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CANNABINOIDS AUGMENT THE RELEASE OF NEUROPEPTIDE Y FROM THE RAT HYPOTHALAMUS Kevin M. Gamber, Heather Macarthur, and Thomas C. Westfall Department of Pharmacological and Physiological Science, Saint Louis University, USA The orexigenic properties of Neuropeptide Y (NPY) have been well established within the hypothalamus. This activity is located specifically to pathways emerging from the arcuate nucleus (ARC) and projecting to the paraventricular nucleus (PVN), lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and ventromedial hypothalamus (VMH). The orexigenic effect of cannabinoids has also been well established. Both exogenous (as the psychoactive constituents found in marijuana) and endogenous (as the arachidonic acid derivative anandamide) forms of cannabinoids have been shown to produce appetite-stimulating effects. Furthermore, cannabinoid CB1 receptors have been found throughout the hypothalamus, including the ARC, PVN, LH, and VMH. Cannabinoids have been shown to affect the release of a variety of neurotransmitters via action at presynaptic receptors, and, depending on the transmitter, may inhibit or augment release. The regulatory effect of cannabinoids on NPY has been previously unknown. However, the release of NPY is regulated by a variety of other factors with orexigenic and anorectic activity. Typically, anorectic factors such as leptin and alpha melanocyte stimulating hormone (-MSH) inhibit NPY release, whereas orexigenic factors such as agouti related peptide (AgRP) and orexin stimulate its release. The functional similarities of cannabinoids and NPY as well as the localization in the same brain structures strongly suggest the existence of an interaction between them. Therefore, we have investigated the effect of cannabinoids on the release of NPY within the hypothalamus of the rat. The hypothalamus of the rat brain was removed and placed in a wire mesh basket and immersed into a Krebs’-MOPS buffer. The hypothalamic slices were then incubated for a 30-minute equilibration period followed by a 60-minute exposure to cannabinoid agonist and/or antagonist, and a final 15-minute exposure to 50 mM KCl. The resulting superfusates were first examined for cAMP content as a positive control, as cannabinoids are known to modulate adenylate cyclase activity. In addition, these studies established the necessity of a full 60-minute exposure time. In subsequent experiments, the superfusates were analyzed by enzyme immunoassay for NPY content. The cannabinoid CP 55,940 was found to dose-dependently enhance the KCl-induced release of NPY, with a maximal effect at 100 nM. Furthermore, the cannabinoid antagonist AM 251 was found to block this effect. (Supported by USPHS Grant NHLBI-60260 and NIGMS GM08306)