People with neuropsychiatric disorders, particularly those with schizophrenia and depression, tend to be heavy smokers. It has been suggested that this behavior is directly related to the reinforcing properties of nicotine in the brain. For example, nicotine induces the release of the neurotransmitter glutamate, the brain's major excitatory neurotransmitter, from sites implicated in arousal and attentive behavior. It also facilitates dopamine release from areas that activate the brain reward system. Nicotine has also been shown to reduce the sedative and sometimes aversive effects of antipsychotic medications by increasing their metabolism and clearance. Smoking also reduces, in some patients, the parkinson's-like rigidity caused by neuroleptics. The conclusion drawn from these studies is that patients self-medicate with nicotine to improve their concentration, reduce boredom and anxiety, and ameliorate the negative symptoms of schizophrenia. Recently, a number of neurpathological changes in nAChR levels and expression have been described in brains from schizophrenics, adding to the interest in studying the interaction between nicotinic receptors and psychosis. It is the objective of this proposal to determine the identity and location of the nicotinic iacetylcholine receptor(s) involved in nicotine-induced dopamine release and to characterize the molecular mechanisms that regulate this nicotinic effect. Our hypothesis is that nicotine plays a direct role in some of these effects by regulating dopamine release in selected brain areas and that this release is accomplished by a specific nicotinic acetylcholine receptor (nAChR) subtype(s) located presynaptically on doparninergic neurons. Therefore, Our specific aims are 1) to determine the distribution and levels of expression of nAChRs and dopamine transporters in mesolimbic, nigrostriatal, and mesocortical target areas, 2) to determine the co-expression of nAChR subunits upon dopaminergic nerve terminals at the ultrastructural level, and 3) to determine the mechanism of nicotine-induced responses of the dopaminergic system to short- and long-term presence of nicotine. All of these studies will be performed in control (sham) animals and in an animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia.
