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The spontaneous activity of neurons in the pars reticulata of substantia nigra (SNpr) was studied in chloral hydrate anesthetized rats. As a function of dose, intravenous diazepam decreased, and methyl-beta-carboline-3-carboxylate (beta CCM) increased discharge frequency. Two days after terminating a one week treatment with flurazepam (FZP), both diazepam and beta CCM showed decreased ability to alter SNpr neuronal activity. Neither residual FZP nor down-regulation of benzodiazepine receptors can account for these results. In contrast, behavioral testing revealed no change in the ability of i.v. beta CCM to cause convulsions, suggesting that sites other than the SNpr are of prime importance in expressing the convulsant actions of systemically injected beta CCM.
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Pigeons responded under schedules in which either the 60th response (fixed-ratio schedule) or the first response after 3 minutes (fixed-interval schedule) resulted in food delivery. The effects of chlordiazepoxide HCl (1-30 mg/kg) and pentobarbital sodium (1-17 mg/kg) were determined before and during chronic daily exposure to either 10 or 17 mg/kg chlordiazepoxide--doses that markedly suppressed responding when given acutely. After about three weeks of daily injections of chlordiazepoxide, there was at least a three-fold shift to the right of the dose-effect curve for chlordiazepoxide, but not consistent change in the effects of pentobarbital.
Oral administration of myelin basic protein (MBP) inhibits clinical and histopathological manifestations of experimental autoimmune encephalomyelitis (EAE), but only partially reduces serum anti-MBP antibody titers. We report here that orally administered MBP alters the isotypic distribution of anti-MBP antibody-forming cells (AFC) among various lymphoid tissues, with the most profound differences seen in mucosal tissues. We observed an isotype-selective reduction in anti-MBP IgA but not IgM AFC frequencies in Peyer's patches. The anti-MBP IgA AFC frequencies could be reconstituted by addition of interleukin 4 (IL-4) and interleukin 5(IL-5). The cytokines did not appear to generate de novo responses since no increases in anti-MBP lgA AFC frequencies were observed in control cultures. These results indicate that decreased antibody production, as a result of oral antigen administration, can be reversed by exposure to the appropriate cytokines.
Experiments with transgenic mice expressing genes encoding both antigens in defined tissues and T-cell receptor genes of known specificities have enhanced our understanding of the mechanisms involved in the pathogenesis of autoimmune states. They have also shed light on the means by which potentially autoreactive cells may be prevented from exerting their autoaggressive potential. The value of the transgenic approach is that it can overcome the low frequency of peptide-specific T cells occurring in normal animals, and also provide a tissue-specific, cognate antigen that is absent in controls. These factors allow reactive T cells to be isolated or quantified by flow cytometry and their responses to antigen in vitro and in vivo be defined.
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5-HT(1A) receptor activation by the very-high-efficacy, selective 5-HT(1A) receptor agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-([(5-methyl-pyridin-2-ylmethyl)-amino]-methyl)piperidin-1-yl]-methanone] was recently discovered to constitute a novel central mechanism of broad-spectrum analgesia that, remarkably, grows rather than decays with chronicity. However, in rodents not exposed to nociception, F 13640 induces its analgesic effect only after having initially induced hyperalgesia. Numerical simulations implementing a signal transduction theory here show that the progressive increase in the intensity of nociceptive stimulation which F 13640 presumably mimics should eventually produce a large analgesic effect without initially causing marked pain. In vivo studies examined the effects of progressively increasing doses of F 13640 on the threshold of mechanically induced vocalization and, also, on the 5-HT syndrome in rats. The infusion of increasing (0.04-0.63 mg/rat/day) doses of F 13640 over a 5-week period induced a large analgesia preceded by a hyperalgesic effect that was small and comparable to that induced by initial exposure to a low, 0.04 mg/rat/day dose. Furthermore, increasing the dose of F 13640 induced tachyphylaxis to the 5-HT syndrome. Producing the mirror opposite of morphine's neuroadaptive actions, F 13640 causes an analgesia that becomes more powerful with chronic administration, and this at the expense of the initial hyperalgesia which it may also produce.
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