Cigarette smoking is the number one health problem accounting for more illnesses and deaths than any other single factor. The abuse liability of the major tobacco alkaloid, nicotine (NIC), stems from its intrinsic reinforcing properties suggested to be the result of activation of dopamine (DA) pathways in brain. Elucidation of NIC's mechanism of action and determination of the effects of chronic administration are important for understanding the initiation/maintenance of smoking behavior, and for overcoming problems that smokers experience in extinguishing this behavior. Considering the plethora of information on the peripheral metabolism of NIC, little is known about NIC metabolism in brain and about the potential pharmacologic activity of NIC metabolites. The overall objective of this proposal is to test the hypothesis that CNS effects resulting from NIC exposure during tobacco usage are not solely due to NIC, but result at least in part from actions of NIC metabolites. We have recently demonstrated that NIC metabolites (cotinine, nornicotine (norNIC), norcotinine, and an as yet unidentified fourth metabolite) are present in brain 4 hours after acute peripheral [2'-14C]NIC administration. Also, we have found that norNIC increases DA release from superfused rat striatal slices in a concentration-dependent, Ca++ -dependent, mecamylamine-sensitive, dihydro-beta-erythroidine-sensitive, and stereo-selective manner, indicating nicotinic receptor mediation. Also similar to NIC, repeated S(-) or R(+)norNIC administration were capable of activating the neural mechanism(s) responsible for behavioral sensitization, even though R(+)norNIC produced no overt behavioral effects after its repeated administration. The proposed project will determine the kinetics of accumulation of NIC metabolites in brain, the pharmacological activity and mechanism of action of NIC metabolites, and the time-dependent behavioral and neurochemical changes in response to repeated norNIC administration. The results of the proposed studies will increase our knowledge of the molecular mechanisms that are involved in the neurobehavioral effects resulting from tobacco use and NIC exposure.
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