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.
Svenningsson
Per
P
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA. per.svenningsson@ki.se
Tzavara
Eleni T
ET
Qi
Hongshi
H
Carruthers
Robert
R
Witkin
Jeffrey M
JM
Nomikos
George G
GG
Greengard
Paul
P
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism* / Q000494:pharmacology; D003863:Depression / Q000378:metabolism* / Q000523:psychology; D019417:Hindlimb Suspension / Q000379:methods / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology
D000928:Antidepressive Agents; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor