Abstract

Nicotinic acetylcholine receptor (nAChR) activation is well known to stimulate dopamine release in the striatum. This phenomenon may be physiologically significant in the control of motor function, as well as in pathological conditions such as Parkinson's disease. An understanding of the mechanisms that influence nAChR expression and function is therefore important. Because the dopamine precursor l-DOPA is the most commonly used therapeutic agent for Parkinson's disease, we investigated the effects of l-DOPA treatment on striatal nAChR expression in unlesioned and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. In unlesioned animals, l-DOPA (15 mg/kg) administered twice daily for 2 weeks decreased both ¹²⁵I-epibatidine and [¹²⁵I]iodo-3-[2(S)-azetidinylmethoxy]pyridine (A-85380) binding sites in the caudate and putamen, but did not affect ¹²⁵I-α-CtxMII sites. α-CtxMII inhibition of striatal ¹²⁵I-epibatidine and [¹²⁵I]A-85380 binding with α-CtxMII suggest that there are both high- (K_i < 0.2 nM) and low-affinity (K_i > 100 nM) α-CtxMII-sensitive sites, as well as α-CtxMII-resistant sites, and that l-DOPA treatment influences only the low-affinity α-CtxMII-sensitive subtype. The l-DOPA effect was selective for striatal nAChRs with no change in cortical sites. Monkeys with severe nigrostriatal damage did not exhibit l-DOPA-induced declines in striatal nAChRs, suggesting that l-DOPA primarily affects nAChRs associated with dopaminergic terminals. In summary, these data show that l-DOPA treatment decreases nAChR expression, in contrast with the well established up-regulation of these sites by chronic nicotine exposure. Furthermore, they demonstrate preferential l-DOPA regulation of a novel low-affinity α-CtxMII-sensitive site. These declines in nAChRs with l-DOPA may be relevant to both the therapeutic and side effect profiles of l-DOPA therapy in Parkinson's disease.