Conditioned flavor aversion and brain Fos expression following exposure to arsenic.

Recent advances in the knowledge of the cellular effects of arsenic have provided insights into the molecular mechanisms of arsenic-associated carcinogenesis, immunotoxicity and cardiovascular disease. In the present experiments we tested the hypothesis that the arrival of arsenic to the gastrointestinal (GI) tract is detected by the gut-brain axis, which includes hindbrain and forebrain nuclei activated by GI stimulation. As a marker of neuronal activation we measured Fos expression using immunohistochemistry. Because Fos expression in these nuclei is closely linked to the development of conditioned flavor aversion (CFA) we also tested the effect of arsenic on CFA. Our experiments indicate that arsenic ingestion is readily detected by the brain, as shown by increased Fos expression after oral administration of arsenic. Furthermore, the vagus nerve, which supplies information from the GI tract to the brain, is not involved in this response because a complete subdiaphragmatic vagotomy did not reduce the effect of arsenic on brain Fos expression, but enhanced this response. In parallel, arsenic ingestion is associated with a robust, dose-dependent CFA, which started at doses as low as 0.1 mg/kg body weight. In summary, these data indicate that arsenic given by oral administration is detected by the brain in low concentrations, and activates specific nuclei, which might trigger behavioral responses, such as CFA.

Brain Fos expression during 48 h after cisplatin treatment: neural pathways for acute and delayed visceral sickness.

Cancer chemotherapy drugs, such as cisplatin, are extremely potent for producing nausea and vomiting. The acute effects of these treatments are partly controlled using anti-emetic drugs, but the delayed effects (>24 h), especially nausea, are much more difficult to treat. Furthermore, cisplatin induces a long-term (up to 48 h) increase in pica in rats. Pica is manifested as an increase in consumption of kaolin (clay) and is used as a measure of visceral sickness. It is unknown what brain pathways might be responsible for this sickness associated behavior. As a first attempt to define this neural system, rats were injected (i.p.) with 3, 6, or 10 mg/kg cisplatin (doses reported to produce pica) and sacrificed at 6, 24, or 48 h to determine brain Fos expression. The primary results indicate: 1) increasing the dose of cisplatin increased the magnitude and duration of brain Fos expression, 2) most excitatory effects on hindbrain nucleus of the solitary tract (NTS) and area postrema (AP) Fos expression occurred within 24 h after cisplatin injection, 3) 6 and 10 mg/kg cisplatin treatment produced large increases in Fos expression in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), including 48 h after injection, and 4) cisplatin treatment produced little effect on Fos expression in the paraventricular and supraoptic nuclei of the hypothalamus. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex (NTS and AP), CeA, and BNST.