Orexin 2 Receptor Antagonists from Prefrontal Cortical Circuitry to Rodent Behavioral Screens

Orexin is a neuropeptide contained in neurons from several hypothalamic nuclei that project throughout the forebrain analogously to monoamines synthesized by brainstem nuclei. Orexin, like 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), histamine and acetylcholine (ACh) exerts prominent effects on the sleep-wake cycle of all mammals. Activation of the orexin 2 receptor appears to induce spontaneous excitatory synaptic currents (EPSCs) on layer V pyramidal neurons due to release of glutamate from thalamocortical terminals similar to activation of 5-HT 2A and α 1 -adrenergic receptors. Layer V pyramidal cells are the major descending output cell in the prefrontal cortex with projections to the thalamus, striatum, amygdala, brainstem and spinal cord. In keeping with salient modulation of prefrontal cortical physiology, orexin 2 receptor antagonists exert similar effects to 5-HT 2A receptor antagonists in suppressing hallucinogen (e.g., DOI)-induced head twitches and producing antidepressant-like effects on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement. Currently, there is both negative and some preliminary positive evidence that blocking orexin 2 receptors may result in antidepressant efficacy in patients with major depressive disorder. Overall, the treatment of mood disorders is an additional potential indica-tion for orexin receptor antagonists beyond simply improving sleep.