Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH 2C receptor stimulation facilitates their seizure activities

• Published in: Brain research Vol. 1057; no. 1; pp. 153 - 160
• Main Authors: Morita, Katsuya, Hamamoto, Masahiro, Arai, Shigeaki, Kitayama, Shigeo, Irifune, Masahiro, Kawahara, Michio, Kihira, Kenji, Dohi, Toshihiro
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 2005
• Subjects: Cocaine; Convulsion; Local anesthetics; Serotonin transporter; SSRI; Uptake and transporters; SSRI; Serotonin transporter; Convulsion; Cocaine; Neurotransmitters, modulators, transporters, and receptors; Local anesthetics
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2005.07.049

The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice. Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT 2A,2C receptor agonist, R(−)-DOI and the 5-HT 2C receptor agonists, mCPP, and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT 2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(−)-DOI, mCPP, and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions was significantly reduced by 5-HT 2A,2B,2C antagonist, LY-53857, and 5-HT 2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT 2A antagonists MDL 11,939 and ketanserin, and 5-HT 2B antagonist SB 204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT 2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine-induced convulsions through their direct inhibitory action on central SERT.