NOS and fos in Rat and Mouse Brain Regions.

Abstract

In the preceeding article, we replicated O’Hearn and finding that acute exposure to ibogaine is neurotoxic to the rat cerebellum. Both our groups reported necrosis of Purkinje neurons in the cerebellar vermis as indicated by several neurohistological biomarkers including argyrophilic degeneration, loss of calbindin immunoreactivity , and astrocytosis. Therefore, it is quite cer- tain that ibogaine can indeed be a potent neurotoxicant to the rat cerebellar Purkinje cells. However, we also found that mice treated with the identical dose (100 mg/kg) and route of administration (i.p.) of ibogaine exhibited no such damage. One way to seek to explain the species difference would be to evaluate the pharmacokinetics and pharmacodynamics of ibogaine in rats and mice. This kind of data would allow concluding whether the mice, apparently spared from ibogaine neurotoxicity to the cerebellum, really were seeing similar brain levels of the compound or its active metabolite. Even better would be a biomarker of a down- stream effect of the drug, in case the relevant ibogaine membrane receptors or their coupled signal transduction mechanisms differ between species. A study reported in abstract form by O’Hearn and Molliver in rats3 (as our experiments were in progress) utilized c-fos protein immunohistochemical staining to study forebrain actions of ibogaine, both with and without an intact inferior olivary nucleus, which is needed for ibogaine or harmaline-induced neurodegenerative loss of Purkinje neurons.] They found that forebrain c-fos protein induction occurred whether or not the inferior olive was lesioned, independently of cerebellar neuro- toxicity. Thus the inferior olive is necessary for ibogaine neurotoxicity to take place, but may not be sufficient. The present study reports the localization of the nuclear earlyhmediate gene product c-fos as a biomarker of the ibogaine drug effect on cells in various brain regions, including the cerebellum, of rats compared to mice. We hypothesized that an equal dose of ibogaine given to mice (no neurode- generation) or rats (neurodegeneration) would cause simiIar levels of expression ofc-fos protein in all the brain regions of both mice and rats, if the pharmacokinetics was similar in both species. We indeed found that a similar induction of c-fos occurred in both rats and mice in most brain regions, with the notable exception of the cortex. These data indicate the pharmacokinetics may be similar in rats and mice, although the pharmacodynamic effects of the drug on cortex may differ

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