The alpha7 Nicotinic Receptor Agonist ABT-107 Protects against Nigrostriatal Damage in Rats with Unilateral 6-Hydroxydopamine Lesions

Abstract

The finding that smoking is inversely correlated with Parkinson’s disease and that nicotine attenuates nigrostriatal damage in Parkinsonian animals supports the idea that nicotine may be neuroprotective. Nicotine is thought to exert this effect by acting at nicotinic receptors (nAChRs), including the α7 subtype. The objective of this study was twofold: first, to test the protective potential of ABT-107, an agonist with high selectivity for α7 nAChRs; and second, to investigate its cellular mechanism of action. Rats were implanted with minipumps containing ABT-107 (0.25mg/kg/d). In addition, we tested the effect of nicotine (1mg/kg/d) as a positive control, and also DMXB (2mg/kg/d) which acts primarily with α7 but also α4β2* nAChRs. Two weeks after minipump placement, the rats were lesioned by unilateral administration of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Lesioning alone decreased contralateral forelimb use and adjusted stepping, two measures of Parkinsonism. ABT-107 and nicotine treatment significantly improved these behaviors at all weeks tested, with variable improvement with DMXB. We next investigated the cellular mechanism involved. The striatal dopamine transporter (DAT), a marker of dopaminergic integrity, was reduced ~70% with lesioning. ABT-107 or nicotine treatment significantly increased DAT levels in lesioned striatum; these drugs did not alter DAT levels in intact striatum. ABT-107 and nicotine also significantly improved basal dopamine release from lesioned striatum, as well as nicotine-stimulated dopamine release mediated via α4β2* and α6β2* nAChRs. These data suggest that α7 nAChR agonists may improve motor behaviors associated with nigrostriatal damage by enhancing striatal dopaminergic function.