The chain of cause and effect of nicotine addiction starts with the interaction of this tobacco alkyloid withnicotinic acetylcholine receptors (nAChRs). This interaction leads to activation of reward centers in the CMS,including the mesoaccumbens dopamine (DA) system, which ultimately leads to behavioral reinforcementand addiction. Our recent investigations into the contribution of nAChRs to the control of midbrain dopamine(DA) neuron excitability indicate that nAChRs can modify both inhibitory and excitatory inputs to DA neurons.The enhancement of excitatory glutamatergic transmission by nAChRs can contribute to long-termpotentiation of these synapses. Interestingly, the modulation of inhibitory GABAergic transmission hasbiphasic characteristics, where nicotine causes both an increase and then a decrease in activity, leading todisinhibition of the DA neurons. While these observations on acute responses to nicotine provide interestingconnections between nAChRs and the excitability of VTA DA neurons, experiments in this proposal willextend these observations to test the impact of nicotine exposure on the sensitivity and function of nAChRswithin the reward circuitry. Nicotine exposure is known to cause upregulation of nAChR function andradioligand binding. In addition, nicotine along with other drugs of abuse can induce long term potentiation(LTP) of the excitatory inputs to DA neurons. We will test the hypothesis that nAChR upregulationcontributes to LTP induction within the DA system and its afferent projections. Using electrophysiology inbrain slices from adult rats, we will assess the changes in nAChR properties that occur in animals that havebeen exposed to nicotine in one of four regimens, ranging from one to 15 days of exposure. The regimensvary in intensity and duration and are designed to represent a spectrum of nicotine exposure, mimicking tothe wide variation in nicotine exposure seen in humans. We expect that the different regimens will result in arange of upregulation of nAChR function and radioligand binding. Experiments in this project will investigatefunctional upregulation and LTP expression following nicotine exposure. Results will be correlated with datafrom behavioral, biochemical, and molecular assays conducted in Projects 1 and 3. Correlating the findingswith our collaborators' will provide novel insights into the nicotine-induced changes in reward circuitry thatultimately contribute to the etiology of nicotine addiction.
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