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Appetite-related circuits: integration of endocannabinoid and leptin signaling regulates the excitability of neurons


Marijuana, or more specifically its active ingredient, tetrahydrocannabinol, has a well-documented tendency to stimulate hunger.
And while researchers have traced this property to cannabinoid receptors in the brain, they have had little understanding of the neural circuitry underlying this effect.

Understanding this circuitry has important practical implications because blocking the cannabinoid receptor, CB1, offers a promising approach to treating obesity.
One such compound, Rimonabant ( Acomplia) is already undergoing clinical testing.

In an article in the journal Neuron, Young-Hwan Jo and colleagues report how the circuitry of CB1 is integrated with signaling by the appetite-suppressing hormone leptin. The CB1 receptor is normally triggered by natural regulatory molecules, called endocannabinoids.

In their studies, the researchers concentrated on the lateral hypothalamus of the brain, known to be a center of control of food intake. Their studies involved detailed electrophysiological measurements of the effects of specific neurons that they had identified in previous studies as being important in endocannabinoid signaling.

Their studies revealed that activation of CB1 receptors, as by endocannabinoid molecules, induced these neurons to be rendered more excitable by a mechanism called " depolarization-induced suppression of inhibition " (DSI).

They found that leptin inhibits DSI. However, leptin did not appear to interfere with the CB1 receptors themselves. Rather, leptin "short-circuits" the endocannabinoid effects by inhibiting pore-like channels in the neurons that regulate the flow of calcium into the neurons. Such calcium is necessary for the synthesis of endocannabinoids.

In further studies of mice genetically altered to be leptin deficient, the researchers found the DSI to be more prolonged than in normal mice. Thus, they said, the findings "implicate this mechanism for leptin receptor/endocannabinoid signaling in contributing to the maintenance of weight balance…." The researchers also included that "upregulation of endocannabinoid signaling in the lateral hypothalamus may explain, at least in part, the increased body weight consistent with a prior report of elevated endocannabinoids" in such leptin-deficient mice.

The researchers concluded that their findings "are consistent with the hypothesis that the integration of endocannabinoid and leptin signaling regulates the excitability of neurons on appetite-related circuits."

They also wrote that "the cellular mechanisms of recently developed antiobesity drugs, such as Rimonabant, may include decreased endocannabinoid signaling and hence decreased excitability of lateral hypothalamus circuits related to appetite, even in the context of leptin insufficiency or resistance."

Source: Neuron, 2005


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