Numerous studies have reported high glutamate levels in the

Numerous studies have reported high glutamate levels in the brains of patients with depression, indicating that the glutamate system plays a crucial role in depression (Sanacora et al., 2004; Kendell et al., 2005; Hashimoto et al., 2007). Furthermore, several clinically effective antidepressant drugs can depress glutamate receptor function and glutamate release in rat brains (Bonanno et al., 2005; Lin et al., 2011a,b; Milanese et al., 2013; Musazzi et al., 2013). Hence, an increase in the glutamate levels in the palmitoylethanolamide reviews may be involved in the pathogenesis of depression, and reducing glutamate release appears to be an efficient means to achieve antidepressant activity. The present study demonstrates that the 5-HT1B receptor agonist CGS12066 reduces the 4-AP-evoked glutamate release from hippocampal nerve terminals. Based on these considerations, reduced glutamate release from nerve endings may explain the antidepressant-like effects of 5-HT1B receptor agonists in several rodent behavioral tests. In conclusion, the present study is the first to demonstrate that the activation of presynaptic 5-HT1B receptors by CGS12066 in rat hippocampal nerve terminals results in the inhibition of glutamate release, which is associated with reduction in cAMP production and PKA activity as well as subsequent suppression of Ca2+ influx through the N- and P/Q-type Ca2+ channels. Based on our results, we suggest that presynaptic 5-HT1B heteroreceptors might play a physiological role in preventing excessive accumulation of extracellular glutamate, which may result from repetitive activity, thereby exerting a potential neuroprotective effect.
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Conflicts of interest
Acknowledgements This work was supported by grants from the Ministry of Science and Technology (MOST-105-2314-B-418-001).
Introduction Serotonin (5-hydroxytryptamine; 5-HT) as a neurotransmitter acts via membrane receptors in the central nervous (CNS) and the peripheral nervous system (PNS), as well as in non-neuronal tissues (e.g. blood, gastro intestinal, endocrine, sensory and cardiovascular systems, to name a few). 5-HT is one of the oldest neurotransmitters/hormones in evolution, and its receptors are estimated to have appeared 700–800Mio years in single cell eukaryotes such as paramecia; 5-HT receptors are found in such diverse species from planaria, c. Elegans, and drosophila to man are, and are rather well conserved. This may explain why 5-HT interacts with such a diversity of receptors of the G-protein-coupled family and the ligand-gated family, similarly to acetylcholine, GABA or glutamate, but with more receptor subtypes and a larger diversity at play. They may actually have been amongst the first rhodopsin-like receptors reacting to a chemical. The major classes of 5-HT receptors must have diverged about 750 millions years ago, long before cholinergic, adrenergic or dopaminergic receptors, although the GPCR family may date from >1billion years. Serotonin was first described as enteramine, which was isolated from the gut in the 1930s by Ersparmer and colleagues and shown to cause contraction of the uterus. 5-HT was rediscovered in the 1940s by Irvin Page's group in the circulation and called serotonin, based on its vasoconstrictor features (although it also relaxes blood vessels); eventually Maurice Rapport purified, crystallized and characterized the molecule from vast amounts of blood. Rapport found that enteramine and serotonin covered the same entity, namely 5-hydroxytryptamine, which indeed contained an indole as already suggested by Ersparmer and eventually the two groups came to the same conclusion. The availability of synthetic 5-HT was the real start of the 5-HT saga in pharmacological terms.
Class A GPCRs can be subdivided depending on their coupling to second messengers via the G-proteins and 5-HT1 receptors are mostly linked to Gi/o, which are pertussis toxin sensitive and couple negatively to adenylate cyclase; in cells, this may lead to membrane depolarization and inhibition of firing. The 5-HT1 receptor class is composed of five receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-ht1e and 5-HT1F) which, in humans, share 40–63% overall sequence identity and couple somewhat preferentially to Gi/o to inhibit cAMP formation. The 5-ht1E receptor has still a lower case appellation since the corresponding endogenous receptor has not yet been established. Actually 5-ht1E may not be found in rodents, but has been reported in guinea-pig brain [210]. 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1F receptors have been demonstrated functionally in a variety of tissues. The 5-HT1C receptor was renamed 5-HT2C, due to structural, operational and transductional similarities with the 5-HT2 receptor subclass [6]; it was assigned to the 5-HT1 group due to its high affinity binding of [3H]-5-HT, a classic feature of 5-HT1 receptors, but this has long been revised.