Clozapine Reverses Hyperthermia and Sympathetically Mediated Cutaneous Vasoconstriction Induced by 3,4-Methylenedioxymethamphetamine (Ecstasy) in Rabbits and Rats

Abstract

Life-threatening hyperthermia occurs in some individuals taking 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). In rabbits, sympathetically mediated vasoconstriction in heat-exchanging cutaneous beds (ear pinnae) contributes to MDMA-elicited hyperthermia. We investigated whether MDMA-elicited cutaneous vasoconstriction and hyperthermia are reversed by clozapine and olanzapine, atypical antipsychotic agents. Ear pinna blood flow and body temperature were measured in conscious rabbits; MDMA (6 mg/kg, i.v.) was administered; and clozapine (0.1-5 mg/kg, i.v.) or olanzapine (0.5 mg/kg, i.v.) was administered 15 min later. One hour after MDMA, temperature was 38.7 Ϯ 0.5°C in 5 mg/kg clozapine-treated rabbits and 39.0 Ϯ 0.2°C in olanzapine-treated rabbits, less than untreated animals (41.5 Ϯ 0.3°C) and unchanged from pre-MDMA values. Ear pinna blood flow increased from the MDMA-induced near zero level within 5 min of clozapine or olanzapine administration. Clozapine-induced temperature and flow responses were dose-dependent. In urethane-anesthetized rabbits, MDMA (6 mg/kg, i.v.) increased ear pinna postganglionic sympathetic nerve discharge to 217 Ϯ 33% of the pre-MDMA baseline. Five minutes after clozapine (1 mg/kg, i.v.) discharge was reduced to 10 Ϯ 4% of the MDMA-elicited level. In conscious rats made hyperthermic by MDMA (10 mg/kg, s.c.), body temperature 1 hr after clozapine (3 mg/kg, s.c.) was 36.9 Ϯ 0.5°C, Ͻ38.6 Ϯ 0.3°C (Ringer's solution-treated) and not different from the pre-MDMA level. One hour after clozapine, rat tail blood flow was 24 Ϯ 3 cm/sec, greater than both flow in Ringer's solution-treated rats (8 Ϯ 1 cm/sec) and the pre-MDMA level (17 Ϯ 1 cm/sec). Clozapine and olanzapine, by interactions with 5-HT receptors or by other mechanisms, could reverse potentially fatal hyperthermia and cutaneous vasoconstriction occurring in some humans after ingestion of MDMA.

Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction

“…Clozapine (1-5 mg/kg) has been previously shown to decrease high-dose MDMA-induced body hyperthermia via vasodilation, as assessed by an ear pinna artery Doppler signal in rabbits (Blessing et al, 2003) and blood flow Doppler signal in the tails of rats (Blessing et al, 2003). Consistent with these data, we found that a low intraperitoneal dose of clozapine (5 mg/kg or~2% of LD50; Lindt et al, 1971) completely reversed MDMA-induced brain and body hyperthermia.…”

“…This treatment protocol allowed us to compare the effectiveness of each drug in terms of the onset of its therapeutic action, strength, and duration. All drugs tested in this study are FDA-approved, currently used to treat chronic diseases in humans, and have previously been shown to decrease MDMA-induced body hyperthermia under standard laboratory conditions (Blessing et al, 2003;Sprague et al, 2005;Hysek et al, 2012;Liechti, 2014).…”

“…We also dissolved labetalol in saline and carvedilol in a 3 : 1 volume ratio of DMSO:PBS. We injected all 'treatment' drugs intraperitoneally at the same dose (5 mg/kg, 1 ml/kg volume); this dose was chosen based on previous studies (Blessing et al, 2003;Sprague et al, 2005).…”

“…We assessed the effects of clozapine, an atypical neuroleptic, and carvedilol and labetalol, mixed alpha-and beta-adrenoceptor blockers. These medications are routinely used to treat chronic health problems in humans, and were chosen because of their preclinical success in attenuating MDMA-induced body hyperthermia (Blessing et al, 2003;Sprague et al, 2005). Clozapine acts on multiple neural receptors and glial cells in the brain, presumably inhibiting MDMA-induced metabolic activation, sympathetic tone, and centrally mediated vasoconstriction (Baldessarini and Frankenburg, 1991;Breier et al, 1994).…”

Microinjection of muscimol into the dorsomedial hypothalamus suppresses MDMA-evoked sympathetic and behavioral responses

“…In anesthetized animals, a condition in which animals are incapable of experiencing exteroceptive or "emotional" stress, administration of MDMA still evokes increases in heart rate, mean arterial pressure and body temperature (Blessing et al, 2003; Rusyniak et al, 2005a;Rusyniak et al, 2005b). Likewise, in humans recreational doses of MDMA (doses chosen by users presumably for pleasureprovoking responses) cause increases in temperature, heat rate, blood pressure and cortisol similar to those observed in conscious animal models (de la Torre et al, 2000).…”