Interaction between orexin A and cannabinoid system in the lateral hypothalamus of rats and effects of subchronic intraperitoneal administration of cannabinoid receptor inverse agonist on food intake and the nutritive utilization of protein.

Crosstalk may occur between cannabinoids and other systems controlling appetite, since cannabinoid receptors are present in hypothalamic circuits involved in feeding regulation, and likely to interact with orexin. In this study, an immunohistochemical approach was used to examine the effect of the intracerebroventricular administration of cannabinoid receptor inverse agonist AM 251 on orexin neuropeptide in the hypothalamic system. AM-activated neurons were identified using c-Fos as a marker of neuronal activity. The results obtained show that AM 251 decreases orexin A immunoreactivity, and that it increases c-Fos-immunoreactive neurons within the hypothalamus when compared with the vehicle-injected control group. We also studied the effects of subchronic intraperitoneal administration of AM 251 on food intake, body weight, and protein utilization. The administration of AM 251 at 1, 2, or 5 mg/kg led to a significant reduction in food intake, along with a significant decrease in the digestive utilization of protein in the groups injected with 1 and 2 mg/kg. There was a dose-related slowdown in weight gain, especially at the doses of 2 and 5 mg/kg, during the initial days of the trial. The absence of this effect in the pair-fed group reveals that any impairment to digestibility was the result of administering AM 251. These data support our conclusion that hypothalamic orexigenic neuropeptides are involved in the reduction of appetite and mediated by the cannabinoid receptor inverse agonist. Furthermore, the subchronic administration of AM 251, in addition to its effect on food intake, has significant effects on the digestive utilization of protein.

Progressive reduction of sleep time and quality in rats with hepatic encephalopathy caused by portacaval shunts.

Patients with liver cirrhosis show sleep disturbances. Insight into their relationship with hepatic encephalopathy (HE) can be obtained using animal models of HE. The aims of this work were to assess (1) whether rats with portacaval shunts (PCS), a model of HE, show alterations in sleep and if they are similar to those in patients with HE; (2) Whether hyperammonemia plays a role in these sleep alterations; and (3) the time course of sleep alterations in these animal models. Rats were subjected to PCS to induce HE. Another group of rats was fed an ammonium-containing diet to induce hyperammonemia. Polysomnographic recordings were acquired for 24 h and sleep architecture was analyzed in control, PCS, and hyperammonemic rats at 4, 7, and 11 weeks after surgery or diet, respectively. PCS rats show a significant reduction in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep time and increased sleep fragmentation, whereas reduced sleep occurs at 4 weeks and worsens at 7 and 11 weeks, sleep fragmentation appears at 7 weeks and worsens at 11 weeks. Hyperammonemic rats show decreased REM sleep, starting at 7 weeks and worsening at 11 weeks, with no changes in NREM sleep or sleep fragmentation. Therefore, PCS rats are a good model to study sleep alterations in HE, their mechanisms, and potential treatment. Mild hyperammonemia mainly impacts mechanisms involved in REM generation and/or maintenance but does not seem to be involved in sleep fragmentation.