Dopamine and norepinephrine in the gastrointestinal tract of mice and the effects of neurotoxins.

Evidence is lacking for neurons containing dopamine and acting as a neurotransmitter in the gastrointestinal tract. The relative percentage of dopamine to norepinephrine in noradrenergically innervated tissues (e.g., spleen) is known to be relatively constant within a species, and an increased percentage in any given tissue supports the premise that dopaminergic cells are present. We measured levels of norepinephrine, dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) from segments of the gastrointestinal tract of mice after injection of: 1) saline (control); 2) 6-hydroxydopamine (6-OHDA); or 3) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In control tissues the ratio of dopamine/norepinephrine was higher (P less than .001) than in the spleen; DOPAC was present and the DOPAC/dopamine ratios were similar to those in the central nervous system (where dopaminergic neurons are present). Dopamine and norepinephrine were decreased by 6-OHDA in most myenteric plexus/smooth muscle tissues compared with controls and DOPAC was unmeasurable in most samples after 6-OHDA. In contrast, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine decreased norepinephrine but not dopamine in the smooth muscle/myenteric plexus. High dopamine/norepinephrine percentages, 6-OHDA depletion of dopamine and presence of DOPAC together suggest the presence of dopamine-containing neurons in the myenteric plexus of the gastrointestinal tract of mice.

Chronic alterations in jejunal myoelectric activity in rats due to MPTP.

Parkinsonian patients may have symptoms consistent with intestinal pseudo-obstruction, but a primary intestinal abnormality has not been shown. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after conversion to a toxic metabolite via the monoamine oxidase system, can induce Parkinson's disease by destroying dopaminergic neurons in the substantia nigra in humans and primates. Rodents have some catecholamine depletion but much less so than primates. Using chronic bipolar electrodes on the proximal jejunum of Wistar rats, we show significant, chronic migrating myoelectric complex disruption (P less than 0.001) and prolongation of irregular spike activity (P less than 0.001). Pargyline (a monoamine oxidase inhibitor) pretreatment significantly blocked these myoelectric changes. Sinemet (L-dopa and carbidopa), given after MPTP to replete dopamine, decreased the MPTP-induced migrating myoelectric complex disruption. Jejunal myenteric plexus dopamine levels were significantly decreased (to 61% of control) after MPTP but after much higher doses than were required to disrupt migrating myoelectric complex activity (180 mg/kg total vs. 30 mg/kg). Dopamine in the central nervous system was not depleted. We conclude that MPTP causes intestinal myoelectric disruption (which can be blocked by pargyline and decreased by Sinemet) possibly through enteric, but not central, nervous system effects.

Effects of Newcastle disease virus administration to mice on the metabolism of cerebral biogenic amines, plasma corticosterone, and lymphocyte proliferation.

Newcastle disease virus (NDV) administration to mice increased concentrations of plasma corticosterone, with a maximal effect at 8 h. This elevation of plasma corticosterone concentrations was not observed in hypophysectomized animals in which the completeness of the hypophysectomy was verified by functional tests. NDV administration consistently increased concentrations of free tryptophan in all brain regions examined (prefrontal cortex, hypothalamus, and brain stem). It also caused an activation of cerebral catecholamine and indoleamine metabolism as determined by measurement of the amines and their catabolites. 3-Methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of norepinephrine (NE), homovanillic acid (HVA), a major catabolite of dopamine (DA), and 5-hydroxyindoleacetic acid (5-HIAA), the major catabolite of serotonin (5-HT), were all increased in both hypothalamus and brain stem. Ratios of catabolites to the parent amine, considered to be an index of utilization of the neurotransmitters, were increased for NE, DA, and 5-HT in the hypothalamus and for DA and 5-HT in the brain stem. This pattern of changes resembles that observed following stressors such as footshock or restraint. There were also significant increases of tryptophan, HVA, dihydroxyphenylacetic acid (DOPAC), and 5-HIAA in hypophysectomized relative to sham-operated mice. The NDV treatment also increased thymus weights and markedly decreased the proliferative responses of isolated spleen cells to phytohemagglutinin, concanavalin A, pokeweed mitogen, and Escherichia coli lipopolysaccharide. These changes were not caused by increased circulating corticosterone because they were present at equal magnitude in hypophysectomized mice. Thymosin alpha 1 concentrations in the plasma were not altered by NDV or hypophysectomy. These results indicate that administration of NDV to mice can initiate neurochemical and endocrine responses like those observed during stress and can also cause immunosuppression. They are thus consistent with the hypothesis that a virus can be a stressor.