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Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain

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Abstract

Hypocretin/orexin (HCRT) neurons provide excitatory input to wake-promoting brain regions including the basal forebrain (BF). The dual HCRT receptor antagonist almorexant (ALM) decreases waking and increases sleep. We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals. To test this hypothesis, rats were given bilateral IgG-192-saporin injections, which predominantly targets cholinergic BF neurons. BFx and intact rats were then given oral ALM, the benzodiazepine agonist zolpidem (ZOL) or vehicle (VEH) at lights-out. ALM was less effective than ZOL at inducing sleep in BFx rats compared to controls. BF adenosine (ADO), γ-amino-butyric acid (GABA), and glutamate levels were then determined via microdialysis from intact, freely behaving rats following oral ALM, ZOL or VEH. ALM increased BF ADO and GABA levels during waking and mixed vigilance states, and preserved sleep-associated increases in GABA under low and high sleep pressure conditions. ALM infusion into the BF also enhanced cortical ADO release, demonstrating that HCRT input is critical for ADO signaling in the BF. In contrast, oral ZOL and BF-infused ZOL had no effect on ADO levels in either BF or cortex. ALM increased BF ADO (an endogenous sleep-promoting substance) and GABA (which is increased during normal sleep), and required an intact BF for maximal efficacy, whereas ZOL blocked sleep-associated BF GABA release, and required no functional contribution from the BF to induce sleep. ALM thus induces sleep by facilitating the neural mechanisms underlying the normal transition to sleep.

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Acknowledgments

The authors declare no competing financial interests. This research was supported by the U.S. Army Medical Research Acquisition Activity (USAMRAA) award number W81XWH-09-2-0081 to T.S.K. We thank Tsui-Ming Chen, Webster Lincoln, Helen Liu, Alan J. Wilk, and Dr. Lars Dittrich for technical assistance, Dr. Ling Jong for synthesis of almorexant, and Dr. Rhiannan Williams for helpful comments on the manuscript.

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  1. Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA

    Jacqueline Vazquez-DeRose, Michael D. Schwartz, Alexander T. Nguyen, Deepti R. Warrier, Srishti Gulati, Thomas K. Mathew & Thomas S. Kilduff

  2. UCSF San Francisco VA Medical Center/NCIRE, San Francisco, CA, 94121, USA

    Thomas C. Neylan

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  1. Jacqueline Vazquez-DeRose
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  2. Michael D. Schwartz
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Correspondence to Thomas S. Kilduff.

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J. Vazquez-DeRose and M. D. Schwartz contributed equally to the study.

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Vazquez-DeRose, J., Schwartz, M.D., Nguyen, A.T. et al. Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain. Brain Struct Funct 221, 923–940 (2016). https://doi.org/10.1007/s00429-014-0946-y

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