Cannabinoids exert a profound impact on the hypothalamic control of biological processes such as reproduction and energy homeostasis. The overall goal of this proposal is to gain a better understanding of the cannabinoid regulation of appetite, and the cellular mechanism(s) by which they affect the excitability of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus to alter food seeking behavior. The fundamental hypothesis is that cannabinoids modulate food intake in a sex-dependent fashion. They do so by presynaptically inhibiting glutamatergic neurotransmission, thereby reducing POMC neuronal excitability in a manner that is sexually differentiated and dependent on the gonadal steroid milieu. Cannabinoid regulation of appetite and glutamatergic synaptic input onto anorexigenic POMC neurons will be studied both in the guinea pig and in transgenic, POMC-deficient mice. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively. In Specific Aim 1, I will evaluate whether sex differences exist in the cannabinoid regulation of appetite by assessing the capability of CB1 receptor agonists and antagonists to respectively increase and decrease feeding behavior in vehicle- and gonadal steroid-treated male and female animals under different dietary and motivational conditions. In Specific Aim 2, the objective is to determine the role of anorexigenic POMC neurons in the sexually differentiated, cannabinoid-induced hyperphagia. Specifically, I will evaluate whether cannabinoids inhibit POMC neurons via the presynaptic attenuation of glutamatergic synaptic input. I will also investigate the potential for endogenous cannabinoids released from POMC neurons to transynaptically inhibit the glutamatergic currents impinging upon them. These studies will be accomplished using whole-cell patch clamp recordings with biocytin-filled electrodes in hypothalamic slices. To verify that POMC neurons are indeed integral to the cannabinoid modulation of appetite, I will evaluate the effects of CB1 receptor and blockade on feeding behavior in POMC-deficient mice. This proposal describes an integrated approach using two different animal models to study sex differences in the cannabinoid regulation of food intake, and will elucidate the relevant neural substrates, cellular mechanisms and gonadal steroid hormonal influences involved in the acute perturbation of appetite regulation very early in cannabinoid abuse. PUBLIC HEALTH RELEVANCE Sex differences in the cannabinoid regulation of feeding means that there are differences between males and females in their sensitivity to the appetite-stimulating and appetite suppressing effects of cannabinoid receptor agonists and antagonists. The findings generated from this research will have profound implications for the therapeutic effectiveness of cannabinoids in men and women - from the prevention of cancer - and AIDS-related body wasting to the treatment of obesity. [unreadable] [unreadable] [unreadable] [unreadable]