Pharmacological modulation of conditioned fear in the fear-potentiated startle test: a systematic review and meta-analysis of animal studies

Abstract

Rationale and objectives Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear. Methods Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals. Results Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT1A agonists, 5-HT1A antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT1A antagonists. No associations were found between drug effects and methodological characteristics, except for strain. Conclusions The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review.

Recent advances in anxiety disorders: Focus on animal models and pathological mechanisms

“…Conditioned fear combines certain neutral conditioned stimulus (sound, light, and environment) with an aversive unconditioned stimulus (foot shock) to elicit a conditioned reflex in the animal. It is followed by a neutral conditioned stimulus given alone to induce fear and anxiety caused by the aversive conditioned fear 24 . Based on this theory, the conditioned fear model commonly used in animal models of anxiety generally combines sound signals with electrical stimulation signals, and then emits the sound signal alone to trigger anxiety response in animals 25 …”

“…It is followed by a neutral conditioned stimulus given alone to induce fear and anxiety caused by the aversive conditioned fear. 24 Based on this theory, the conditioned fear model commonly used in animal models of anxiety generally combines sound signals with electrical stimulation signals, and then emits the sound signal alone to trigger anxiety response in animals. 25 …”

Conditioned immunological memory: implication for cognition of immune cells

“…For example, conditioned fear memory represents the formation of an association between a neutral conditioned stimulus (e.g., a tone, context, or odor) and an unconditioned aversive or punitive stimulus (e.g., a foot-shock or loud noise). Following conditioning, the presentation of the CS alone evokes a defensive response (e.g., freezing of movement or escape behavior) [3]. The defensive response is stable and results from retrieval of the stored fear memory.…”