Constitutive Release of ECs

Research on EC biology is progressing at a rapid rate. One consequence is that exceptions to the general model proposed above have become apparent. For example, although increased intracellular calcium is necessary for EC synthesis and release in most neuronal circuits (40), others appear to be calcium-independent (41,42). More pertinent to this review, although ECs are generally thought to be synthesized and released only when presynaptic neurons become highly activated, there is evidence for constitutive release, in the absence of external stimulation, in both the hippocampus (43) and the arcuate nucleus (ARC) in the hypothalamus (44). In the latter case, neurons in the ARC that synthesize pro-opiomelanocortin (POMC) and that initiate a net catabolic response, including reducing food intake when activated, have been reported to secrete ECs con-

stitutively, in the absence of external stimulation. These locally released ECs in turn suppress presynaptic GABAergic inputs to the same POMC cells. In this situation, the POMC cells are chronically disinhibiting themselves (44). What is particularly intriguing is that when exogenous cannabinoid agonists are administered, they elicit a somewhat different profile of actions than the constitutively released cannabinoids—whereas the endogenously released ECs suppress only the inhibitory GABAergic inputs to the POMC cells, exogenously administered cannabinoids additionally suppress excitatory glutamatergic inputs to the same POMC neurons (44). The adiposity hormone, leptin, has important actions on these same POMC neurons in the ARC. Leptin directly stimulates the POMC neurons (45), and the ability of leptin to reduce food intake depends on the melanocortin transmitters released by the POMC neurons (46). Leptin also reduces EC activity in the ARC, and obese animals deficient in leptin have elevated hypotha-lamic, but not cerebellar, ECs levels (47), implying that ECs may normally exert a net anabolic tone in the hypothalamus, and especially within the ARC, that favors food intake and fat storage.

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