RT Journal Article
SR Electronic
T1 Enteric dysfunctions in experimental Parkinson’s disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.228510
DO 10.1124/jpet.115.228510
A1 Matteo Fornai
A1 Carolina Pellegrini
A1 Luca Antonioli
A1 Cristina Segnani
A1 Chiara Ippolito
A1 Elisabetta Barocelli
A1 Vigilio Ballabeni
A1 Gaia Vegezzi
A1 Zainab al Harraq
A1 Fabio Blandini
A1 Giovanna Levandis
A1 Silvia Cerri
A1 Corrado Blandizzi
A1 Nunzia Bernardini
A1 Rocchina Colucci
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/11/18/jpet.115.228510.abstract
AB Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate.