Nicotine, the primary psychoactive gent in tobacco, interacts with specific neurotransmitter systems including the noradrenergic system. Noradrenergic neurotransmission is mediated by several receptor subtypes including alpha2-adrenoceptors. Nicotine-alpha2-adrenoceptors interactions may not only be responsible for some of the beneficial effects of nicotine, but may also be involved in nicotine dependence and nicotine withdrawal symptoms. Indeed, smoking cessation may be facilitated by clonidine, an alpha2-adrenoceptor agonist. However, clonidine's adverse effects preclude its use as a first-line treatment in smoking cessation. Various subtypes of alpha-2 adrenoceptors with distinct central distribution have been identified. Chronic nicotine administration results in increased density of cortical alpha2-adrenoceptors. However, it is not know whether alpha2-adrenoceptors in other discrete brain regions are also affected by nicotine. More importantly, no information is available on interactions between nicotine and specific alpha2-adrenoceptor subtype(s). This information is critical in identifying specific alpha2-adrenoceptor subtypes as potential targets for the development of novel agents in treatment of nicotine dependence and/or withdrawal. Thus, we propose to establish the specificity, time-course, duration, and dose-response relationship between nicotine administration/withdrawal and central alpha 2-adrenoceptors. Furthermore, since gender differences in the effects of nicotine and clonidine have been observed, both male and females will be studied. Nicotine will be administered to rats by osmotic mini-pumps. Autoradiography will be used to quantify alpha2-adreneceptor subtypes plasma levels of nicotine and cotinine (a major nicotine metabolite) will be determined by gas chromatography/mass spectrography and will be correlated with receptor binding data. These studies will significantly enhance our understanding of nicotine-alpha2-adrenoceptor interactions in the brain and will set the stage for further characterization of this interaction which may lead to novel pharmacotherapy in smoking cessation.
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