Pharmacological inhibition of nitric oxide synthase 1 adaptor protein in adult offspring after maternal immune activation
Year: 2022
Type: article
Abstract: Background: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with 5-HT1A agonist activity currently in Phase 3 clinical trials for the treatment of schizophrenia.Metabolic Syndrome, characterized by central obesity, dyslipidemia, hypertension, and hyperglycemia, is highly prevalent in patients with schizophrenia and can be induced or exacerbated by antipsychotic drugs (APDs).The need for novel treatments that lack APD class-specific metabolic side effects is therefore apparent.As a new pharmacological class, ulotaront has no significant activity at receptors commonly associated with APD-induced metabolic alterations (i.e.D2, 5-HT2C, H1 and M3).Recent preclinical evidence has identified TAAR1 as novel regulator of metabolic control and a promising target for treating obesity and type 2 diabetes.Here we evaluated the risk-benefit profile of ulotaront for the treatment of schizophrenia by assessing its effects on metabolic parameters in rodent models of iatrogenic weight gain and hyperglycemia.Methods: Effects of 15-day oral ulotaront treatment on body weight (BW), food intake and metabolic parameters were investigated in rats on a high-fat diet (HFD).In addition, body weight effects were determined in a rat (8-day treatment) and mouse (21-day treatment) model of olanzapine-, and corticosteroneinduced BW gain, respectively.Glucose tolerance was assessed in C57Bl6 and diabetic db/db mice following acute oral dosing.The acetaminophen absorption test was used to evaluate effects on gastric emptying in C57Bl6 mice.To obtain insights into the neurocircuits modulated by ulotaront, whole-brain 3D c-fos imaging was performed in C57Bl6 mice.Results: Administration of ulotaront to rats on a HFD resulted in a dosedependent reduction in BW, food intake and liver triglyceride content compared to vehicle controls.A more rapid reversal of olanzapine-induced BW gain and food intake was observed in rats switched to ulotaront treatment compared to vehicle alone.Consistent with the BW-lowering effects in rats, chronic treatment with ulotaront normalized corticosterone-induced BW gain in mice.Acute ulotaront dosing dose-dependently reduced plasma glucose excursion in C57Bl6 and diabetic db/db mice during an oral glucose tolerance test (oGTT).Neither glucose nor insulin levels were changed in response to ulotaront during an ivGTT.Acute TAAR1 activation delayed gastric emptying in mice, which is likely the main mechanism driving reductions in glucose excursion during the oGTT.Ulotaront increased neuronal activity (c-fos expression) in several brain regions associated with the regulation of food intake and integration of peripheral metabolic signals, which was distinct from the signature produced by the APD haloperidol.Conclusion: Our data indicate that ulotaront not only lacks APD-induced metabolic liabilities but can reduce BW and improve glucose tolerance in rodent models.The underlying mechanisms are not fully elucidated but may include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying, and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance.The beneficial metabolic effects of ulotaront suggest a substantially improved risk-benefit profile compared to established APDs.Thus, TAAR1 agonists may not only represent a novel therapeutic class for the treatment of schizophrenia, but potentially also for metabolic disorders.
Source: Neuroscience Applied
Language: English
Subfield: Biological Psychiatry
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,000
OpenAlex ID: W4313200701