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Male BALB/c mice, assessed for spontaneous nocturnal rotation that has been linked with functional differences in striatal dopamine (DA) content, were divided into right (R), left (L), and no turning preference (NP) groups. Both total turning activity and turning in the preferred direction were greatest in the R mice. To determine whether turning preference influences the response to exposure to an environmental toxicant known to reduce striatal DA function, striatal tissues from R, L, or NP mice were exposed to polychlorinated biphenyls (PCBs). In vitro exposure of striata from these mice to varying concentrations of PCBs for 4 h concentration-dependently decreased tissue DA content and increased the concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the media, a phenomenon already observed, although of smaller magnitude, with rat tissues. These effects were independent of the turning preference of the mice. Although the DA content initially did not differ among the striatal tissue from R, L, and NP mice, following 4 h of incubation in control medium (without PCBs), there was significantly greater DA content in striata from R mice in comparison to that from either L or NP mice. This difference was also apparent after 6 h of incubation, and it was not due to differences in DA turnover or cytotoxicity. Rather, the greater DA content in the striata of R mice was due to increased DA synthesis, since tyrosine hydroxylase (TH) activity was greater in striata from R mice than in striata from either L or NP mice. These differences in striatal DA synthesis, if present in vivo, may explain the observed greater nocturnal turning activity of the R mice. Additionally, the in vitro analyses suggest that striata from R mice have differential responses to stress compared with striata from L or NP mice. With regard to the effects of PCBs, however, it appears that (1) striata derived from mice with different turning preference are equally sensitive to this dopaminergic toxicant and (2) mice appear more sensitive to PCBs than rats.

The ergopeptine alkaloid ergotamine (ET) mimics the effects of ergopeptine alkaloids found in endophyte-infected (E+) fescue forage considered causative for fescue toxicosis. Altered immune capacity, compromised intake and thermoregulation, and inflammatory changes are observed in fescue toxicosis. Taken together, these suggest the cytokine pattern may be altered by ergot alkaloids. Thus, the objective of this study was to determine whether major splenocyte-derived cytokines--interleukin 2 (IL-2), interleukin 4 (IL-4), interferon gamma (IFN-gamma)--and macrophage-derived cytokines--interleukin 1beta, (IL-1beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)--were affected by ergotamine. Two sets of male BALB/c mice (n = 5/treatment) were treated with ergotamine tartrate (s.c.) for 10 d at doses of 0 (control), 0.4, 2, 10, or 50 mg/kg body weight. Twenty-four hours after the last treatment, splenocytes (S) were isolated from one set of animals and macrophages (Mphi) from the other set for determination of IL-2, IL-4, INF-gamma, and IL-1beta, IL-6, TNF-alpha, respectively. Following activation with 5 microg/ml concanavalin A (Con A) (S) and 10 microg/ml lipopolysaccharide (LPS) (Mphi), cells were incubated for 48 and 24 h, respectively, and supernatants were collected and assayed for respective cytokines by enzyme-linked immunosorbent assay (ELISA). Additionally, differential white blood cell (WBC) counts were performed and the neutrophil (N):lymphocyte (L) ratio calculated. Ergotamine treatment significantly increased IL-6 levels at the 2.0 mg/kg dose and greater and TNF-alpha at the highest dose. There was no treatment effect on IL-1beta, IL-2, IL-4, and IFN-gamma. Also, no effect was observed upon total and differential WBC counts as well as N:L ratio. Ergotamine affected the proinflammatory cytokine IL-6, and this increase may contribute to fescue tosicosis.

Ergot alkaloids (EA) such as the ergopeptine alkaloid ergotamine (ET) are adrenergic, dopaminergic, and serotonergic agents. The objective of this experiment was to investigate regional brain neurotransmitter alterations caused by EA. Male BALB/c mice were treated s.c. daily with ergotamine tartrate for 10 d at 0 (saline), 0.4, 2, 10, or 50 mg/kg body weight. Twenty-four hours after the last treatment, animals were sacrificed and brains dissected. Regional concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography (HPLC). Moreover, selected organ weights and plasma prolactin (PRL) were determined. Dopamine concentration was significantly reduced by ET at all doses in the striatal and hypothalamic regions. A reduction of the DA metabolite HVA occurred in striatum at only the highest dose, whereas in the hypothalamus both HVA and DOPAC were markedly reduced. Concentrations of NE, MHPG, 5-HT, and 5-HIAA were not affected by treatment in these regions. In the cerebellum, MHPG was significantly elevated at the 50 mg/kg dose. No effect of treatment was observed in the cerebrum, medulla, and midbrain. Further, no treatment-related differences in plasma PRL and organ weights other than a significant liver weight decrease at intermediate doses were found. Therefore, the effects of ET were predominantly upon DA metabolism in the corpus striatum and hypothalamus. The reductions in DA, HVA, and DOPAC indicate decreased DA synthesis.