Protein kinase C epsilon modulates nicotine consumption and dopamine reward signals in the nucleus accumbens

Abstract

Nicotine addiction and alcohol use disorders are very widespread and often occur together. Currently, there is no single drug approved for the simultaneous treatment of both conditions. Although these conditions share common genetic factors, the molecular mechanisms underlying their comorbidity are unknown. We have previously shown that mice lacking protein kinase C epsilon (PKCε) show decreased ethanol self-administration and reward as well as increased aversion to ethanol. Here we find that Prkce −/− mice self-administer less nicotine and show decreased conditioned place preference for nicotine compared with wild-type mice. In Prkce −/− mice, these behaviors are associated with reduced levels of α 6 and β 3 nicotinic receptor subunit mRNA in the ventral midbrain and striatum as well as a functional deficit in cholinergic modulation of dopamine release in nucleus accumbens. Our results indicate that PKCε regulates reward signaling through α 6 -containing nicotinic receptors and suggest that PKCε could be a target for the treatment of comorbid nicotine and alcohol addictions.T obacco addiction remains the leading cause of premature mortality in the world, and half of all tobacco users will die of tobacco-related disease (1). Nicotine is the primary, if not the only, compound that maintains addiction to tobacco (2), and smokers will adjust their level of cigarette smoking to maintain constant levels of plasma nicotine (3). Current approved pharmacotherapies for smoking cessation all target nicotinic acetylcholine receptors (nAChRs) and include nicotine-replacement therapy, bupropion (a nicotinic antagonist) (4), and varenicline (a partial nicotinic agonist) (5). Although this approach is effective in the short term, long-term abstinence rates are low, underscoring the need for the discovery of new drug targets and development of new treatments.It is striking that, among all drug addictions, alcohol and tobacco addictions are highly comorbid with more than 60% of smokers in the US reporting concurrent binge drinking or heavy use of alcohol (6). Likewise, the prevalence of smoking among those with alcohol use disorders has been reported to be as high as 88-96% (7, 8). In humans, a single exposure to alcohol can increase the urge to smoke and increase cigarette consumption (9, 10). Conversely, in rats, s.c. injections of nicotine can increase ethanol self-administration (11) and promote reinstatement for ethanol responding after extinction (11,12). In rats that selfadminister i.v. nicotine and oral alcohol, the extinction of alcohol responding is prolonged if nicotine remains available (13), suggesting that combined use of both substances may make it more difficult to successfully quit the use of nicotine or alcohol alone. Nicotine and alcohol addictions appear to share common genetic factors (14-16), but the molecular mechanisms underlying their comorbidity are unknown. Currently, no pharmaceutical agent has been approved to treat comorbid nicotine and alcohol addictions.The protein kinase C (PKC) family of serine/...

Transcriptional Regulation of Oncogenic Protein Kinase Cϵ (PKCϵ) by STAT1 and Sp1 Proteins

“…This ubiquitously expressed kinase has been associated with multiple disease conditions, including obesity, diabetes, heart failure, neurological diseases, and cancer (7)(8)(9)(10). PKC⑀ is primarily activated by the lipid second messenger diacylglycerol (11), a product of phosphatidylinositol 4,5-bisphosphate hydrolysis by phospholipase C, which, like phorbol esters, binds to the C1 domains located in the N-terminal regulatory region.…”

Genetic matters: Thirty years of progress using mouse models in nicotinic research

“…Nicotine conditioned place preference is modified by changes in the expression of cannabinoid receptors [84–85], NMDA receptors [86], μ-opioid receptors [87], δ-opioid receptors [88], galanin [89], protein kinase C ε activity [90], and CREB expression [91]. Furthermore, nAChR are known to mediate the release of neurotransmitters dopamine, GABA, glutamate, and serotonin [92–93] and hormones such as corticosterone [94].…”

Development of Novel Pharmacotherapeutics for Tobacco Dependence: Progress and Future Directions

“…The PKCε KO mice also demonstrated decreased levels of α6 and β3 nAChR subunit mRNA transcripts in the midbrain and striatum, and deficits in cholinergic modulation of dopamine release in the NAc (Lee & Messing, 2011). Hence, it was hypothesized that PKCε may regulate α6 (and also β3) nAChR signaling and thereby influence nicotine reinforcement (Lee & Messing, 2011). Using an "acute" nicotine selfadministration procedure in which mice are restrained but can nose-poke for intravenous nicotine infusions via a catheter in the tail vein during a single session, it was shown that α6 subunit KO mice had attenuated levels of nicotine intake compared with wildtype mice (Pons et al, 2008).…”

“…Similarly, Brunzell and colleagues reported that intra-NAc infusion of CntxMII decreased the motivation of rats to self-administer nicotine, as measured using a progressive ratio schedule of reinforcement (Brunzell, Boschen, Hendrick, Beardsley, & McIntosh, 2010). More recently, it was shown that KO mice lacking protein kinase C epsilon (PKCε KO mice) self-administered less nicotine and had attenuated place conditioning for nicotine than their wildtype counterparts (Lee & Messing, 2011). The PKCε KO mice also demonstrated decreased levels of α6 and β3 nAChR subunit mRNA transcripts in the midbrain and striatum, and deficits in cholinergic modulation of dopamine release in the NAc (Lee & Messing, 2011).…”

“…More recently, it was shown that KO mice lacking protein kinase C epsilon (PKCε KO mice) self-administered less nicotine and had attenuated place conditioning for nicotine than their wildtype counterparts (Lee & Messing, 2011). The PKCε KO mice also demonstrated decreased levels of α6 and β3 nAChR subunit mRNA transcripts in the midbrain and striatum, and deficits in cholinergic modulation of dopamine release in the NAc (Lee & Messing, 2011). Hence, it was hypothesized that PKCε may regulate α6 (and also β3) nAChR signaling and thereby influence nicotine reinforcement (Lee & Messing, 2011).…”