Calcitonin gene-related peptide (CGRP) exerts membrane, cellular and synaptic actions on serotonergic dorsal raphe neurons ex vivo: Functional implications for a role in dorsal raphe-controlled functions

Serotonin (5-HT) plays a role in limbic-controlled behaviors and is implicated in migraine, which is often co-morbid with cognitive-based affective disorders. The neuropeptide calcitonin gene-related peptide (CGRP) regulates vascular tone. Serotonin-acting drugs and CGRP receptor antagonists have proved therapeutic in management of migraine. Clinical interactions between the two systems have been shown, however, whether CGRP exerts direct actions on serotonergic Dorsal Raphe (DR) neurons is unknown. To fully understand the role of CGRP in control of behavior and to predict how CGRP targeted therapies (i.e. CGRP receptor antagonists) could alter DR neuronal activity, investigation of whether CGRP can directly affect 5-HT DR activity was conducted. Patch clamp electrophysiology and single photon calcium imaging in DR brain slices revealed that CGRP (10^-6 M) elicited postsynaptically mediated, potassium-involved outward currents in the majority of 5-HT DR cells. Miniature excitatory synaptic events were reduced in frequency. Further, intracellular calcium was reduced in the majority of neurons, which did not involve actions on the L-type calcium channel. The CGRP agonist SAX replicated effects on the membrane and intracellular calcium. In contrast, the CGRP receptor antagonist MK-3207 blocked the effects on outward current and attenuated the action of CGRP on reducing intracellular calcium. Despite inhibitory membrane and synaptic effects, no change was noted in firing rate. Our findings raise the intriguing possibility that the CGRP system plays a role in mediating limbic-controlled behaviors, at least in part, through direct actions on serotonergic DR neurons, however the effect of CGRP on DR 5-HT output remains to be investigated.