Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis

Abstract

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.

Positive Allosteric Modulation of α5-GABAA Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle

“…These studies provide preclinical evidence that targeting α5-GABA A Rs may represent an effective treatment for psychosis. Although aberrant dopamine neuron activity and deficits in PPI are also observed in animal models used to study PTSD ( Elam et al, 2021 ), the underlying pathology likely differs and whether the efficacy of therapeutic approaches is consistent across diagnosis is not currently known. Nonetheless, we posit that augmenting hippocampal interneuron function by targeting α5-GABA A Rs will correct this deficit.…”

Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

“…4 A ) that begins with projections to the NAc ( Lodge and Grace, 2011a ; Perez and Lodge, 2018 ). Importantly, increased activity in glutamatergic projections from the vHipp and PVT to the NAc has been observed in a variety of rodent models of psychiatric disorders, including PTSD ( Elam et al, 2021 ) and schizophrenia ( Perez and Lodge, 2013 ; Boley et al, 2014 ), and this hyperactivity results in increased dopamine neuron population activity in the VTA. Previous research has demonstrated that selective inactivation of the vHipp or PVT in rodent models used to study psychosis can restore normal dopamine system function ( Lodge and Grace, 2007 ; Perez and Lodge, 2018 ).…”

A study on the effect of JNJ-10397049 on proliferation and differentiation of neural precursor cells

“…The orexin system was first discovered to regulate sleep (wakefulness) and appetite but recently studies revealed its role in pain regulation, cardiovascular function, neuroendocrine modulation, and other biological processes [ 21 , 38 ]. Orexin receptor antagonists have shown great promise in treatment of insomnia, substance use disorder and psychosis [ 39 - 41 ]. Suvorexant, almorexant, and several other dual and single orexin receptors antagonists promote sleep in humans and are commercially available in the market [ 39 - 46 ].…”

“…Orexin receptor antagonists have shown great promise in treatment of insomnia, substance use disorder and psychosis [ 39 - 41 ]. Suvorexant, almorexant, and several other dual and single orexin receptors antagonists promote sleep in humans and are commercially available in the market [ 39 - 46 ]. In demyelinating diseases such as MS, healthy sleeping patterns is disrupted [ 47 ]; oligodendrocyte proliferation and/or differentiation and lipid biogenesis patterns are altered throughout sleep and wakefulness [ 48 ].…”