title: Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain.
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.
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Vazquez-DeRose
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schwartz
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA.
authors.forename: Deepti R
authors.initials: DR
authors.lastname: Warrier
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA.
authors.forename: Srishti
authors.initials: S
authors.lastname: Gulati
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Mathew
authors.affiliation: UCSF San Francisco VA Medical Center/NCIRE, San Francisco, CA, 94121, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Neylan
authors.affiliation: Biosciences Division, Center for Neuroscience, SRI International, 333 Ravenswood Ave., Menlo Park, CA, 94025, USA. thomas.kilduff@sri.com.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D066187:Basal Forebrain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020148:Butyric Acid; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009479:Neuropeptides / Q000378:metabolism; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology; D000076985:Saporins; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects; D014851:Wakefulness; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C085696:192 IgG-saporin; D000081:Acetamides; D000911:Antibodies, Monoclonal; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009479:Neuropeptides; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D000068797:Orexins; D011725:Pyridines; D054789:Ribosome Inactivating Proteins, Type 1; D020148:Butyric Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; C519150:almorexant; D000076985:Saporins; D000241:Adenosine
keywords: Arousal state; Hypocretin; Microdialysis; Orexin; Saporin lesions