive tool for the assessment of alterations in sensorimotor reactivity produced by a variety of drugs of abuse, including nicotine (for review see Koch & Schnitzler, 1997;Swerdlow et al, 2001).…”

Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system

“…For nicotine addiction, studies show that in rats, nicotine withdrawal (but not chronic treatment with nicotine itself) significantly reduced the levels of CREB and phosphorylated CREB in rat cortex and the amygdala [78] . Phosphorylated CREB also decreased in the NAc in mice following chronic consumption of nicotine in their drinking water [79] .…”

Translational Research in Nicotine Dependence

“…Entry of these ions can either directly impact cell excitability or trigger calcium-sensitive molecules, such as protein kinase C (PKC) (Soliakov and Wonnacott 2001), protein kinase A (PKA) (Dajas-Bailador et al 2002), calmodulin-dependent protein kinase II (CAMKII) (Steiner et al 2007), and extracellular signal-regulated kinases (ERKs) (Dajas-Bailador et al 2002;Steiner et al 2007). These calcium-sensitive kinases then have myriad downstream effects, including activation of transcription factors such as CREB (Chang and Berg 2001;Pandey et al 2001;Hu et al 2002;Brunzell et al 2003;Walters et al 2005) (for a review of signaling effects of nicotine, see Shen and Yakel 2009).…”