Further investigations on the anxiogenic action of isatin

Abstract

The present study was designed to investigate the mechanism of the anxiogenic action of isatin (2,3-dioxoindole), which has been held responsible for at least pari of the activity of tribulin, a postulated endocoid marker of stress and anxiety. The anxiogenic dose of isatin (20 mg/kg, i.p.) was found to increase rat brain levels of serotonin (5-HT) and dopamine (DA), and to enhance 5-HT concentrations in several rat brain areas, the maximal increase being noted in midbrain and least in cerebellum. There was significant increase in 5-HT levels of frontal cortex, hypothalamus, pons-medulla and spinal cord. The anxiogenic action of isatin, as assessed by the Montgomery's conflict test in mice using the elevated plus-maze, was significantly attenuated by metergoline, a non-specific 5-HT receptor antagonist, 5,6-dihydroxytryptamine (5,6-DHT), a serotonin neurotoxin, zacopride, a 5-HT3 antagonist, and by pimozide, a DA D2 receptor antagonist, but remained unaffected following pretreatment with propranolol, a 5HT1 receptor antagonist, ketanserin, a 5-HT2 receptor antagonist, buspirone, a 5-HT(1A) receptor agonist/antagonist, and flumazenil, a benzodiazepine receptor antagonist. The anxiogenic action of a sub-effective dose (10 mg/kg, i.p.) of isatin was potentiated by fluoxetine, a 5-HT neuronal uptake inhibitor, but remained unaffected by 5-methoxy-N,N-dimethyltryptamine, a 5-HT(1A) receptor agonist, though quipazine, a 5-HT2 receptor agonist, induced some degree of potentiation. Isatin (20 mg/kg, i.p.) induced increase in rat brain DA was attenuated following pretreatment with 5,6-DHT and zacopride. The results indicate that the anxiogenic action of isatin is 5-HT mediated and a function of the 5-HT3 receptor subtype, involving modulation of DA activity.