A Faster Route Up?

Abstract

The selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressants. Like other antidepressant drugs in current use, however, SSRIs are effective only after weeks of administration, likely because of the time required for various pre- and postsynaptic adaptations to take place (see Duman). Lucas et al ., a group that previously showed that enhancement of 5-HT neuron firing in rats by 5-HT 4 receptor agonists was maximal after only 3 days of treatment, investigated these agonists’ effects on several adaptations associated with chronic SSRI exposure. Three days of treatment with the 5-HT 4 receptor agonist RS 67333 desensitized presynaptic 5-HT 1A autoreceptors (assessed by a decrease in the inhibition of the firing rate of 5-HT neurons in the dorsal raphe nucleus in response to acute administration of an SSRI). Three days of treatment with 5-HT 4 receptor agonists also increased tonic input to postsynaptic 5-HT 1A receptors on hippocampal pyramidal cells, an effect that was abolished by pharmacological depletion of endogenous 5-HT. Moreover, 3 days of treatment with RS 67333 increased phosphorylation of hippocampal CREB (cAMP response element-binding protein) and hippocampal neurogenesis. In two rat behavioral models of antidepressant activity in which the effects of SSRIs were slow to emerge (inhibition of hyperlocomotion in response to olfactory bulbectomy and reversal of the inhibition of sucrose intake in response to chronic mild stress), the effects of RS 67333 were apparent earlier. Thus, 5-HT 4 receptor agonists may hold promise as a more rapidly acting class of antidepressants than existing antidepressant drugs. G. Lucas, V. V. Rymar, J. Du, O. Mnie-Filali, C. Bisgaard, S. Manta, L. Lambas-Senas, O. Wiborg, N. Haddjeri, G. Piñeyro, A. F. Sadikot, G. Debonnel, Serotonin 4 (5-HT 4 ) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55 , 712-725 (2007). [PubMed] R. S. Duman, A silver bullet for the treatment of depression? Neuron 55 , 679-681 (2007). [PubMed]