title: Pharmacological or genetic orexin1 receptor inhibition attenuates MK-801 induced glutamate release in mouse cortex.
abstract: The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward, and emotion. Recent studies have demonstrated that orexins and glutamate interact at the synaptic level and that orexins facilitate glutamate actions. We tested the hypothesis that orexins modulate glutamate signaling via OX1 receptors by monitoring levels of glutamate in frontal cortex of freely moving mice using enzyme coated biosensors under inhibited OX1 receptor conditions. MK-801, an NMDA receptor antagonist, was administered subcutaneously (0.178 mg/kg) to indirectly disinhibit pyramidal neurons and therefore increase cortical glutamate release. In wild-type mice, pretreatment with the OX1 receptor antagonist GSK-1059865 (10 mg/kg S.C.) which had no effect by itself, significantly attenuated the cortical glutamate release elicited by MK-801. OX1 receptor knockout mice had a blunted glutamate release response to MK-801 and exhibited about half of the glutamate release observed in wild-type mice in agreement with the data obtained with transient blockade of OX1 receptors. These results indicate that pharmacological (transient) or genetic (permanent) inhibition of the OX1 receptor similarly interfere with glutamatergic function in the cortex. Selectively targeting the OX1 receptor with an antagonist may normalize hyperglutamatergic states and thus may represent a novel therapeutic strategy for the treatment of various psychiatric disorders associated with hyperactive states.
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Fraser
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Berdyyeva
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Volha
authors.initials: V
authors.lastname: Tryputsen
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Brock T
authors.initials: BT
authors.lastname: Shireman
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: James
authors.initials: J
authors.lastname: Shoblock
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lovenberg
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Dugovic
authors.affiliation: Janssen Pharmaceutical Research and Development, LLC San Diego, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
keywords: MK-801; biosensor; cortex; glutamate; orexin; orexin 1 receptor