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The Journal of Neuroscience, January 26, 2005, 25(4):896-905; doi:10.1523/JNEUROSCI.3258-04.2005

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Behavioral/Systems/Cognitive
The Wake-Promoting Peptide Orexin-B Inhibits Glutamatergic Transmission to Dorsal Raphe Nucleus Serotonin Neurons through Retrograde Endocannabinoid Signaling

Samir Haj-Dahmane and Roh-Yu Shen

Research Institute on Addictions, University at Buffalo, State University of New York, Buffalo, New York 14203

The wake-promoting neuropeptides orexins (hypocretins) play a crucial role in controlling neuronal excitability and synaptic transmission in the CNS. In this study, using whole-cell patch-clamp recordings in an acute dorsal raphe nucleus (DRN) slice preparation, we report that orexin B (Orx-B) depresses the evoked glutamate-mediated synaptic currents in DRN 5-HT neurons. The Orx-B-induced depression is accompanied by an increase in the paired-pulse ratio and the coefficient of variance, suggesting a presynaptic site of action. Orx-B also reduces the frequency but not the amplitude of miniature EPSCs, indicating that depression of glutamatergic transmission is mediated by a decrease in glutamate release. Surprisingly, the Orx-B-induced inhibition of glutamatergic transmission is abolished by postsynaptic inhibition of G-protein signaling with GDPS, suggesting that this effect is signaled by postsynaptic orexin receptors and expressed presynaptically, presumably through a retrograde messenger. Interestingly, the Orx-B-induced depression of glutamate release is mimicked and occluded by the cannabinoid receptor agonist WIN 55,212-2, and is abolished by the CB₁ cannabinoid receptor antagonist AM 251. These results imply that the Orx-B-induced depression of glutamatergic transmission to DRN 5-HT neurons is mediated by retrograde endocannabinoid release. Examination of downstream signaling pathways involved in this response indicates that the effect of Orx-B requires the activation of phospholipase C and DAG lipase enzymatic pathways but not a rise in postsynaptic intracellular calcium. Therefore, our findings reveal a previously unsuspected mechanism by which postsynaptic orexin receptors can modulate glutamatergic synaptic transmission to DRN 5-HT neurons.

Key words: raphe; serotonin; orexin; cannabinoid; glutamate; synaptic transmission

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Received Aug 9, 2004; revised December 8, 2004; accepted December 8, 2004.

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