Olanzapine-Induced Hyperphagia and Weight Gain Associate with Orexigenic Hypothalamic Neuropeptide Signaling without Concomitant AMPK Phosphorylation

The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance

Alterations to Melanocortinergic, GABAergic and Cannabinoid Neurotransmission Associated with Olanzapine-Induced Weight Gain

Background/Aim: Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/ metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapineinduced obesity. Methodology/Results: Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD65, enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [ 3 H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (36/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD65 mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine. Conclusions: Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly b

An assessment of the potential influence of rainforest fragmentation on small terrestrial mammal predation in French Guiana

I present here an assessment of the abundance and rich ness of the main small mammal predators (snakes and carnivores) in a fragmented forest due to the Petit Saut hydroelectric dam (French Guiana). Small terrestrial mammals (Rodents and Marsupials) and their predators were trapped and censused respectively, in a reference zone, on two islands (28 and 60 ha) and on 33 islets isolated by ftooding. Four felids, 2 mustelids and 1 procyonid species were observed from 1994 to 1996. A total of 121 snakes of 28 species were censused, of which 72 snakes of 13 species were predators of small mammals. The results showed that mammalian predators regularly visit small forest fragments 2 years after their isolation. Snakes increased during the year following the flooding, then decreased in both abundance and species richness, especially on islands and islets. At the same time, small mammal abundance decreased throughout the study period. These results, obtained during and just after the forest fragmentation, suggest that excessive predation on small mammals in newly formed forest fragments may play an important role in density variations and local extinctions of prey speciesL'abondance et la richesse des principaux prédateurs de petits mammifères (serpents et carnivores) ont été estimées dans une forêt fragmentée suite à la mise en service du barrage de Petit-Saut (Guyane française). Les petits mammifères terrestres (Rongeurs et Marsupiaux) ont été capturés et leurs prédateurs recensés dans une zone de référence, sur deux îles (28 et 60 ha) et sur 33 îlots créés par l'inondation. Quatre espèces de félins et deux espèces de Mustélidés ont été observées de 1994 à 1996. Nous avons observé 121 serpents dont 72, appartenant à 13 espèces, étaient des prédateurs de petits mammifères. Les résultats montrent que les prédateurs de petits mammifères visitent régulièrement les îlots forestiers deux ans après leur isolement. Le nombre de serpents a augmenté au cours de l'année qui a suivi l'inondation, puis a chuté à la fois en terme d'abondance et en terme de richesse spécifique, en particulier sur les îles et les îlots. Au cours de la même période, l'abondance des petits mammifères diminuait. Ces résultats, obtenus pendant et juste après la fragmentation forestière, suggèrent qu'une forte prédation sur les petits mammifères dans les îlots forestiers nouvellement formés, peut jouer un rôle important dans les variations de densité et les extinctions locales d'espèces-proies