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Somatostatin Receptor 4 Agonism Normalizes Stress-Related Excessive Amygdala Glutamate Release and Pavlovian Aversion
Irina Adamcyzk1, Diana Kúkeľová2, Stefan Just3
1Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
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.
Insights
Targeting somatostatin receptor 4 (SSTR4) with agonists may treat anxiety and depression. SSTR4 agonism reduced stress responses and aversion learning in preclinical models, showing therapeutic potential.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Excessive processing of aversive events is central to anxiety and depressive disorders.
- Current treatments lack specific mechanisms; somatostatin receptor 4 (SSTR4) is implicated in aversion processing.
- SSTR4 is found in brain regions like the amygdala, crucial for negative valence neuropathology.
Purpose of the Study:
- To investigate the effects of SSTR4 agonism on neurobehavioral aversion processing.
- To assess if SSTR4 agonism can normalize stress-related hyperresponsiveness.
- To examine SSTR4 agonism's impact on reward processing under stress.
Main Methods:
- Experiments were conducted on male rats and mice to study SSTR4 agonism effects.
- Glutamate release in the amygdala was measured in rats under stress.
- Behavioral assays in mice assessed aversion learning, memory, and reward processing.
Main Results:
- SSTR4 agonism attenuated stress-induced glutamate release in rat amygdala.
- In mice, SSTR4 agonism reduced aversion learning and memory, even under chronic social stress.
- SSTR4 agonism did not impair reward learning but enhanced reward-to-effort valuation.
Conclusions:
- SSTR4 agonism shows preclinical efficacy in normalizing aversion processing.
- Findings support SSTR4 agonism as a potential therapeutic strategy for anxiety and depression.
- This research provides proof-of-concept for SSTR4-targeted neuropsychopharmacology.
