Somatostatin Receptor 4 Agonism Normalizes Stress-Related Excessive Amygdala Glutamate Release and Pavlovian Aversion Learning and Memory in Rodents

Irina Adamcyzk; Diana Kúkeľová; Stefan Just; Ricardo Giovannini; Hannes Sigrist; Rene Amport; Nagiua Cuomo-Haymour; Giulia Poggi; Christopher R Pryce

doi:10.1016/j.bpsgos.2021.11.006

Somatostatin Receptor 4 Agonism Normalizes Stress-Related Excessive Amygdala Glutamate Release and Pavlovian Aversion Learning and Memory in Rodents

Biol Psychiatry Glob Open Sci. 2021 Nov 17;2(4):470-479. doi: 10.1016/j.bpsgos.2021.11.006. eCollection 2022 Oct.

Authors

Affiliations

¹ Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
² Preclinical Laboratory, Department of Psychiatry, Psychotherapy and Psychosomatics, University of Zurich, Zurich, Switzerland.
³ Department of CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
⁴ Department of Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
⁵ Neuroscience Center Zurich, Zurich, Switzerland.

Abstract

Background: Excessive processing of aversive life events is a major pathology in stress-related anxiety and depressive disorders. Current pharmacological treatments have rather nonspecific mechanisms of action. Somatostatin is synthesized and released as an inhibitory co-neurotransmitter by specific GABA (gamma-aminobutyric acid) interneurons, and one of its receptors, SSTR4 (somatostatin receptor 4), 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 hyperresponsiveness. 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, in both control mice and mice exposed to chronic social stress, which induces excessive Pavlovian aversion learning and memory. Specificity of SSTR4 agonism effects to aversion learning/memory was demonstrated by absence of effects on discriminative reward (sucrose) learning/memory in both control mice and mice exposed to chronic social stress; SSTR4 agonism did increase reward-to-effort valuation in a dose-dependent manner and in both control mice and mice exposed to chronic social stress, 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: Amygdala; Aversion; GABA interneuron; Reward; Somatostatin receptor 4; Stress.