Nicotine Reward and Affective Nicotine Withdrawal Signs Are Attenuated in Calcium/Calmodulin-Dependent Protein Kinase IV Knockout Mice

Abstract

The influx of Ca2+ through calcium-permeable nicotinic acetylcholine receptors (nAChRs) leads to activation of various downstream processes that may be relevant to nicotine-mediated behaviors. The calcium activated protein, calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates the downstream transcription factor cyclic AMP response element binding protein (CREB), which mediates nicotine responses; however the role of CaMKIV in nicotine dependence is unknown. Given the proposed role of CaMKIV in CREB activation, we hypothesized that CaMKIV might be a crucial molecular component in the development of nicotine dependence. Using male CaMKIV genetically modified mice, we found that nicotine reward is attenuated in CaMKIV knockout (−/−) mice, but cocaine reward is enhanced in these mice. CaMKIV protein levels were also increased in the nucleus accumbens of C57Bl/6 mice after nicotine reward. In a nicotine withdrawal assessment, anxiety-related behavior, but not somatic signs or the hyperalgesia response are attenuated in CaMKIV −/− mice. To complement our animal studies, we also conducted a human genetic association analysis and found that variants in the CaMKIV gene are associated with a protective effect against nicotine dependence. Taken together, our results support an important role for CaMKIV in nicotine reward, and suggest that CaMKIV has opposing roles in nicotine and cocaine reward. Further, CaMKIV mediates affective, but not physical nicotine withdrawal signs, and has a protective effect against nicotine dependence in human genetic association studies. These findings further indicate the importance of calcium-dependent mechanisms in mediating behaviors associated with drugs of abuse.

New mechanisms and perspectives in nicotine withdrawal

“…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). …”

A Role for p38 Mitogen-activated Protein Kinase-mediated Threonine 30-dependent Norepinephrine Transporter Regulation in Cocaine Sensitization and Conditioned Place Preference

“…An unbiased mouse CPP paradigm was utilized as described by several investigators (32)(33)(34)(35)(36). In brief, mice were placed in an enriched environment and handled for 3 days prior to initiation of CPP testing.…”

Unraveling the neurobiology of nicotine dependence using genetically engineered mice

“…CPA is similar to the CPP procedure and involves pairing an environment with either nicotine withdrawal or vehicle withdrawal (e.g., [9]). The contextual fear conditioning procedure can be used to detect learning deficits that typically occur during nicotine withdrawal (e.g., [10]), whereas hyperalgesia reflects the pain associated with nicotine withdrawal (e.g., [11]).…”

“…The somatic signs of mecamylamine-precipitated nicotine withdrawal were attenuated in γ-aminobutyric acid-B1 receptor knockout mice [49]. Nicotine-induced CPP was attenuated in δ opioid receptor knockout mice [50] and Ca 2+ /calmodulin-dependent kinase IV knockout mice [11]. Thus, additional central nervous system receptors and neurotransmitter systems, in addition to nAChRs and acetylcholine, may be involved in various aspects of nicotine dependence and potentially interact with acetylcholine neurotransmitter function.…”