A microdialysis study of ST1936, a novel 5-HT6 receptor agonist

The function of 5-HT6 receptors, one of the last additions to the large family of 5-HT receptors, is largely unknown due to the limited knowledge of their transduction mechanisms, lack of full centrally acting agonists and inconsistencies in the pharmacological and neurochemical effects of the antagonists. Recently, a new full agonist, ST1936, with nanomolar affinity for 5-HT6 receptors, has become available. Here we report the effect of ST1936 (5–10–20 mg/kg/ip) on dialysate DA, NA and 5-HT in the medial prefrontal cortex (PFCX) and in the shell and core of the nucleus accumbens (NAc). Systemic administration of ST1936 dose-dependently increased dialysate DA and NA in the NAc shell and PFCX and to a lesser extent in the NAc core; these effects were prevented by systemic administration of the two 5-HT6 receptor antagonists, SB271046 (10–20 mg/kg/ip) and SB399885 (5 mg/kg/ip).These properties of ST1936 suggest that 5-HT6 receptors control the activity of DA and NA neurons projecting to the NAc and to the PFCX.

Research highlights► We further characterise the role of 5-HT6 receptors and its involvement in monoaminergic systems. ► We evaluated the biochemical effect of the agonist ST1936 with microdialysis experiments. ► The stimulation of 5-HT6 receptors exerts reinforcing effects via stimulation of DA release in the NAc. ► Agonists of 5-HT6 receptors could be indirect psychostimulants with a completely novel mechanism of action.