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Jun 3, 2018

Euroanaesthesia 2018

02 / Serotonin 1B receptor agonist diminishes depolarization-evoked glutamate release by suppressing the adenylyl cyclase/PKA pathway in rat cerebral cortex endings

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nerve

synaptosome

Abstract

Abstract

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Keywords

nerve

synaptosome

Abstract

Background and Goal of Study: Serotonin (5-HT) 1B receptors are expressed predominantly on axonal terminals and have been implicated in the involvement of several behavior and psychiatric diseases. In addition, several studies have demonstrated that 5-HT1B receptor agonists can alleviate neuropathic pain such as trigeminal neuralgia. Since neuropathic pain might be associated with excessive glutamatergic transmission in CNS, we aimed to examine the presynaptic effect of the 5-HT1B receptor agonist on the modulation of glutamate release and elucidate the underlying mechanisms. Materials and Methods: Isolated nerve terminals (synaptosomes) purified from male Sprague-Dawley rat cerebral cortex were used to examine the effect of CGS-12066, a 5-HT1B receptor agonist, on glutamate release evoked by 4-aminopyridine (4-AP). Pharmacological activators and inhibitors of protein kinase cascades were used to investigate the possible downstream signaling pathway. Results and Discussion: Our results showed that CGS-12066 exhibited a concentration-dependent inhibition of 4-AP-evoked release of glutamate. In addition, this inhibition was prevented by chelating the intrasynaptosomal Ca2+ ions and by the vesicular transporter inhibitor, but was insensitive to the glutamate transporter inhibitor. The inhibition of evoked glutamate release was abolished by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking intracellular Ca2+ release. Inhibition of Gi/Go-protein, adenylyl cyclase, and PKA also prevented the inhibitory effect of CGS-12066 on evoked glutamate release. Conclusion: These results suggest that 5-HT1B receptor agonist inhibits glutamate release from rat cortical synaptosomes through the suppression of presynaptic voltage-dependent Ca2+ entry and G protein and the downstream adenylyl cyclase and PKA signaling cascade. These findings may delineate the possible analgesic mechanism of 5-HT1B receptor agonist.

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© Copyright 2019 Morressier GmbH.
All rights reserved.