Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

Abstract

Patients are at high risk of developing serotonin-toxicity syndrome (toxidrome) when they take multiple serotonergic drugs, particularly co-administered with monoamine oxidase inhibitors or 5-hydroxytryptamine (5-HT) reuptake blockers. The toxidrome can vary from mild to severe. The primary goal of the present study was to understand the relationship between behavioral signs and degrees of toxidrome induced by 5-hydroxy-L-tryptophan (5-HTP) in clorgylinized rats. The severity was obtained by scoring behavioral signs including head shakes, penile erection, forepaw treading, hind limb abduction, Straub tail and tremor. It was found that 5-HTP produced a dosedependent increase in degrees of the toxidrome. Furthermore, correlation between the toxidrome and changes in body-core temperature (claudqcT cor ) was determined. There was hypothermia in the mild toxidrome (claudqcT cor < −1 °C), high hyperthermia in the severe toxidrome (claudqcT cor > +2 °C) and a small change in T cor in the moderate toxidrome (−1 °C < claudqcT cor < +2 °C). Thus, claudqcT cor in response to drugs can be used to estimate the severity of the toxidrome. The second attempt was to identify the receptors mediating those changes. 5-HT 1A receptors were involved in the hypothermic response while 5-HT 2A and NMDA receptors mediated head shakes, hyperthermia, forepaw treading and Straub tail. Lastly, antidotal effect of cyproheptadine and (+)-MK-801 was examined. Both drugs blocked hyperthermia and death. However, the effects on mortality became poor when the antidotes were injected 60 min after high hyperthermia had been induced. These findings demonstrate the importance of the time frame using antidotes in the treatment of the 5-HT toxidrome.

Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats

“…Behavioral syndrome was scored according to an established method described in our previous work (Ma et al, 2008). Scoring was performed 30 - 60 min after MDMA or vehicle administration.…”

“…Measurements and data analysis procedures were similar to our previous work (Ma et al, 2008) with minor modifications. Rats were allowed to acclimatize to the temperature-controlled measurement chamber for at least a 2 h period prior to obtaining body temperature measurements.…”

How Much Serotonin in the CNS is Too Much?

“…Our studies further demonstrated that a 10-fold increase in 5HT ext was sufficient to cause a mild syndrome, showing hypothermia, head shakes and myoclonus but no signs indicative of advanced or severe syndrome (e.g., tremor, forepaw treading or hindlimb abduction) (Ma et al, 2008;Zhang et al, 2009). This suggests that the brain is most likely intolerant of the double digit increase in 5HT ext in terms of fold-change in the cerebrospinal fluid.…”

“…To simplify the analysis, 5HT precursors (e.g., 5HTP) in combination with MAOI (e.g., clorgyline) are more applicable for elucidating the 5HT threshold. Many studies have demonstrated that a single injection of 5HTP combined with clorgyline was sufficient to produce a dose-dependent increase in 5HT ext in the brain, causing serotonin syndrome (Ma et al, 2008;Nisijima et al, 2004;Nisijima et al, 2000;Nisijima et al, 2001;Shioda et al, 2004). To obtain the threshold level of 5HT ext , we designed a 5HTP dosing regimen in clorgyline-pretreated rats.…”

“…To obtain the threshold level of 5HT ext , we designed a 5HTP dosing regimen in clorgyline-pretreated rats. Male Sprague-Dawley rats were examined under controlled ambient temperature (22 ± 1°C) and humidity (70%) in test chambers (Ma et al, 2008;Zhang et al, 2009). Animals received 2 mg/kg clorgyline, 2 hours before injection of 5HTP at the dose range of 1 to 25 mg/kg.…”