The effect of endocannabinoids on glutamate synaptic transmission in the rat dorsomedial hypothalamus

Abstract

Endogenous cannabinoids (eCBs) are a class of neurotransmitters that modulate the release of other classical neurotransmitters, such as glutamate and GABA, onto their target neurons by activating type I cannabinoid (CB1) receptors on presynaptic terminals. eCBs stimulate appetite, but the mechanisms are not entirely understood. The dorsomedial hypothalamus (DMH) is a key appetite-regulatory center, and research shows that CB1Rs are expressed in this region. eCBs have been reported to decrease the release of GABA onto DMH neurons in rats, but there are no reports of their effects on glutamate release in the DMH, despite observations that eCBs modulate glutamate release elsewhere in the brain. We hypothesized that eCBs would alter glutamate release onto rat DMH neurons with the prediction that eCBs will decrease glutamate release. To test this, we used young male Sprague Dawley rats and performed patch clamp electrophysiology to record glutamate-mediated currents in living DMH neurons. Here we show that activation of CB1R with a synthetic agonist decreases glutamate release onto DMH neurons, confirming that CB1R are present on glutamate terminals in the DMH. Surprisingly, when eCB release from DMH neurons was induced with depolarization or high frequency stimulation of DMH synapses, we did not observe a decrease in glutamate release. Accumulating evidence suggests that another transmitter, nitric oxide, can interfere with eCB signaling, so we repeated the HFS experiment but with NO synthesis inhibited to determine if eCBs would then trigger a long-term decrease in glutamate release. Under these conditions, we observed a significant decrease in glutamate release that was mediated by CB1R activation. This research could enhance our understanding of the mechanisms by which eCBs control appetite.