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Received for publication March 14, 2005.
Revised May 24, 2005.
Accepted for publication June 1, 2005.
3*/6* nicotinic receptors but not nicotine-evoked dopamine release in monkey brain after nigrostriatal damage
Nicotinic receptors (nAChRs) are decreased in the striatum of Parkinson's disease (PD) patients or in experimental models following nigrostriatal damage. Since presynaptic nAChRs on striatal dopamine terminals mediate dopamine release, receptor loss may contribute to behavioral deficits in PD. The present experiments were done to determine whether nAChR function is affected by nigrostriatal damage in nonhuman primates as this model shares many features with PD. Initial characterization of nicotine-evoked [3H]dopamine release from monkey striatal synaptosomes revealed that release was calcium-dependent and inhibited by selective nAChR antagonists. Interestingly, a greater proportion (~ 70%) of release was inhibited by the 
3*/6* antagonist -conotoxinMII (-CtxMII) compared to rodents. Next, monkeys were lesioned with MPTP, and [3H]dopamine release, dopamine transporter and nAChRs measured. As anticipated, lesioning decreased the transporter and 3*/6* nAChRs in caudate and putamen. In contrast, 3*/6* nAChR-evoked [3H]dopamine release was reduced in caudate, but not putamen demonstrating a dissociation between nAChR sites and function. A different pattern was observed in the mesoolimbic dopamine system. Dopamine transporter levels were not reduced in nucleus accumbens after MPTP, as expected, however, there was a 50% decline in 3*/6* nAChR sites with no decrease in 3*/6* receptor-evoked dopamine release. No declines in -CtxMII-resistant nAChR (4*) binding or nicotine-evoked release were observed in any region. These results show a selective preservation in 3*/6* nAChR-mediated function in the nigrostriatal and mesolimbic dopamine systems following nigrostriatal damage. Maintenance of function in putamen, a region with selective loss of dopaminergic terminals, may be important in PD.
Key words:
Dopamine, Nicotinic cholinergic, Receptor binding studies, Excitotoxicity, neurodegeneration
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