Modulation of neurotransmitter release in orexin/hypocretin‐2 receptor knockout mice: A microdialysis study

Abstract

Orexinergic neurons are discretely localized within the lateral hypothalamus and have widespread projections to the whole brain. Here, the role of orexin/hypocretin-2 receptors (OX2) in modulating extracellular concentrations of neurotransmitters was evaluated in the hypothalamus and the prefrontal cortex (PFC) of OX2 knockout (KO) mice by using a microdialysis technique. In the hypothalamus, basal concentrations of norephinephrine (NE), acetylcholine (ACh), and histamine (Hist) were significantly higher in KO mice, whereas KCl perfusion (147 mM) resulted in significantly lesser increases in NE, ACh, and Hist release in KO compared with wild-type (WT) mice. No differences in basal concentrations or evoked release of serotonin (5-HT) or dopamine (DA) were found in the hypothalamus between genotypes. In the PFC, no differences in the basal concentrations of the studied neurotransmitters were found between genotypes. After KCl perfusion, significantly higher increases in NE, 5-HT, and DA release were found in KO compared with WT mice. No differences in the evoked release of ACh and Hist in the PFC were found between genotypes. The present results demonstrate that genetic deletion of OX2 receptors differentially modulates extracellular concentrations of distinct neurotransmitters in the somatodendritic region vs. a nerve terminal region of the orexinergic neurons. In the hypothalamus, an inhibitory role of the OX2 receptors in modulating basal concentrations of NE, ACh, and Hist was revealed, which probably accounts for the reduced responsiveness to KCl as well. In the PFC, the evoked release of the monoamines NE, 5-HT, and DA seems to be controlled negatively by OX2 receptors.

Selective Knockdown of TASK3 Potassium Channel in Monoamine Neurons: a New Therapeutic Approach for Depression

“…Extracellular 5-HT and NE concentrations were evaluated by in vivo microdialysis as previously described [9,10,[27][28][29]. A full description is given in Supplementary Information.…”

LSN2424100: a novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy

“…Although orexin-containing neurons are predominantly localized in the lateral and posterior hypothalamus, they send widespread projections throughout the neuro-axis (Spinazzi et al, 2006). Orexin has been demonstrated to play a role in mediating feeding (Sakurai et al, 1998), regulation of sleep/wake states (Chemelli et al, 1999), addiction and reward-seeking behavior (Richards et al, 2008; Aston-Jones et al, 2009), monoaminergic transmission (Borgland et al, 2008; Ortega et al, 2012), and stress modulation (Boutrel et al, 2005). That many of these functions are often dysregulated in depression has led researchers to propose that orexins may be involved in the pathophysiology of depression (reviewed in Nollet and Leman, 2013).…”

Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring

“…The composition of the aCSF was 148 mM NaCl, 2.7 mM KCl, 1.2 mM CaCl 2 and 0.85 mM MgCl 2 with pH of 7.4, adjusted with 1 mM K 2 HPO 4 . Following 1 h of stabilization, aCSF was perfused through the probes and dialysate samples were collected every 35 min in refrigerated vials containing 5 µl acetic acid (0.1 M) [ 56 , 57 ]. Six samples were obtained before drug administration.…”