Functional interactions of alpha4beta2*-type nicotinic acetylcholine receptors with GABAB autoreceptors and calcineurin

Nicotine dependence represents a significant source of preventable mortality across the entire human population. Despite the advancement of public health education and increasing prohibition of public smoking, a certain percentage of the population persists in the habitual consumption of tobacco. The primary interface of nicotine in the mammalian central nervous system is the nicotinic acetylcholine receptor (nAChR). Regulation of the functional characteristics of nAChRs in the mammalian brain beyond ligand-receptor interactions represent a target that could prove to be of some utility in extending the current understanding of cholinergic neurotransmission, and how nicotine is capable of interacting with this system to produce certain hallmark physiological effects. Principle among these are promoting or enhancing activity of the reward pathways in the mammalian brain and the phenomenon of nAChR upregulation that occurs following long-term repeated exposure to nicotine. The experiments recorded in this research project attempt to define and characterize a potentially cell-specific regulatory pathway that targets alpha4beta2* nAChRs; the major subset of high affinity nicotinic receptors expressed in mouse brain. This pathway appears to involve the activation of a GABAB autoreceptor signaling cascade that results in the modification of alpha4beta2* nAChRs by the protein phosphatase calcineurin. Additional experiments demonstrate that both acute and chronic nicotine exposure can alter the function and expression of calcineurin in the mouse striatum. These results inform a model of cellular adaptation to repeated nicotine exposure which favors the development of enhanced reward pathway activity that is potentially unique to nicotine and highlights its particular tenacity as a commonly abused substance.