Nicotinestimulated Dopamine Release From Nigrostriatal Neurons

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The findings that the concentration of DA in the striatum is about ten times higher than any other brain area, and the recognition that this area plays a major role in motor function, suggested that nicotine might act to release DA from striatal tissue. The technique of in vitro perfusion of specific brain areas developed in the late 1960s allowed a determination to be made of the concentration and efficacy of drug-induced effects on neurotransmitter systems in living brain tissue. Besson and coworkers (1969) studied the effect of cholinergic stimulation on DA release in rat striatal tissue and found that the application of acetylcholine produced a marked increase in newly synthesized [3H]DA release. The first direct evidence of nicotine-stimulated DA release in striatum was reported by Westfall (1974), and this finding was soon confirmed by a number of other investigators (Goodman, 1974; Giorguieff et al. 1977; Arqueros et al., 1978).

These initial studies, which employed relatively high concentrations of nicotine, indicated that nicotine-stimulated DA release occurred by a calcium-independent process. It was suggested by Arqueros that the mechanism of nicotine's action was by displacement of DA from synaptic vesicles in a manner analogous to amphetamine (Arqueros et al., 1978). This mechanism had actually been proposed several years earlier by Long and Chiou to explain nicotine-stimulated acetylcholine release (Chiou et al., 1970). Later experiments using lower concentrations of nicotine demonstrated that the effect was indeed calcium dependent (Westfall et al., 1987) and this has been confirmed in most subsequent studies. More recent experiments with selective Ca++ channel antagonists have shown that nicotine-evoked DA release requires the activation primarily of N-type calcium channels (Harsing et al., 1992; Prince et al., 1996; Soliakov and Wonnacott, 1996). Studies using synaptosomes along with nicotinic receptor antagonists have confirmed that the nicotine-evoked release of DA in the striatum can be produced by the drug's interaction with presynaptic nicotinic heteroreceptors located on the nerve terminals (Sakurai et al., 1982; Rapier et al., 1988; Wonnacott et al., 1989).

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