Role of calcineurin in nicotine-mediated behavior and signaling

Recent estimates indicate that there are 46.2 million smokers in the United States alone, with yearly smoking related deaths numbering over 440,000 (CDC 2004) and smoking-related health care costs of {dollar}75.5 billion (CDC, 2005). Preclinical research has focused on nicotine, which is the primary reinforcing agent in tobacco (CDC, 1988). Nicotine exposure leads to several neurobiological changes in the brain that ultimately lead to behaviors that reflect nicotine craving and reward (Rose and Corrigall, 1997; Mansvelder and McGehee, 2002; Wonnacott et al., 2005). In chapter 1 of this thesis, we review the extensive body of work demonstrating long-term changes in the brain that occur as a result of nicotine administration. In animal models, in particular, behavioral responses to nicotine are known to result from nicotine-mediated changes in the brain (Corrigall et al., 1994; Ferrari et al., 2002; Laviolette and Van der Kooy, 2003). While several effector proteins are implicated in nicotine reward and reinforcement (Brunzell et al., 2003; Zhu et al., 2005), we specifically examine the role of calcineurin, a serine/threonine phosphatase which can modulate nicotine-mediated changes at several sites of action. In chapter 2, we demonstrate a role for calcineurin in nicotine-mediated locomotor sensitization, conditioned place preference and phosphorylation of the dopamine and cAMP regulated phosphoprotein-32. In chapter 3, we illustrate the importance of calcineurin in a specific brain locus, the ventral tegmental area in nicotine-mediated locomotor sensitization. Finally, in chapter 4, we show that calcineurin is also involved in responses to other drugs of abuse and normally suppresses the behavioral and molecular actions of cocaine. Together our work suggests an important role for calcineurin in behaviors associated with psychostimulant exposure.