35. Differential effects of endocannabinoid catabolic enzyme inhibition on thermal homeostasis following environmental or immunological stressors S.G. Kinsey a , S.R. Nass a , B.F. Cravatt b , A.H. Lichtman c a West Virginia University, Psychology, PO Box 6040, Morgantown, WV 25606-6040, USA b The Scripps Research Institute, USA c Virginia Commonwealth University, USA Cannabinoid receptor agonists have been repeatedly shown to have anti-pyrogenic effects in a variety of assays. In rodents, high doses of CB1 cannabinoid receptor agonists induce hypothermia. Recently, attention has turned to how endocannabinoids (eCBs), including 2-arachidonoyglycerol (2-AG) and anandamide (AEA), reg- ulate a host of homeostatic processes including thermoregulation. Exogenous administration of 2-AG or AEA has limited efficacy, because of their rapid degradation by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. Inhibit- ing either enzyme elevates levels of each respective target eCB. This experiment tested the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. Male C57BL/6 J mice were administered a MAGL or FAAH inhibitor and challenged with a cold ambient envi- ronment or the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/ kg ip). MAGL inhibition exacerbated cold-induced hypothermia. Pre- treatment with the selective CB1 receptor antagonist rimonabant blocked this decrease, whereas the selective CB2 antagonist SR144528 had no effect. MAGL inhibition also exacerbated LPS- induced hypothermia via CB1 receptors. In contrast, FAAH inhibition had no effect on Tb following either stressor. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit pro- found hypothermic responses, neither MAGL nor FAAH inhibitors affect normal body temperature. However, MAGL inhibition leads to a dysregulation of Tb via a CB1 receptor mechanism of action in mice subjected to physical or physiological stress. http://dx.doi.org/10.1016/j.bbi.2014.06.055 36. Prenatal zinc prevents BDNF disturbance in a rat model of autism induced by prenatal lipopolysaccharide T.B. Kirsten a,b , N. Queiroz-Hazarbassanov a , M.M. Bernardi b , L.F. Felício a a School of Veterinary Medicine, University of São Paulo, Department of Pathology, Av. Prof. Dr. Orlando Marques de Paiva, 87, Sao Paulo, SP 05508-270, Brazil b Graduate Program of Environmental and Experimental Pathology, Paulista University, Sao Paulo, Brazil Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS), an endotoxin that mimics infection with Gram-negative bacteria, induces autistic-like behav- ior. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS because LPS induces hypozincaemia. Reproductive performance was assessed to evaluate LPS and zinc toxic effects. Plasma levels of brain-derived neurotrophic factor (BDNF) were determined because it has been considered an important biomarker of autism. Prenatal LPS exposure reduced offspring number and treatment with zinc prevented this reduction. Moreover, prenatal LPS increased BDNF levels in adult offspring. This BDNF hyperactivity was also found in several studies of autistic patients. Together with our previous studies, our model induced autistic-like behavioral, brain, and immune disturbances, demonstrating that it is a robust rat model of autism. Additionally, we demonstrated that posttreat- ment with zinc reduced the elevation of BDNF induced by LPS to the same levels as controls. The present study revealed a potential beneficial effect of prenatal zinc administration for the prevention of autism with regard to the BDNF pathway. FAPESP and CAPES. http://dx.doi.org/10.1016/j.bbi.2014.06.056 37. Chronic stress promotes lymph node metastasis through beta-adrenergic regulation of lymphangiogenesis C.P. Le a , C. Kim-Fuchs a , M.A. Pimentel a , M.G. Chai a , C.J. Nowell a , T. Karnezis b , M. Herald c , S.A. Stacker b , E.K. Sloan a,b,d a Monash Institute of Pharmaceutical Sciences, Melbourne, Australia b Peter MacCallum Cancer Centre, Australia c Walter Eliza Hall Institute of Medical Research, Australia d Cousins Center for PNI, UCLA Semel Institute, and Jonsson Compre- hensive Cancer Center, University of California Los Angeles, USA Remodelling of tumor lymphatic vasculature facilitates tumor cell metastasis to lymph nodes. However, the physiological path- ways that regulate lymphatic remodelling – or lymphangiogenesis – and lymphatic metastasis are yet to be defined. To investigate the impact of beta-adrenergic signaling on lymphangiogenesis and lymphatic metastasis, we explored the effect of restraint stress in an orthotopic xenograft model of triple negative breast cancer. Lon- gitudinal bioluminescence imaging revealed that chronic stress reduced time to lymph node metastasis and increased tumor cell load in draining lymph nodes. Pharmacological activation of beta- adrenergic pathways similarly induced lymphatic remodelling and this effect was blocked with pharmacological beta-blockade. Chronic stress increased the expression of lymphangiogenic growth factor VEGFC and its receptor Vefgr3, and shRNA knock-down of VEGFC reversed the effect of stress on lymph vessel density within primary tumors. We recently found that inflammation increased dilation of lymphatic collector vessels to promote breast cancer metastasis. Consistent with those studies, we found that stress regulated VEGFC by modulating expression of pro-inflammatory COX-2. Treatment with COX-2 inhibitor celecoxib reversed stress-induced lymph vessel dilation and blocked stress-enhanced tumor lymphangiogenesis and lymph node metastasis. These data show that stress acts through a betaAR-inflammation-VEGFC axis to promote lymph node metasta- sis. Importantly, these studies identify critical opportunities for ther- apeutic intervention that may help protect women with breast cancer from the adverse effects of stress biology. http://dx.doi.org/10.1016/j.bbi.2014.06.057 38. Prenatal zinc prevents mTOR disturbance in a rat model of autism induced by prenatal lipopolysaccharide G.P. Chaves-Kirsten a,b , C. Scavone b , M.M. Bernardi c , L.F. Felício a , T.B. Kirsten a a Department of Pathology, School of Veterinary Medicine, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, Sao Paulo, SP 05508-270, Brazil b Department of Pharmacology, Institute of Biomedical Science, Univer- sity of São Paulo, SP 05508-900, Brazil c Graduate Program of Environmental and Experimental Pathology and Graduate Program of Dentistry, Paulista University, Sao Paulo, Brazil Abstracts from the 21st Annual PNIRS Meeting 40 (2014) e1–e52 e11