Increasing evidence suggests that environmental neurotoxicants or misfolded α-synuclein generated by such neurotoxicants are transported from the gastrointestinal tract to the central nervous system via the vagus nerve, triggering degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and causing Parkinson’s disease (PD). We tested the hypothesis that gastric co-administration of subthreshold doses of lectins and paraquat can recreate the pathology and behavioral manifestations of PD in rats. A solution containing paraquat + lectin was administered daily for 7 days via gastric gavage, followed by testing for Parkinsonian behavior and gastric dysmotility. At the end of the experiment, brainstem and midbrain tissues were analyzed for the presence of misfolded α-synuclein and neuronal loss in the SNpc and in the dorsal motor nucleus of the vagus (DMV). Misfolded α-synuclein was found in DMV and SNpc neurons. A significant decrease in tyrosine hydroxylase positive dopaminergic neurons was noted in the SNpc, conversely there was no apparent loss of cholinergic neurons of the DMV. Nigrovagally-evoked gastric motility was impaired in treated rats prior to the onset of parkinsonism, the motor deficits of which were improved by l-dopa treatment. Vagotomy prevented the development of parkinsonian symptoms and constrained the appearance of misfolded α-synuclein to myenteric neurons. These data demonstrate that co-administration of subthreshold doses of paraquat and lectin induces progressive, l-dopa-responsive parkinsonism that is preceded by gastric dysmotility. This novel preclinical model of environmentally triggered PD provides functional support for Braak’s staging hypothesis of idiopathic PD.

Parkinson’s disease (PD) is predominantly idiopathic in origin, and a large body of evidence indicates that gastrointestinal (GI) dysfunctions are a significant comorbid clinical feature; these dysfunctions include dysphagia, nausea, delayed gastric emptying, and severe constipation, all of which occur commonly before the onset of the well-known motor symptoms of PD. Based on a distinct distribution pattern of Lewy bodies (LB) in the enteric nervous system (ENS) and in the preganglionic neurons of the dorsal motor nucleus of the vagus (DMV), and together with the early onset of GI symptoms, it was suggested that idiopathic PD begins in the ENS and spreads to the central nervous system (CNS), reaching the DMV and the substantia nigra pars compacta (SNpc). These two areas are connected by a recently discovered monosynaptic nigro-vagal pathway, which is dysfunctional in rodent models of PD. An alternative hypothesis downplays the role of LB transport through the vagus nerve and proposes that PD pathology is governed by regional or cell-restricted factors as the leading cause of nigral neuronal degeneration. The purpose of this brief review is to summarize the neuronal electrophysiological findings in the SNpc and DMV in PD.

Fluoroquinolones (FQs) are a broad class of antibiotics typically prescribed for bacterial infections, including infections for which their use is discouraged. The FDA has proposed the existence of a permanent disability (Fluoroquinolone Associated Disability; FQAD), which is yet to be formally recognized. Previous studies suggest that FQs act as selective GABA_A receptor inhibitors, preventing the binding of GABA in the central nervous system. GABA is a key regulator of the vagus nerve, involved in the control of gastrointestinal (GI) function. Indeed, GABA is released from the Nucleus of the Tractus Solitarius (NTS) to the Dorsal Motor Nucleus of the vagus (DMV) to tonically regulate vagal activity. The purpose of this review is to summarize the current knowledge on FQs in the context of the vagus nerve and examine how these drugs could lead to dysregulated signaling to the GI tract. Since there is sufficient evidence to suggest that GABA transmission is hindered by FQs, it is reasonable to postulate that the vagal circuit could be compromised at the NTS-DMV synapse after FQ use, possibly leading to the development of permanent GI disorders in FQAD.

The majority of patients with Parkinson’s disease (PD) experience gastrointestinal dysfunction. Recently, we described a nigro-vagal pathway that uses dopaminergic (DA) inputs to the dorsal motor nucleus of the vagus (DMV) and A2 area neurons to modulate gastric motility and tone. This pathway is disrupted in a rodent model of PD. The aim of the present study was to test the hypothesis that brain-stem DA modulation of gastric tone and motility is altered in a rodent model of PD. Male Sprague-Dawley rats received three weekly intraperitoneal injections of paraquat (10 mg/kg) or saline (control). In naive conditions, microinjection of DA into the DMV induced a gastroinhibitory response in 100% of animals. In 19 of 28 PQ-treated animals, however, microinjection of DA into the DVC induced a biphasic response, with an initial increase in gastric tone and motility followed by a profound gastroinhibition. The excitatory response to DA microinjection was attenuated by a combination of DA type 1 (DA1)- and DA2-like receptor antagonists. Conversely, the inhibitory response was reduced by the DA2-like receptor antagonist only. Pretreatment with the α₂-adrenoceptor antagonist yohimbine did not modulate the response to DA, thus excluding involvement of the A2 area. At the end of the experiments, induction of the Parkinson phenotype was confirmed by the presence of α-synuclein immunoreactivity in the DMV and substantia nigra pars compacta. These data suggest a maladaptive neural plasticity in brain-stem vagal circuits regulating gastric motility in PQ-treated rats that may be responsible for the gastric dysfunction observed in PD models. NEW & NOTEWORTHY After paraquat treatment and induction of Parkinson’s disease, brain-stem dopamine (DA) application induces a biphasic gastric response in the majority of rats, with an initial increase in tone and motility followed by gastroinhibition. The initial increase in gastric tone and motility is mediated via a combined activation of DA type 1 (DA1)- and DA2-like receptors. The inhibitory effects of DA are mediated by DA2-like receptors and are not affected by blockade of adrenergic inputs mediated by α₂-adrenoceptors.

Dopamine (DA)-containing fibers and neurons are embedded within the brain stem dorsal vagal complex (DVC); we have shown previously that DA modulates the membrane properties of neurons of the dorsal motor nucleus of the vagus (DMV) via DA1 and DA2 receptors. The vagally dependent modulation of gastric tone and phasic contractions, i.e., motility, by DA, however, has not been characterized. With the use of microinjections of DA in the DVC while recording gastric tone and motility, the aims of the present study were 1) assess the gastric effects of brain stem DA application, 2) identify the DA receptor subtype, and, 3) identify the postganglionic pathway(s) activated. Dopamine microinjection in the DVC decreased gastric tone and motility in both corpus and antrum in 29 of 34 rats, and the effects were abolished by ipsilateral vagotomy and fourth ventricular treatment with the selective DA2 receptor antagonist L741,626 but not by application of the selective DA1 receptor antagonist SCH 23390. Systemic administration of the cholinergic antagonist atropine attenuated the inhibition of corpus and antrum tone in response to DA microinjection in the DVC. Conversely, systemic administration of the nitric oxide synthase inhibitor nitro-l-arginine methyl ester did not alter the DA-induced decrease in gastric tone and motility. Our data provide evidence of a dopaminergic modulation of a brain stem vagal neurocircuit that controls gastric tone and motility. NEW & NOTEWORTHY Dopamine administration in the brain stem decreases gastric tone and phasic contractions. The gastric effects of dopamine are mediated via dopamine 2 receptors on neurons of the dorsal motor nucleus of the vagus. The inhibitory effects of dopamine are mediated via inhibition of the postganglionic cholinergic pathway.