L-Type Calcium Channels and Calcium/Calmodulin-Dependent Kinase II Differentially Mediate Behaviors Associated with Nicotine Withdrawal in Mice

Abstract

Smoking is a widespread health problem. Because the nicotine withdrawal syndrome is a major contributor to continued smoking and relapse, it is important to understand the molecular and behavioral mechanisms of nicotine withdrawal to generate more effective smoking cessation therapies. Studies suggest a role for calcium-dependent mechanisms, such as L-type calcium channels and calcium/calmodulin-dependent protein kinase II (CaMKII), in the effects of nicotine dependence; however, the role of these mechanisms in nicotine-mediated behaviors is unclear. Thus, the goal of this study was to elucidate the role of L-type calcium channels and CaMKII in nicotine withdrawal behaviors. Using both pharmacological and genetic methods, our results show that L-type calcium channels are involved in physical, but not affective, nicotine withdrawal behaviors. Although our data do provide evidence of a role for CaMKII in nicotine withdrawal behaviors, our pharmacological and genetic assessments yielded different results concerning the specific role of the kinase. Pharmacological data suggest that CaMKII is involved in somatic signs and affective nicotine withdrawal, and activity level is decreased after nicotine withdrawal, whereas the genetic assessments yielded results suggesting that CaMKII is involved only in the anxiety-related response, yet the kinase activity may be increased after nicotine withdrawal; thus, future studies are necessary to clarify the precise behavioral specifics of the relevance of CaMKII in nicotine withdrawal behaviors. Overall, our data show that L-type calcium channels and CaMKII are relevant in nicotine withdrawal and differentially mediate nicotine withdrawal behaviors.Nicotine withdrawal represents a motivational component of nicotine dependence that promotes continued tobacco use and relapse after smoking cessation. Although there are smoking cessation therapies available, the success rate of these therapies after 1 year remains only approximately 20 to 25% (Gonzales et al., 2006). Severity of the nicotine withdrawal syndrome is a better predictor of unsuccessful smoking attempts than smoke intake or dependence (West et al., 1989). Because smoking is such a widespread health problem, it is important to understand the molecular and behavioral mechanisms of nicotine withdrawal to generate more effective smoking cessation therapies.Behaviors associated with nicotine withdrawal are mediated through nicotinic acetylcholine receptors (nAChRs), which are calcium-permeable, and the initial targets for nicotine. Recent studies from our lab indicate that nAChR subtypes have differential roles in physical and affective nicotine withdrawal behaviors (Jackson et al., 2008). Activation of these receptors leads to increases in intracellular calcium via various routes. Upon nicotine binding, there is a direct influx of calcium through nAChRs, which leads to an indirect calcium influx through voltage-gated calcium channels and intracellular calcium stores (Rathouz and Berg, 1994; DajasBailador et al., 2002)...

CaM Kinases: From Memories to Addiction

“…Pharmacological inhibition of CaMKII reduced somatic nicotine withdrawal signs, but enhanced anxiety [119].…”

“…It was also suggested that the nicotine-induced 2 mediated phosphorylation of cAMP response-element binding protein (CREB), which is required for the rewarding properties of nicotine [117,118], is mediated by CaMKII activation in the VTA and NAc [116]. CaMKII appears to play a role in nicotine withdrawal behaviours.Pharmacological inhibition of CaMKII reduced somatic nicotine withdrawal signs, but enhanced anxiety [119]. …”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…The adverse motivational state associated with withdrawal can promote renewed drug intake (Koob, 2009;Koob and Volkow, 2010), and agents that reduce these effects could be useful therapeutically in human addicts. Thus, LCBBs reduce withdrawal signs related to morphine (Bongianni et al, 1986;Baeyens et al, 1987;Ramkumar and el-Fakahany, 1988;Antkiewicz-Michaluk et al, 1990;Esmaeili-Mahani et al, 2008), nicotine (Jackson and Damaj, 2009), and ethanol (Bone et al, 1989;Watson and Little, 2002). LCCBs had no general anticonvulsant action against bicuculline-or pentylenetetrazol-induced seizures (Watson and Little, 2002), suggesting a more specific impact on drug-related physical signs rather than a more general effect on seizures and convulsions.…”

New mechanisms and perspectives in nicotine withdrawal

“…In mice, L-type calcium channel blockers attenuated physical (somatic signs, hyperalgesia), but not affective (CPA, anxiety-like response) nicotine withdrawal signs, implicating L-type calcium channels in physical nicotine dependence (Jackson and Damaj 2009). More recently, other investigators showed that L-type calcium channels attenuated expression of CPA in rats, suggesting involvement of L-type calcium channels in this affective nicotine withdrawal measure (Budzynska et al 2012) in a species-specific fashion.…”

“…Behaviorally, CaMKII antagonists attenuated somatic withdrawal signs, but enhanced affective nicotine withdrawal signs, suggesting opposing roles for CaMKII in affective vs. somatic nicotine withdrawal behaviors (Jackson and Damaj 2009). Similarly, studies with the less abundant kinase, CaMKIV, reveal that affective, but not physical measures are attenuated in CaMKIV −/− mice (Jackson et al 2012).…”