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

Particle size distribution of nitrated and oxygenated polycyclic aromatic hydrocarbons (NPAHs and OPAHs) on traffic and suburban sites of a European megacity: Paris (France)

The size distribution of particulate nitrated and oxygenated polycyclic aromatic hydrocarbons (NPAHs and OPAHs) was determined during two field campaigns at a traffic site in summer 2010 and at a suburban site during the MEGAPOLI (Megacities: Emissions, urban, regional and Global Atmospheric POLlution and climate effects, and Integrated tools for assessment and mitigation) experiment in summer 2009. Both, OPAHs and NPAHs were strongly associated (>85%) to fine particles (<i>D</i><sub>p</sub>< 2.5 μm) increasing the interest of their study on a sanitary point of view. Results showed really different NPAH and OPAH particle size distributions between both sites. At traffic site, clearly bimodal (notably for NPAHs) particle size distributions (<i>D</i><sub>p</sub> = 0.14 and 1.4 μm) were observed, while the particle size distributions were more scattered at the suburban site, especially for OPAHs. Bimodal particle size distribution observed at traffic site for the NPAH could be assigned to the vehicle emissions and the particle resuspension. Broadest distribution observed at the suburban site could be attributed to the mass transfer of compounds by volatilization/sorption processes during the transport of particles in the atmosphere. Results also showed that the combination of the study of particle size distributions applied to marker compounds (primary: 1-nitropyrene; secondary: 2-nitrofluoranthene) and to NPAH or OPAH chemical profiles bring some indications on their primary and/or secondary origin. Indeed, 1,4-anthraquinone seemed only primary emitted by vehicles while 7-nitrobenz[a]anthracene, benz[a]antracen7,12-dione and benzo[b]fluorenone seemed secondarily formed in the atmosphere

Mechanisms of nerve growth factor signaling in bone nociceptors and in an animal model of inflammatory bone pain

Sequestration of nerve growth factor has been used successfully in the management of pain in animal models of bone disease and in human osteoarthritis. However, the mechanisms of nerve growth factor-induced bone pain and its role in modulating inflammatory bone pain remain to be determined. In this study, we show that nerve growth factor receptors (TrkA and p75) and some other nerve growth factor-signaling molecules (TRPV1 and Nav1.8, but not Nav1.9) are expressed in substantial proportions of rat bone nociceptors. We demonstrate that nerve growth factor injected directly into rat tibia rapidly activates and sensitizes bone nociceptors and produces acute behavioral responses with a similar time course. The nerve growth factor-induced changes in the activity and sensitivity of bone nociceptors we report are dependent on signaling through the TrkA receptor, but are not affected by mast cell stabilization. We failed to show evidence for longer term changes in expression of TrkA, TRPV1, Nav1.8 or Nav1.9 in the soma of bone nociceptors in a rat model of inflammatory bone pain. Thus, retrograde transport of NGF/TrkA and increased expression of some of the common nerve growth factor signaling molecules do not appear to be important for the maintenance of inflammatory bone pain. The findings are relevant to understand the basis of nerve growth factor sequestration and other therapies directed at nerve growth factor signaling, in managing pain in bone disease