SU2045 Characterization of Excitatory and Inhibitory Neuromuscolar Pathways Regulating Colonic Motility in a Rat Model of Parkinson's Disease

Introduction. Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons. Patients with PD can develop gastrointestinal motor dysfunctions, and alterations of their enteric nervous system have been also observed. This study examined the patterns of colonic neuromuscular excitatory and inhibitory pathways in a rat model of PD. Methods. PD was induced in rats by intra-nigral injection of 6-hydroxydopamine (6- OHDA). Animals were sacrificed 28 or 56 days after surgery. Colonic circular muscle preparations were set up in organ baths with Krebs solution, and connected to isometric transducers to record contractions (g/g tissue) elicited by electrical stimulation (ES, 10 Hz), in the presence of guanethidine (10 μM) and N ω-nitro-L-arginine methylester (L-NAME, 100 μM). L-732,138 (NK1 receptor antagonist, 10 μM) or atropine (1 μM) were used to record contractions driven primarily by acetylcholine or tachykinins, respectively. In addition, contractions elicited by exogenous substance P (SP, 10 μM) or carbachol (10 μM), in the presence of tetrodotoxin (1 μM), were assessed. Electrically evoked contractile responses (5 Hz) in the presence L-NAME were also recorded and expressed as % of contractions in the absence of L-NAME. Each value represents the mean ± S.E.M obtained from 6 experiments. Results. Electrically evoked cholinergic contractions were decreased in rats sacrificed at day 28 and 56 after 6-OHDA injection (77.2±6.3 and 53.8±0.1, respectively), in comparison with controls (99±6.51). Conversely, carbachol-evoked contractions were enhanced in rats with PD both at day 28 and 56 (81.5±3.4 and 98.2±3.8, respectively), as compared to controls (52.2±5.6). Electrically evoked tachykininergic contractions were enhanced both at day 28 (85.6±5.2) and 56 (67.3±3.3), in comparison with controls (43.6±6.5). Likewise, contractions elicited by exogenous SP in colonic preparations from PD rats were also increased both at day 28 (244±11.9) and 56 (188.2±13.9), as compared to controls (79.6±6.3). In the presence of L-NAME, electrically evoked contractions in controls were enhanced (+42.3±11.9%), while they were decreased in rats at day 28 and 56 after 6-OHDA injection (+29.1±4.4% and +15±5.3%, respectively). Conclusion. Experimental PD, elicited by nigrostriatal dopaminergic degeneration, is associated with changes in neurotransmitter pathways driving colonic excitatory and inhibitory motor functions: an impairment of nitrergic and cholinergic transmission occurs in concomitance with an enhancement of tachykininergic control. Such a shift takes place along with an up-regulation of the contractile responses mediated by muscarinic receptors on smooth muscle, which might be compensatory in nature.