Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Abstract

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

Functional and neurochemical changes of the gastrointestinal tract in a rodent model of Parkinson's disease

“…Overall, available data indicate either unchanged [2] or increased numbers of myenteric nitrergic neurons in the MPTP model of PD [10]. In our hands, rats lesioned with 6-OHDA showed a significant reduction in the percentage of myenteric neurons expressing nNOS in the distal ileum and proximal colon, while the total number of neurons was unchanged.…”

“…However, MPTP does not cause parkinsonism in rats (unlike primates and mice) [19], thus limiting the value of these observations. Anderson et al [2] reported a 40% reduction of dopamine neurons in the ENS of mice receiving intraperitoneal MPTP administration, without loss of cholinergic or nitrergic neurons. Recently, Tian et al [28] reported increased expression of TH and DAT in the GI tract of rats bearing bilateral lesions of the SNc obtained by stereotaxic injection of 6-hydroxydopamine (6-OHDA), a neurotoxin with selective toxicity for dopaminergic neurons [30].…”

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

“…Additionally, the MPTP primate model has been indispensable in the development and testing of novel PD therapeutics as well as in studies examining side-effects of current PD therapies, such as dyskinesias in response to levodopa (49). Furthermore, recent data reporting gastrointestinal dysfunction in the MPTP mouse model (2,70) support the notion that MPTP-treated mice may be an appropriate model in which to study extranigral PD pathophysiology.…”

Role of peripheral dopaminergic system in the pathogenesis of experimental colitis in rats

“…Thus, we could exclude the role of neither central nor peripheral dopaminergic system in the beneficial effect of D2 agonists on the colonic lesion. Moreover, the data on duodenal ulceration indicated that dopamine-related drugs affect experimental duodenal ulcers both by peripheral and central actions [15][16][17]. Furthermore the importance of central dopamine in intestinal mucosal integrity was confirmed by Ray et al [16].…”