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

Effectiveness of manual therapies: the UK evidence report

<p>Abstract</p> <p>Background</p> <p>The purpose of this report is to provide a succinct but comprehensive summary of the scientific evidence regarding the effectiveness of manual treatment for the management of a variety of musculoskeletal and non-musculoskeletal conditions.</p> <p>Methods</p> <p>The conclusions are based on the results of systematic reviews of randomized clinical trials (RCTs), widely accepted and primarily UK and United States evidence-based clinical guidelines, plus the results of all RCTs not yet included in the first three categories. The strength/quality of the evidence regarding effectiveness was based on an adapted version of the grading system developed by the US Preventive Services Task Force and a study risk of bias assessment tool for the recent RCTs.</p> <p>Results</p> <p>By September 2009, 26 categories of conditions were located containing RCT evidence for the use of manual therapy: 13 musculoskeletal conditions, four types of chronic headache and nine non-musculoskeletal conditions. We identified 49 recent relevant systematic reviews and 16 evidence-based clinical guidelines plus an additional 46 RCTs not yet included in systematic reviews and guidelines.</p> <p>Additionally, brief references are made to other effective non-pharmacological, non-invasive physical treatments.</p> <p>Conclusions</p> <p>Spinal manipulation/mobilization is effective in adults for: acute, subacute, and chronic low back pain; migraine and cervicogenic headache; cervicogenic dizziness; manipulation/mobilization is effective for several extremity joint conditions; and thoracic manipulation/mobilization is effective for acute/subacute neck pain. The evidence is inconclusive for cervical manipulation/mobilization alone for neck pain of any duration, and for manipulation/mobilization for mid back pain, sciatica, tension-type headache, coccydynia, temporomandibular joint disorders, fibromyalgia, premenstrual syndrome, and pneumonia in older adults. Spinal manipulation is not effective for asthma and dysmenorrhea when compared to sham manipulation, or for Stage 1 hypertension when added to an antihypertensive diet. In children, the evidence is inconclusive regarding the effectiveness for otitis media and enuresis, and it is not effective for infantile colic and asthma when compared to sham manipulation.</p> <p>Massage is effective in adults for chronic low back pain and chronic neck pain. The evidence is inconclusive for knee osteoarthritis, fibromyalgia, myofascial pain syndrome, migraine headache, and premenstrual syndrome. In children, the evidence is inconclusive for asthma and infantile colic.</p

FAAH deficiency promotes energy storage and enhances the motivation for food.

RationaleFatty acid amide hydrolase (FAAH) is the main degrading enzyme of the fatty acid ethanolamides anandamide (AEA) and oleoylethanolamide (OEA), which have opposite effects on food intake and energy balance. AEA, an endogenous ligand of CB(1) cannabinoid receptors, enhances food intake and energy storage, whereas OEA binds to peroxisome proliferator-activated receptors-alpha to reduce food intake and promoting lipolysis. To elucidate the role of FAAH in food intake and energy balance, we have evaluated different metabolic and behavioral responses related to feeding in FAAH-deficient (FAAH(-/-)) mice and their wild-type littermates.Methodology and resultsTotal daily food intake was similar in both genotypes, but high-fat food consumption was enhanced during the dark hours and decreased during the light hours in FAAH(-/-) mice. The reinforcing and motivational effects of food were also enhanced in FAAH(-/-) mice as revealed by operant behavioral paradigms. These behavioral responses were reversed by the administration of the selective CB(1) cannabinoid antagonist rimonabant. Furthermore, body weight, total amount of adipose tissue, plasma-free fatty acids and triglyceride content in plasma, liver, skeletal muscle and adipose tissue, were increased in FAAH(-/-) mice. Accordingly, leptin levels were increased and adiponectin levels decreased in these mutants, FAAH(-/-) mice also showed enhanced plasma insulin and blood glucose levels revealing an insulin resistance. As expected, both AEA and OEA levels were increased in hypothalamus, small intestine and liver of FAAH(-/-) mice.ConclusionThese results indicate that the lack of FAAH predominantly promotes energy storage by food intake-independent mechanisms, through the enhancement of AEA levels rather than promoting the anorexic effects of OEA