Somatostatin receptor 4 agonism normalizes stress-related excessive amygdala glutamate release and Pavlovian aversion learning and memory in rodents

Background Excessive processing of aversive life events is a major pathology in stress-related anxiety and depressive disorders. Current pharmacological treatments have rather non-specific mechanisms of action. Somatostatin is synthesized and released as an inhibitory co-neurotransmitter by specific GABA interneurons and one of its receptors, SSTR4, is localized in brain regions involved in adaptive aversion processing and implicated in negative valence neuropathology, including the amygdala. Methods Rat and mouse experiments were conducted to investigate effects of specific SSTR4 agonism on neurobehavioral aversion processing including any normalization of stress-related hyper-responsiveness. A mouse experiment to investigate stress and SSTR4 agonism effects on reward processing was also conducted. Results In male rats (N=5-10/group) fitted with glutamate biosensors in basolateral amygdala, SSTR4 agonism attenuated glutamate release to restraint stress in control rats and particularly in rats previously exposed to chronic corticosterone. In male mice (N=10-18/group), SSTR4 agonism dose-dependently attenuated Pavlovian tone-footshock learning and memory measured as freezing behavior, both in controls (CON) and following exposure to chronic social stress (CSS) which induces excessive Pavlovian aversion learning-memory. Specificity of SSTR4 agonism effects to aversion learning-memory was demonstrated by absence of effects on discriminative reward (sucrose) learning-memory in both CON and CSS mice; SSTR4 agonism did increase reward-to-effort valuation in a dose-dependent manner, and in both CON mice and mice exposed to CSS which attenuates reward motivation. Conclusions These neuropsychopharmacological findings add substantially to the preclinical proof-of-concept evidence for SSTR4 agonism as a treatment in anxiety and depressive disorders. Keywords Somatostatin receptor 4 Amygdala Stress Aversion Reward GABA interneuro

Engagement of basal amygdala‐nucleus accumbens glutamate neurons in the processing of rewarding or aversive social stimuli

Basal amygdala (BA) neurons projecting to nucleus accumbens (NAc) core/shell are primarily glutamatergic and are integral to the circuitry of emotional processing. Several recent mouse studies have addressed whether neurons in this population(s) respond to reward, aversion or both emotional valences. The focus has been on processing of physical emotional stimuli, and here, we extend this to salient social stimuli. In male mice, an iterative study was conducted into engagement of BA‐NAc neurons in response to estrous female (social reward, SR) and/or aggressive‐dominant male (social aversion, SA). In BL/6J mice, SR and SA activated c‐Fos expression in a high and similar number/density of BA‐NAc neurons in the anteroposterior intermediate BA (int‐BA), whereas activation was predominantly by SA in posterior (post‐)BA. In Fos‐TRAP2 mice, compared with SR‐SR or SA‐SA controls, exposure to successive presentation of SR‐SA or SA‐SR, followed by assessment of tdTomato reporter and/or c‐Fos expression, demonstrated that many int‐BA‐NAc neurons were activated by only one of SR and SA; these SR/SA monovalent neurons were similar in number and present in both magnocellular and parvocellular int‐BA subregions. In freely moving BL/6J mice exposed to SR, bulk GCaMP6 fibre photometry provided confirmatory in vivo evidence for engagement of int‐BA‐NAc neurons during social and sexual interactions. Therefore, populations of BA‐NAc glutamate neurons are engaged by salient rewarding and aversive social stimuli in a topographic and valence‐specific manner; this novel evidence is important to the overall understanding of the roles of this pathway in the circuitry of socio‐emotional processing

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy

Engagement of basal amygdala-nucleus accumbens glutamate neurons in the processing of rewarding or aversive social stimuli

Basal amygdala (BA) neurons projecting to nucleus accumbens (NAc) core/shell are primarily glutamatergic and are integral to the circuitry of emotional processing. Several recent mouse studies have addressed whether neurons in this population(s) respond to reward, aversion or both emotional valences. The focus has been on processing of physical emotional stimuli, and here, we extend this to salient social stimuli. In male mice, an iterative study was conducted into engagement of BA-NAc neurons in response to estrous female (social reward, SR) and/or aggressive-dominant male (social aversion, SA). In BL/6J mice, SR and SA activated c-Fos expression in a high and similar number/density of BA-NAc neurons in the anteroposterior intermediate BA (int-BA), whereas activation was predominantly by SA in posterior (post-)BA. In Fos-TRAP2 mice, compared with SR-SR or SA-SA controls, exposure to successive presentation of SR-SA or SA-SR, followed by assessment of tdTomato reporter and/or c-Fos expression, demonstrated that many int-BA-NAc neurons were activated by only one of SR and SA; these SR/SA monovalent neurons were similar in number and present in both magnocellular and parvocellular int-BA subregions. In freely moving BL/6J mice exposed to SR, bulk GCaMP6 fibre photometry provided confirmatory in vivo evidence for engagement of int-BA-NAc neurons during social and sexual interactions. Therefore, populations of BA-NAc glutamate neurons are engaged by salient rewarding and aversive social stimuli in a topographic and valence-specific manner; this novel evidence is important to the overall understanding of the roles of this pathway in the circuitry of socio-emotional processing.ISSN:0953-816XISSN:1460-956