Nicotinic Receptor Regulation of Dopamine Transporter

Tobacco use is the number one preventable cause of death in the US. The reinforcing efficacy of nicotine (NIC), the most abundant alkaloid in tobacco, plays a major role in the maintenance of tobacco smoking. Furthermore, tobacco use and depressive disorders are highly comorbid, and NIC maybe be used in part to alleviate depression in this clinical population. Research on the neurobiology of reward and drug addiction has focused on mesocorticolimbic and nigrostriatal dopamine (DA) pathways. NIC activates nicotinic receptors which increases extracellular DA concentrations at both terminal and cell body regions of these pathways. Extracellular DA concentration is the net result of neurotransmitter release from the presynaptic terminal and neurotransmitter clearance from the extracellular space. DA clearance is mediated primarily by the plasma membrane dopamine transporter (OAT). Although there is a wealth of information on NIC stimulated DA release, the ability of NIC to modulate DAT function and the underlying mechanisms responsible for this effect have not been studied in detail. Preliminary data show that in prefrontal cortex, acute NIC increases DA uptake into synaptosomes, DA clearance in in vivo voltammetry studies and OAT trafficking to the cell surface. Thus, NIC augmentation of OAT function appears to sharpen the kinetics of the NlC-induced increase in extracelluar DA concentration in prefrontal cortex. The proposed study will begin to elucidate the underlying mechansims responsible for the NlC-induced enhancement of OAT function. The hypothesis to be tested in the current application is that NIC, via nicotinic receptor activation, mediates the trafficking of OAT. This hypothesis will be tested using the rat as the animal model, and will determine (1) the dose-related effects of acute in vivo administration of NIC on OAT trafficking in striatum, nucleus accumbens, prefrontal cortex and amygdala; (2) if nicotinic receptors mediate the effect of NIC on OAT trafficking; and (3) the effect of intermittent and continuous NIC administration on OAT trafficking. Results of these experiments will begin to elucidate the cellular mechanisms by which NIC and nicotinic receptors modulate OAT function, and thereby, contribute to the regulation of extracellular OA concentration. Thus, insight will be provided with respect to the effect of NIC on OA neurotransmission in brain regions associated with drug abuse.