This is accomplished by nitrosylation (and therefore inactivation) of the GPCR kinases that target the receptors for internalization (Kokkola et al., 2005 and Whalen

et al., 2007). Although the production of eCBs and NO is similarly triggered by a rise in intracellular Ca2+ in the postsynaptic cell, these retrograde signals have opposing actions on GABA release (reviewed in Feil and Kleppisch, 2008 and Wilson and Nicoll, 2002). In this study, we demonstrate that a loss in CB1R signaling is a necessary prerequisite for Enzalutamide mouse NO-mediated LTPGABA following acute food deprivation. This finding, that abolition of CB1R signaling is associated with a drive to eat, appears to be at odds with the overwhelming support for an orexigenic role of the eCB system. For example, following acute food deprivation, most evidence points to an increase in hypothalamic eCB levels (Di Marzo et al., 2001 and Kirkham STAT inhibitor et al., 2002), and CB1−/− mice exhibit hypophagia compared with their wild-type littermates (Bellocchio et al.,

2010). Recent work, however, provides clear evidence that activation of CB1Rs on GABA terminals is associated with a reduction in feeding. In the ventral striatum, CB1R-mediated inhibition of GABAergic transmission is associated with a hypophagic action of eCBs (Bellocchio et al., 2010). Thus, it is possible that a loss of CB1Rs at GABAergic terminals in the DMH in response to food deprivation is akin to removing the brake from the brain’s feeding circuitry. Our findings provide a demonstration of state-dependent plasticity in the DMH, a hypothalamic nucleus that plays a vital role in integrating information

related to caloric status and stress. Evidence suggests that DMH neurons send glutamatergic projections to the PVN (Thompson et al., 1996), an autonomic nucleus that plays a critical role in regulating food intake (Cowley et al., 1999). In agreement with this, our unpublished observations indicate that the majority of DMH neurons from which we record demonstrate antidromic activation from the PVN. An increase in GABAergic drive in the DMH would therefore others suppress glutamatergic signaling to PVN neurons that suppress food intake. This signaling would ultimately result in an enhanced drive to eat in the face of minimal food availability. Although stress-induced increases in CORT down-regulate CB1Rs and therefore promote the increase in GABA drive, signaling at the genomic glucocorticoid receptor has no effect on food intake or body weight (unpublished observations). Overall, these data demonstrate a potentially new form of state-dependent plasticity in a feeding circuit that may ensure satiety-sensing neurons in DMH neurons are not recruited when food is not available. All experiments were performed according to protocols approved by the University of Calgary Animal Care and Use Committee in accordance with guidelines established by the Canadian Council on Animal Care.