Abstract
Abstract It has been shown in electrophysiological studies that the ligand L-655,708 possesses a binding selectivity and a moderate inverse agonist functional selectivity for α5-containing GABA-A receptors. The present study is aimed to investigate the antidepressant effects of the ligand L-655,708 in the forced swim test (FST) and its impact on locomotor activity in rats. The behavior of the animals was recorded with a digital camera, and the data were analyzed by one-way ANOVA, followed by Dunnett’s test. In FST, L-655,708 significantly decreased immobility time at a dose of 3 mg/kg after a single and repeated administration (p<0.05), exerting acute and chronic antidepressant effects. However, it did not induce significant differences in the time of struggling behavior during FST. Furthermore, L-655,708 did not show a significant effect on locomotor activity (p>0.05). These data suggest that negative modulation at GABA-A receptors containing the α5 subunit may produce antidepressant effects in rats. These effects were not confounded by locomotor influences.
Highlights
The majority of fast inhibitory neurotransmissions in the central nervous system (CNS) is governed by the action of γ-aminobutyric acid (GABA) type A receptors (GABA-A)
Data from experimental models demonstrate that the forced swim test represents a reliable and valuable behavioral research model of depression in rodents and an important tool to study neurobiological mechanisms involved in antidepressant activity
Our data suggest that negative modulation at GABA-A receptors containing the α5 subunit might have produced the antidepressant effects in rats and that these effects were not confounded by locomotor influences
Summary
The majority of fast inhibitory neurotransmissions in the central nervous system (CNS) is governed by the action of γ-aminobutyric acid (GABA) type A receptors (GABA-A). The complex structure and function of GABA-A receptors and benzodiazepine binding sites was recently elucidated [1]. GABA-A receptors are pentameric membrane proteins that operate as GABA-gated Cl- channels. The majority contains a benzodiazepine binding site located at the interface of the γ2-subunit and the respective α-subunit (α1, α2, α3, α5) [2]. At these receptors, there are several modulatory sites, which mediate the actions of many drugs, among them benzodiazepines [2].
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