Pharmacological Characterization of the Novel Anxiolytic β-Carboline Abecarnil in Rodents and Primates

Abstract

β-Carboline abecarnil was behaviorally and biochemically characterized as a new anxiolytic agent in rodents and primates in comparison with the benzodiazepine (BZ) anxiolytics. Oral treatment with abecarnil (0.5-10 mg/kg) showed a potent anticonflict activity in the water-lick test in rats. The minimal effective dose was lower than those of BZ anxiolytics, such as etizolam, diazepam, clotiazepam and tofisopam. Abecarnil also showed taming effects to suppress fighting and aggressive behaviors in mice and monkeys with little sedative and ataxic effects, in contrast to the BZ anxiolytics producing marked sedative and ataxic effects. Furthermore, abecarnil suppressed both the sedative and ataxic effects induced by diazepam. Abecarnil bound to rat cerebellar BZ₁ receptors (K_i=0.24 nM) with a higher affinity than to rat spinal cord BZ₂ receptors (K_i=1.3 nM), whereas BZ derivatives bound to both the receptors with a low and equal affinity. GABA-ratios of abecarnil were 1.9 for the BZ₁ receptors and 2.8 for the BZ₂ receptors, and they were smaller than those of diazepam and flunitrazepam. Thus, in contrast to the BZ derivatives, abecarnil may act as a selective partial agonist at central BZ₁ receptors, resulting in its potent anticonflict and taming effects with little sedative and ataxic effects.