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.
Highlights
Activation of neuronal nicotinic receptors by nicotine results in increased permeability to Na+ and Ca2+ [1]
The goal of the current study was to elucidate the role of calmodulin-dependent kinase IV (CaMKIV) in nicotine dependence behaviors using both animal models and genetic association analysis
Anxiety-related behavior is not observed in CaMKIV 2/2 mice after precipitated nicotine withdrawal; somatic signs and the hyperalgesia response are not affected
Summary
Activation of neuronal nicotinic receptors (nAChRs) by nicotine results in increased permeability to Na+ and Ca2+ [1]. Permeability to Ca2+ allows for several long-term and short-term Ca2+dependent processes to occur, which result in neurotransmitter release, synaptic plasticity, and upregulation of genes required for receptor synthesis [2] These processes are thought to be important in mediating acute and chronic effects of nicotine. 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 To test this hypothesis, we used CaMKIV 2/2 mice to elucidate the contribution of CaMKIV to nicotine dependence-like behaviors. Because CREB activity is altered after cocaine administration [10], we tested the specificity of CaMKIV’s role in nicotine behaviors by measuring cocaine CPP in genetically modified CaMKIV mice. Our findings support a significant role for CaMKIV in nicotine and cocaine reward, as well as nicotine withdrawal, and emphasize the importance of calcium-dependent mechanisms in mediating drug-induced behaviors
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