PT - JOURNAL ARTICLE AU - Fornai, Matteo AU - Pellegrini, Carolina AU - Antonioli, Luca AU - Segnani, Cristina AU - Ippolito, Chiara AU - Barocelli, Elisabetta AU - Ballabeni, Vigilio AU - Vegezzi, Gaia AU - al Harraq, Zainab AU - Blandini, Fabio AU - Levandis, Giovanna AU - Cerri, Silvia AU - Blandizzi, Corrado AU - Bernardini, Nunzia AU - Colucci, Rocchina TI - Enteric dysfunctions in experimental Parkinson’s disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats AID - 10.1124/jpet.115.228510 DP - 2015 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.115.228510 4099 - http://jpet.aspetjournals.org/content/early/2015/11/18/jpet.115.228510.short 4100 - http://jpet.aspetjournals.org/content/early/2015/11/18/jpet.115.228510.full 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.