The pharmacology of the acute hyperthermic response that follows administration of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats

MDMA (ecstasy) causes acute hyperthermia in rats by increasing dopamine release, which acts on D1 receptors, rather than through serotonin release. Blocking serotonin receptors or inhibiting serotonin reuptake did not prevent the rise in body temperature, but blocking D1 dopamine receptors with SCH 23390 did. The tail skin temperature did not increase, suggesting MDMA impairs heat dissipation. These findings indicate that dopamine, not serotonin, is the primary driver of MDMA-induced hyperthermia, which has implications for clinical treatment.

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Abstract

The pharmacology of the acute hyperthermia that follows 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) administration to rats has been investigated. MDMA (12.5 mg kg −1 i.p.) produced acute hyperthermia (measured rectally). The tail skin temperature did not increase, suggesting that MDMA may impair heat dissipation. Pretreatment with the 5‐HT 1/2 antagonist methysergide (10 mg kg −1 ), the 5‐HT 2A antagonist MDL 100,907 (0.1 mg kg −1 ) or the 5‐HT 2C antagonist SB 242084 (3 mg kg −1 ) failed to alter the hyperthermia. The 5‐HT 2 antagonist ritanserin (1 mg kg −1 ) was without effect, but MDL 11,939 (5 mg kg −1 ) blocked the hyperthermia, possibly because of activity at non‐serotonergic receptors. The 5‐HT uptake inhibitor zimeldine (10 mg kg −1 ) had no effect on MDMA‐induced hyperthermia. The uptake inhibitor fluoxetine (10 mg kg −1 ) markedly attenuated the MDMA‐induced increase in hippocampal extracellular 5‐HT, also without altering hyperthermia. The dopamine D 2 antagonist remoxipride (10 mg kg −1 ) did not alter MDMA‐induced hyperthermia, but the D 1 antagonist SCH 23390 (0.3 – 2.0 mg kg −1 ) dose‐dependently antagonized it. The dopamine uptake inhibitor GBR 12909 (10 mg kg −1 ) did not alter the hyperthermic response and microdialysis demonstrated that it did not inhibit MDMA‐induced striatal dopamine release. These results demonstrate that in vivo MDMA‐induced 5‐HT release is inhibited by 5‐HT uptake inhibitors, but MDMA‐induced dopamine release may not be altered by a dopamine uptake inhibitor. It is suggested that MDMA‐induced hyperthermia results not from MDMA‐induced 5‐HT release, but rather from the increased release of dopamine that acts at D 1 receptors. This has implications for the clinical treatment of MDMA‐induced hyperthermia. British Journal of Pharmacology (2002) 135 , 170–180; doi: 10.1038/sj.bjp.0704442