Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH2C receptor stimulation facilitates their seizure activities

Abstract

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-HT2C 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-HT2B 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-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL 11,939 and ketanserin, and 5-HT2B 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-HT2C 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.

Cocaine use as an independent predictor of seizures after aneurysmal subarachnoid hemorrhage

“…7,22,29 Increased serotonin neurotransmission due to decreased serotonin reuptake has also been implicated in cocaine-induced seizures. 17 The 5-HT2 receptors appear to play a significant role in this effect. 5-HT2 receptor agonists and serotonin reuptake inhibitors have been shown to increase cocaine-induced seizures in animal models, while 5-HT2 antagonists appear to increase the seizure threshold.…”

“…5-HT2 receptor agonists and serotonin reuptake inhibitors have been shown to increase cocaine-induced seizures in animal models, while 5-HT2 antagonists appear to increase the seizure threshold. 16,17,21 Lastly, chronic cocaine use may increase the body's sensitivity to the convulsant effects of the drug through kindling. Cocaine kindling is postulated to be secondary to modified NDMA receptor expression with repeated exposure, resulting in increased glutamate activity in the brain.…”

Homeostasis of glucose in the rainbow trout (Oncorhynchus mykiss Walbaum): the role of serotonin

“…We decided to use doses within the medium to high range of those used in mammals (Niesink and Van Ree, 1982;Scotti de Carolis et al, 1986;Schechter, 1988;Hagan et al, 1997;Guscott et al, 2003;Morita et al, 2005;Freitas et al, 2006;Egashira et al, 2008).…”

Predictive factors for generalized seizures after deliberate citalopram overdose

“…Conventional citalopram dosages might even increase seizure threshold in selected patient groups [12]. In contrast, administration of very high doses is capable of provoking seizures in mice and dogs [22, 23]. Generalized seizures occurred in a significant proportion of patients who ingested citalopram in the absence of other drugs or ethanol.…”