Effects of the 5-HT6 receptor agonist ST 1936 on depression and anhedonia-like experimental models

Serotonin 5-HT(6) receptor agonists and antagonists have been proposed as possible useful compounds in the treatment of psychiatric disorders such as depression. This study was aimed at characterizing ST 1936, a new 5-HT(6) receptor agonist, as a possible antidepressant/anti-anhedonic drug by studying its effects on three experimental models of depression. These models are based on the behavioral sequelae induced in rats by unavoidable stressors that result in decreased reactivity to avoidable stressors (escape deficit, ED) and an anhedonia-like condition based on the disruptive effect of stress on the competence to acquire an instrumental vanilla sugar-sustained appetitive behavior (VAB). The repeated administration of ST 1936 prevented the development of ED, but did not revert a condition of chronic ED. The protective effect of ST 1936 was antagonized by co-administration of SB 271046, a 5-HT(6) receptor antagonist, indicating that the 5-HT(6) receptor stimulation is crucial for triggering a plasticity process that resulted in the prevention of ED development. ST 1936 administration in rats undergoing VAB training did not interfere with its acquisition, whereas SB 271046 administered in similar conditions prevented VAB acquisition. Moreover, ST 1936 administration in rats trained in the Y-maze while exposed to a chronic stress protocol consistently antagonized the stress-disrupting effect, and also this effect was antagonized by SB 271046 coadministration. It was concluded that a tonic 5-HT(6) receptor activity was crucial for VAB acquisition, and that pharmacological stimulation of 5-HT(6) receptors reinstated a stress-reduced hedonic competence with an efficacy similar to that of classical antidepressant drugs.