Biochemical and behavioral evidence for antidepressant-like effects of 5-HT6 receptor stimulation

The primary action of several antidepressant treatments used in the clinic raises extracellular concentrations of serotonin (5-HT), which subsequently act on multiple 5-HT receptors. The present study examined whether 5-HT6 receptors might be involved in the antidepressant-like effects mediated by enhanced neurotransmission at 5-HT synapses. A selective 5-HT6 receptor antagonist, SB271046, was evaluated for its ability to counteract fluoxetine-induced biochemical and behavioral responses in mice. In addition, biochemical and behavioral effects of the 5-HT6 receptor agonist, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT), were assessed in mice to ascertain whether enhancement of 5-HT6 receptor-mediated neurotransmission engenders antidepressant-like effects. SB271046 significantly counteracted the stimulatory actions of fluoxetine on cortical c-Fos mRNA, phospho-Ser845-GluR1, and in the tail suspension antidepressant assay, whereas it had no effect on these parameters by itself. EMDT increased the phosphorylation states of Thr34-DARPP-32 and Ser845-GluR1, both in brain slices and in the intact brain, which were effects also seen with the antidepressant fluoxetine; as with fluoxetine, these effects were demonstrated to be independent of D1 receptor stimulation. Systemic administration of EMDT increased c-Fos mRNA expression in the striatum and cerebral cortex and reduced immobility in the tail suspension test. The antidepressant-like effects of EMDT in the tail suspension test were prevented by SB271046. Our results indicate that 5-HT6 receptor stimulation may be a mechanism initiating some of the biochemical and behavioral outcomes of 5-HT reuptake inhibitors, such as fluoxetine. These findings also indicate that selective 5-HT6 receptor agonists may represent a novel antidepressant drug class.