S180. THE SELECTIVE GPR139 AGONIST TAK-041 REVERSES ANHEDONIA AND SOCIAL INTERACTION DEFICITS IN RODENT MODELS RELATED TO NEGATIVE SYMPTOMS IN SCHIZOPHRENIA
Authors: Schiffer Hans , Atienza Josephine , Reichard Holly , Mulligan Victoria , Cilia Jackie , Monenschein Holger , Collia Deanna , Ray Jim , Kilpatrick Gavin , Brice Nicola , Carlton Mark , Hitchcock Steve , Corbett Ged , Hodgson Robert 
Published: May 2020

Abstract

Background
Negative symptoms in schizophrenia (SCZ) are poorly treated and interfere with the function of patients. Studies focusing on structural and functional imaging and non-invasive electrophysiology implicate perturbations of the frontocortico-temporal circuits and disruption of cortico-striatal loops to negative symptoms in SCZ. GPR139 is an orphan GPCR that is specifically expressed in the CNS and enriched in the habenula, a brain structure involved in reward and motivation. Structural and functional alterations of the habenula have been found in SCZ patients, who show deficits in feedback processing and lack habenula activation in response to negative outcomes. Rodent experiments demonstrate the involvement of direct projection from the cortex to the habenula controlling social behavior. Alteration in habenula activity have been correlated with depression, and normalization of aberrant habenula activity has been proposed as therapeutic strategy to reverse anhedonia. Building on data previously reported at SIRS2018, we further explored modulation of GPR139 receptors and habenula circuitry in vivo as a novel mechanism to treat negative symptoms in SCZ.

Methods
Animals were submitted to an unpredictable chronic mild stress (uCMS) protocol, an animal model of depression that produces deficits in several behavioral domains affected in depressed patients. The three-chamber (Crawley’s) paradigm has been used to study social interaction in rodents. Induction of the immediate early gene c-fos expression was studied as marker for habenula neuron activation in vivo. Dopamine release in the nucleus accumbens (NAc) was studied by standard in vivo microdialysis in freely moving rats.

Results
The selective GPR139 agonist TAK-041 increased cFOS expression in the habenula in wild type mice, but not in GPR139 knock out mice. No desensitization of cFOS in the habenula was observed after chronic dosing of TAK-041. Microdialysis studies showed that TAK-041 reduced amphetamine- and nicotine-induced dopamine release in the NAc in rats. TAK-041 dosed acutely and chronically reversed anhedonia caused by uCMS in rats. TAK-041 also reversed anxiety related behavior assessed in the novelty suppressed feeding test and depressive-like behavior in the forced swim test in the uCMS model. uCMS-exposed animals develop a disrupted circadian regulation of corticosterone secretion, which was also normalized by TAK-041 treatment. Furthermore, TAK-041 reversed the uCMS-induced atrophy in the basal dendrites of pyramidal neurons in the hippocampus and the uCMS-induced hypertrophy of medium-spiny neurons in the NAc. These results suggest a potential benefit of TAK-041 in the treatment of anhedonia and possibly depression. TAK-041 also completely reversed social interaction (SI) deficits in the maternal immune activation poly-I:C model of SCZ, the subchronic PCP-SI model and in Balb/C and BTBR mice.

Discussion
The GPR139 agonist TAK-041 is proposed as a modulator of habenula circuitry to treat negative symptoms in SCZ based on efficacy in reversing anhedonia and social interaction deficits in multiple rodent models related to negative symptoms in SCZ.
*Employed by Takeda when the study was done.