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Abstract
Cholinergic neurotransmission has a pivotal function in the caudate-putamen, and is highly associated with the pathophysiology of Parkinson's disease. Here, we investigated long-term changes in the densities of the muscarinic receptor subtypes M1, M2, M3 (mAchRs) and the nicotinic receptor subtype α4β2 (nAchRs) in the striatum of the 6-OHDA-induced hemiparkinsonian (hemi-PD) rat model using quantitative in vitro receptor autoradiography. Hemi-PD rats exhibited an ipsilateral decrease in striatal mAchR densities between 6 and 16%. Moreover, a massive and constant decrease in striatal nAchR density by 57% was found. A second goal of the study was to disclose receptor-related mechanisms for the positive motor effect of intrastriatally injected Botulinum neurotoxin-A (BoNT-A) in hemi-PD rats in the apomorphine rotation test. Therefore, the effect of intrastriatally injected BoNT-A in control and hemi-PD rats on mAchR and nAchR densities was analyzed and compared to control animals or vehicle-injected hemi-PD rats. BoNT-A administration slightly reduced interhemispheric differences of mAchR and nAchR densities in hemi-PD rats. Importantly, the BoNT-A effect on striatal nAchRs significantly correlated with behavioral testing after apomorphine application. This study gives novel insights of 6-OHDA-induced effects on striatal mAchR and nAchR densities, and partly explains the therapeutic effect of BoNT-A in hemi-PD rats on a cellular level.
Highlights
Acetylcholine (Ach) effects are mediated via metabotropic G-protein coupled muscarinic receptors and ionotropic nicotinic receptors
Densities were measured in the striatum ipsi- and contralateral to the 6-OHDA injection side, and expressed as relative values by calculating the difference between ipsilateral and contralateral receptor densities normalized by the contralateral density
As dopaminergic deprivation with 6-OHDA increased ipsilateral striatal D2/D3 receptor density (Creese et al, 1977; Creese and Snyder, 1979; Murrin et al, 1979; Staunton et al, 1981; Przedbroski et al, 1995; Sun et al, 2011; Choi et al, 2012), the ipsilateral CPu of hemi-Parkinson’s disease (PD) rats is inhibited more than the left by application of the D2/D3 agonist apomorphine
Summary
Acetylcholine (Ach) effects are mediated via metabotropic G-protein coupled muscarinic receptors (mAchRs) and ionotropic nicotinic receptors (nAchRs). In the striatum (caudate-putamen, CPu), complex bidirectional interactions of the cholinergic and dopaminergic systems are fundamental for normal functioning (Calabresi et al, 2000; Cragg, 2006; Goldberg et al, 2012) Both nAchRs (Giorguieff et al, 1976; Rapier et al, 1988; Grady et al, 1992; El-Bizri and Clarke, 1994; Sharples et al, 2000; Wonnacott et al, 2000; Zhou et al, 2001) and mAchRs (Westfall, 1974; Zhang et al, 2002; Zhang and Sulzer, 2004; Threlfell et al, 2010) modulate dopamine (DA) release from synaptic terminals. The precise functions of nAChRs and mAChRs subtypes are still subject of ongoing research
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