title: Gastric dysregulation induced by microinjection of 6-OHDA in the substantia nigra pars compacta of rats is determined by alterations in the brain-gut axis.
abstract: Idiopathic Parkinson's disease (PD) is a late-onset, chronic, and progressive motor dysfunction attributable to loss of nigrostriatal dopamine neurons. Patients with PD experience significant gastrointestinal (GI) issues, including gastroparesis. We aimed to evaluate whether 6-hydroxy-dopamine (6-OHDA)-induced degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) induces gastric dysmotility via dysfunctions of the brain-gut axis. 6-OHDA microinjection into the SNpc induced a >90% decrease in tyrosine hydroxylase-immunoreactivity (IR) on the injection site. The [13C]-octanoic acid breath test showed a delayed gastric emptying 4 wk after the 6-OHDA treatment. In control rats, microinjection of the indirect sympathomimetic, tyramine, in the dorsal vagal complex (DVC) decreased gastric tone and motility; this inhibition was prevented by the fourth ventricular application of either a combination of α1- and α2- or a combination of D1 and D2 receptor antagonists. Conversely, in 6-OHDA-treated rats, whereas DVC microinjection of tyramine had reduced effects on gastric tone or motility, DVC microinjection of thyrotropin-releasing hormone induced a similar increase in motility as in control rats. In 6-OHDA-treated rats, there was a decreased expression of choline acetyl transferase (ChAT)-IR and neuronal nitric oxide synthase (NOS)-IR in DVC neurons but an increase in dopamine-β-hydroxylase-IR in the A2 area. Within the myenteric plexus of the esophagus, stomach, and duodenum, there were no changes in the total number of neurons; however, the percentage of NOS-IR neurons increased, whereas that of ChAT-IR decreased. Our data suggest that the delayed gastric emptying in a 6-OHDA rat model of PD may be caused by neurochemical and neurophysiological alterations in the brain-gut axis.
authors.affiliation: Department of Neural and Behavioral Sciences, Penn State, College of Medicine, Hershey, Pennsylvania.
authors.forename: Luca
authors.initials: L
authors.lastname: Toti
authors.affiliation: Department of Neural and Behavioral Sciences, Penn State, College of Medicine, Hershey, Pennsylvania rtravagli@hmc.psu.edu.
authors.forename: R Alberto
authors.initials: RA
authors.lastname: Travagli
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D005753:Gastric Mucosa / Q000378:metabolism; D018589:Gastroparesis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008845:Microinjections; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000294:innervation*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013566:Sympathomimetics / Q000008:administration & dosage; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018492:Dopamine Antagonists; D013566:Sympathomimetics; D016627:Oxidopamine; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D002795:Choline O-Acetyltransferase
keywords: Parkinson’s disease; brainstem; gastric motility; immunohistochemistry