MDMA-induced c-Fos expression in oxytocin-containing neurons is blocked by pretreatment with the 5-HT-1A receptor antagonist WAY 100635

The popular party drug MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) increases sociability in both humans and laboratory animals. Recent research suggests that these prosocial effects may involve serotonin (5-HT)-stimulated hypothalamic release of the neuropeptide oxytocin. WAY 100635, a 5-HT1A receptor antagonist, prevents MDMA-induced increases in plasma oxytocin and also reduces MDMA-mediated increases in social interaction in rats. The present study used c-Fos immunohistochemistry to determine the possible role of 5-HT1A receptors in MDMA-mediated activation of oxytocin synthesizing neurons. Male Wistar rats (n = 8/group) were administered MDMA (10 mg/kg, i.p.) with or without WAY 100635 (1 mg/kg, i.p.) pre-treatment and c-Fos expression was then assessed throughout the brain. MDMA significantly increased locomotor activity and this effect was partly prevented by WAY 100635, in agreement with previous studies. WAY 100635 significantly reduced MDMA-induced c-Fos expression in a subset of brain regions examined. A particularly prominent reduction was seen in the oxytocin-positive neurons of the supraoptic nucleus and paraventricular hypothalamus, with more modest reductions in the Islands of Calleja, median preoptic nucleus, somatosensory cortex and nucleus of the solitary tract. WAY 100635 did not alter MDMA-induced c-Fos expression in the striatum, thalamus, or central amygdala. These results indicate that MDMA's action on oxytocin producing cells in the hypothalamus is mediated through 5-HT1A receptors and that certain specific cortical, limbic and brainstem sites are also activated by MDMA via these receptors.

► WAY 100635, a 5HT1A antagonist reduced the MDMA-induced c-Fos expression in two key oxytocin areas - the SON and PVN. ► WAY 100635 also attenuated MDMA-induced hyperactivity. ► These data confirm the importance of 5-HT1A receptors in the actions of MDMA, and further support the notion that MDMA may attain its prosocial effects by stimulating the release of oxytocin.