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

Abstract

Rationale Illicit use of MDMA (3,4-methylenedioxymethamphetamine; 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 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 (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).

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model

“…To test whether motor dysfunction might arise with BCAO, the locomotor activity of mice was measured on a force-plate actometer [27,28,45]. We observed no significant difference in behavior between sham group and BCAO with G-CSF treated group (Fig.…”

“…The force-plate actometer is an ensemble of mechanical, electronic, and computing elements that embody mathematical and physical principles to produce measurement of whole-organism behavioral attributes of relevance to basic neuroscience research. Methods of calibration and details of data acquisition have been described elsewhere [27,28]. Briefly, the force-plate actometer purchased from BASi Corp (model FPA-I; West Lafayette, IN, USA) consists of a force-sensitive plate at a resolution of 200 Hz, a sound attenuation chamber, a computerized data acquisition board, and an analysis system software (FPA 1.10.01).…”

New Insights on Different Response of MDMA-Elicited Serotonin Syndrome to Systemic and Intracranial Administrations in the Rat Brain

“…Rationales for choosing those areas are two-fold. First, systemic administration of MDMA caused simultaneous and also excessive 5HT elevation in many brain areas [ 1 , 2 ], which may be the cause of serotonin syndrome. To determine whether intracranial administration could also cause such responses, it is necessary to investigate at least three different sites in the brain.…”

“…Systemic administration of MDMA elicits excessive increases in extracellular serotonin (5-hydroxytryptamine; 5HT) in many brain areas [ 1 , 2 ], causing a wide spectrum of symptoms, including locomotion problems, anxiety and hyperthermia, collectively called serotonin syndrome [ 3 ]. These effects may be attributed to MDMA molecules that can be taken into serotonergic axon terminals, which leads to the expulsion of 5HT from storage vesicles into the extracellular space [ 4 ].…”

Treadmill running restores MDMA-mediated hyperthermia prevented by inhibition of the dorsomedial hypothalamus

“…Previous research has shown that exercise increases the toxicity and hyperthermia of MDMA (1, 2) but despite this, locomotion and exercise have been discounted as major contributors to hyperthermia from MDMA. If locomotion is a major contributor to heat-related deaths from MDMA, then understanding how stimulants evoke locomotion and allow persons to exert themselves to the point of heat stroke is an important step in developing prevention strategies.…”