Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons


S. Haj-Dahmane: Research Institute on Addictions, University at Buffalo, 1021 Main Street, Buffalo, NY 14203, USA.  Email: dahmane@ria.buffalo.edu

Key points

  • • The modulation of the serotonin system by glucocorticoids plays a central role in the regulation of stress responses. However, the mechanisms by which glucocorticoids regulate the excitability of dorsal raphe serotonin neurons remain unknown.
  • • In this study, we show that glucocorticoids rapidly inhibit glutamatergic synaptic transmission to serotonin neurons by reducing glutamate release.
  • • The rapid inhibition of glutamate release is not signalled by classical intracellular glucocorticoid receptors, but rather by putative membrane-located G-protein-coupled receptors.
  • • Activation of the membrane-located G-protein-coupled receptors increases endocannabinoid signalling, which in turn mediates the inhibition of glutamatergic transmission in the dorsal raphe.
  • • In the dorsal raphe, glucocorticoids increase endocannabinoid tone by inhibiting cyclooxygenase-2.

Abstract  Glucocorticoids play a critical role in the modulation of stress responses by controlling the function of the serotonin (5-HT) system. However, the precise effects of glucocorticoids on the excitability of dorsal raphe (DR) 5-HT neurons remain unknown. In this study, we investigated the effects of glucocorticoids on excitatory synaptic transmission to putative DR 5-HT neurons. We found that corticosterone or the synthetic glucocorticoid agonist dexamethasone rapidly suppressed glutamatergic synaptic transmission to DR 5-HT neurons by inhibiting glutamate release in the DR. This inhibitory effect was mimicked by membrane-impermeable glucocorticoids, indicating the involvement of membrane-located corticosteroid receptors. The glucocorticoid-induced inhibition of glutamatergic transmission was mediated by the activation of postsynaptic G-protein-coupled receptors and signalled by retrograde endocannabinoid (eCB) messengers. Examination of the downstream mechanisms revealed that glucocorticoids enhance eCB signalling via an inhibition of cyclooxygenase-2. Together, these findings unravel a novel mechanism by which glucocorticoids control the excitability of DR 5-HT neurons and provide new insight into the rapid effects of stress hormones on the function of the 5-HT system.