5-HT1A receptor agonist 8-OH-DPAT induces serotonergic behaviors in mice via interaction between PKC delta and p47phox

초록

Serotonin syndrome is an adverse reaction due to increased serotonin (5-hydroxytryptophan: 5-HT) concentrations in the central nervous system (CNS). The full 5-HT1A receptor (5-HT1AR) agonist (+/-)-8-hydroxydipropylaminotetralin (8-OH-DPAT) has been recognized to elicit traditional serotonergic behaviors. Treatment with 8-OH-DPAT selectively increased PKCS expression out of PKC isoforms and 5-HT turnover rate in the hypothalamus of wild-type mice. Treatment with 8-OH-DPAT resulted in oxidative burdens, co-immunoprecipitation of 5-HT1AR and PKC delta, and phosphorylation and membrane translocation of p47phox. Importantly, p47phox also interacted with 5-HT1AR or PKC delta in the presence of 8-OH-DPAT. Consistently, the interaction and oxidative burdens were attenuated by 5-HT1AR antagonism (i.e., WAY100635), PKC delta inhibition (i.e., rottlerin and genetic depletion of PKC delta), or NADPH oxidase/p47phox inhibition (i.e., apocynin and genetic depletion of p47phox). However, WAY100635, apocynin, or rottlerin did not exhibit any additive effects against the protective effect by inhibition of PKC delta or p47phox. Furthermore, apocynin, rottlerin, or WAY100635 also significantly protected from pro-inflammatory/pro-apoptotic changes induced by 8-OH-DPAT. Therefore, we suggest that 8-OH-DPAT-induced serotonergic behaviors requires oxidative stress, pro-inflammatory, and proapoptotic changes, that PKC delta or p47phox mediates the serotonergic behaviors induced by 8-OH-DPAT, and that the inhibition of PKC delta-dependent p47phox activation is critical for protecting against serotonergic behaviors.

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