Abstract
Imepitoin is a low affinity partial agonist for the benzodiazepine binding site of γ-aminobutyric acid (GABAA) receptors, and is currently used as an antiepileptic in dogs. Here we tested imepitoin for anxiolytic properties. In an in vitro model, imepitoin was capable of preventing the effect of corticotrophin releasing factor (CRF) on locus coeruleus neurons without suppressing the basal activity of these cells, an activity which is suggestive for an anti-stress effect of imepitoin. In addition, we applied a battery of standard rodent preclinical tests for anxiety behavior including elevated plus mazes in mice and rats, light-dark-box in mice and rats, social interaction test in rats, or the Vogel conflict test in rats. In all models, the observed profile of imepitoin appeared similar to benzodiazepines and typical for anxiolytic drugs. We also observed anxiolytic activity in dogs in a provoked open field sound-induced fear model, where reactions to noises were elicited by a sound recording of thunderstorms. Imepitoin caused an increase in locomotion measured in distance traveled and an ameliorating effect on cortisol levels in response to thunderstorm noises. For comparison, dexmedetomidine caused a decrease in locomotion and had no effect on cortisol. In all animal models the doses needed for an anxiolytic effect were not associated with sedation. In rodents, there was at least a factor of 10 between anxiolytic doses and doses with mild signs of sedation. In summary, imepitoin showed similar anxiolytic activities as benzodiazepines but without producing the known adverse reactions of benzodiazepines such as sedation.
Highlights
Anxiety is an important protective mechanism to increase vigilance, which allows an individual to react to a perceived present or anticipated threat with an appropriate behavior
Since full agonist benzodiazepines are known to be potent anxiolytics, it was hypothesized that partial agonists could potentially retain anxiolytic activity, but without producing the known adverse reactions of benzodiazepines such as sedation, muscle relaxation, and, upon repeated administration, development of tolerance. (Skolnick, 2012)
Based on imepitoin’s mode of action, we examine whether imepitoin had similar effects as benzodiazepines in commonly used models
Summary
Anxiety is an important protective mechanism to increase vigilance, which allows an individual to react to a perceived present or anticipated threat with an appropriate behavior (e.g., flight). Imepitoin is a centrally acting drug and a low affinity partial agonist for the BZD binding site of γ-aminobutyric acid (GABAA) receptors (Rundfeldt and Loscher, 2014). The compound potentiates the amplitude of GABA evoked chloride (Cl-) currents by acting at the BZD recognition site of the GABAA receptor, creating a higher affinity between GABA and its receptor sites. Imepitoin has a lower affinity for the BZD binding site of GABAA receptors than BZD receptor agonists such as diazepam (DZP). It exhibits a weak calcium (Ca2±) channel blocking effect. Imepitoin is in veterinary use for the treatment of idiopathic epilepsy in dogs (Rundfeldt and Loscher, 2014)
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