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Background: Gastrointestinal (GI) dysfunction, including constipation, is a common non‐motor symptom of Parkinson's disease (PD). The toxin 6‐hydroxydopamine (6OHDA) produces the symptoms of PD, surprisingly including constipation, after it is injected into the medial forebrain bundle (MFB). However, the mechanisms involved in PD‐associated constipation caused by central application of 6OHDA remain unknown. We investigated effects of 6OHDA lesioning of the MFB on motor performance and GI function. Methods: Male Sprague Dawley rats were unilaterally injected with 6OHDA in the MFB. Colorectal propulsion was assessed by bead expulsion after 4 weeks and by recording colorectal contractions and propulsion after 5 weeks. Enteric nervous system (ENS) neuropathy was examined by immunohistochemistry. Key Results: When compared to shams, 6OHDA‐lesioned rats had significantly increased times of bead expulsion from the colorectum, indicative of colon dysmotility. Administration of the colokinetic, capromorelin, that stimulates defecation centers in the spinal cord, increased the number of contractions and colorectal propulsion in both groups compared to baseline; however, the effectiveness of capromorelin in 6OHDA‐lesioned rats was significantly reduced in comparison with shams, indicating that 6OHDA animals have reduced responsiveness of the spinal defecation centers. Enteric neuropathy was observed in the distal colon, revealing that lesion of the MFB has downstream effects at the cellular level, remote from the site of 6OHDA administration. Conclusions & Inferences: We conclude that there are trans‐synaptic effects of the proximal, forebrain, lesion of pathways from the brain that send signals down the spinal cord, at the levels of the defecation centers and the ENS. [ABSTRACT FROM AUTHOR]

Background: Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non‐motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α‐synuclein distribution. Methods: Chronic isolation stress was induced by single‐housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group‐housed. Key Results: Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole‐gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment‐induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single‐housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha‐synuclein (αsyn) in myenteric ganglia under both housing conditions. Conclusions & Inferences: Chronic isolation stress exacerbates PD‐associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation. [ABSTRACT FROM AUTHOR]

Background: Because M1 muscarinic receptors are expressed by enteric neurons, we investigated whether positive allosteric modulators of these receptors (M1PAMs) would enhance colorectal propulsion and defecation in dogs, mice, and rats. Methods: The potencies of the M1PAMs, T662 or T523, were investigated using M1 receptor‐expressing CHO cells. Effectiveness of M1PAMs on defecation was investigated by oral administration in mice and rats, by recording propulsive contractions in anaesthetized rats and by recording high amplitude propagating contractions in dogs. Key Results: PAM EC50 values in M1 receptor‐expressing CHO cells were 0.7‐1.8 nmol/L for T662 and 8‐10 nmol/L for T523. The compounds had 1000‐fold lower potencies as agonists. In anesthetized rats, both compounds elicited propulsive colorectal contractions, and in dogs, mice, and rats, oral administration increased fecal output. No adverse effects were observed in conscious animals. M1PAMs triggered propagated high amplitude contractions and caused defecation in dogs. Nerve‐mediated contractions were enhanced in the isolated mouse colon. M1PAMs were equi‐effective in rats with or without the pelvic nerves being severed. In two models of constipation in mice, opiate‐induced constipation and constipation of aging, defecation was induced and constipation was reversed. Conclusion and Inferences: M1PAMs act at targets sites in the colorectum to enhance colorectal propulsion. They are effective across species, and they reverse experimentally induced constipation. Previous studies have shown that they are safe in human. Because they provide an enhancement of physiological control rather than being direct agonists, they are predicted to provide effective treatment for constipation. [ABSTRACT FROM AUTHOR]