Psychopharmacology (Berl). 2015 Apr;232(7):1245-60.

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

Tao R1, Shokry IM, Callanan JJ, Adams HD, Ma Z.
  • 1Charles E. Schmidt College of Medicine, Florida Atlantic University, 777 Glades Road, Boca Raton, FL, 33431, USA, rtao@fau.edu.

 

Abstract

RATIONALE: Illicit use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors.

OBJECTIVES: Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome.

METHODS: Rats were administered MDMA at doses of 0.3, 1, or 3 mg/kg and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome.

RESULTS: Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine.

CONCLUSIONS: Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5-hydroxytryptamine (5HT)-dependent mechanism) and therefore is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms).

PMID: 25300903

 

Supplementary

MDMA is a popular abused drug in the clubhouses and at parties. MDMA abuse results in mild to severe forms of the serotonin syndrome. The mild syndrome is likely self-resolving while the severe syndrome can be life-threatening. Thus, the severe syndrome should be treated immediately. There are many factors that affect the syndrome severity. Potential factors include drug dosage, physical activity, ambient temperature, crowd, age and gender. For many years, drug overdose has been considered the main factor for inducing the severe syndrome in preclinical investigations. However, the overdose hypothesis could not explain disparities between preclinical research and clinical cases (Green et al., 2012; Parrott, 2012). How other factors and hypotheses contribute to the syndrome severity is not fully understood and without this knowledge, it is difficult to design an evidence-based strategy for treatment of the syndrome.

Physical activity and ambient temperature are two factors that commonly influence patients with drug abuse. As illustrated in Fig. 1, empirical research showed that users who  remain at a sedentary state and low ambient temperature have no or only a mild serotonin syndrome (Bahora et al., 2009). In contrast, users who develop the severe and life-threatening syndrome are those that have vigorous-intensity physical activity(Ben-Abraham et al., 2003). This raises the question as to what mechanisms underlie intensification of the syndrome severity by physical activity and warm ambient temperature.

 

fig-1

 

It appears that excessive 5HT in the brain is the primary cause of serotonin syndrome. As illustrated in Fig 2, we found that serotonin syndrome can be induced when extracellular 5HT exceeds 10-fold above baseline (Tao et al., 2014; Tao et al., 2015). It is likely that 5HT receptors, such as 5HT2A receptors (5HT2ARs) can be overstimulated in postsynaptic neurons by the high levels of 5HT released. Such relationship between excessive 5HT and serotonin syndrome has been characterized as presynaptic mechanisms responsible for initiation of the syndrome. Behavioral observation supports that a syndrome always begins with mild symptoms and then either self-resolves, or progresses into the severe symptoms. It was previously believed that self-resolving of the mild syndrome was primarily due to drug elimination from the body. Recently we have provided an evidence that natural protection against excessive 5HT in the brain is likely the primary mechanism for self-resolving of the mild syndrome (Ma et al., 2008).

5HT receptors are widely distributed in both excitatory and inhibitory postsynaptic neurons and pathways.  Since the severe syndrome was sensitive to competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, it is likely that physical activity and warm ambient temperature are the key factor enhancing the excitatory postsynaptic neurons by which excitatory effects caused by excessive 5HT may overpower the inhibitory effects, and eventually the syndrome becomes life-threatening.

We concluded from our study that the combined effects of both physical activity and warm ambient temperature intensified the syndrome from mild to severe. This intensification, however, was not caused by a greater increase in 5HT levels, but rather the potentiation of the effects of 5HT on 5HT2ARs through other mechanisms (non-5HT-dependent mechanisms).

 

Importance of this study

  1. We characterized that serotonin syndrome consists of two phases: syndrome initiation and syndrome progression.
  2. Syndrome initiation depends on drug doses and the proportional increase in 5HT (5HT-dependent mechanisms).
  3. Physical activity and warm ambient temperature intensify the syndrome from mild to severe, which involves other mechanisms than 5HT (non-5HT-dependent mechanisms).

 

 

fig-2

 

Acknowledgement:

This study was supported by the NIH grant (R15DA029863) and the Ross University School of Veterinary Medicine research grant. We would like to thank the National Institute on Drug Abuse (Rockville, MD) for providing (±)3,4-methylenedioxymethamphetamine (±MDMA) for this work. We also thank Marni Schlanger and Connor Shields of the Florida Atlantic University undergraduate research programs (M30014) for their laboratory assistance.

 

References

Bahora M, Sterk CE, Elifson KW (2009). Understanding recreational ecstasy use in the United States: a qualitative inquiry. Int J Drug Policy 20: 62-69.

Ben-Abraham R, Szold O, Rudick V, Weinbroum AA (2003). ‘Ecstasy’ intoxication: life-threatening manifestations and resuscitative measures in the intensive care setting. Eur J Emerg Med 10: 309-313.

Green AR, King MV, Shortall SE, Fone KC (2012). Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans. Br J Pharmacol 166: 1523-1536.

Ma Z, Zhang G, Jenney C, Krishnamoorthy S, Tao R (2008). Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats. Eur J Pharmacol 588: 198-206.

Parrott AC (2012). MDMA and 5-HT neurotoxicity: the empirical evidence for its adverse effects in humans – no need for translation. Br J Pharmacol 166: 1518-1520; discussion 1521-1512.

Tao R, Rudacille M, Zhang G, Ma Z (2014). Changes in Intensity of Serotonin Syndrome caused by Adverse Interaction between Monoamine Oxidase Inhibitors and Serotonin Reuptake Blockers. Neuropsychopharmacology 39: 1996-2007.

Tao R, Shokry IM, Callanan JJ, Adams HD, Ma Z (2015). Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats. Psychopharmacology (Berl): 1245-1260.

 

 

 

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