The effect of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus

Abstract

Methylenedioxymethamphetamine (MDMA, 'ecstasy'), widely used as a recreational drug, can produce hyponatraemia. The possibility that this could result from stimulation of vasopressin by MDMA or one of its metabolites has been investigated in vitro. Release of both oxytocin and vasopressin from isolated hypothalami obtained from male Wistar rats was determined under basal conditions and following potassium (40 mM) stimulation. The results were compared with those obtained for basal and stimulated release in the presence of MDMA or metabolites in the dose range 1 microM to 100 pM (n=5 - 8) using Student's t-test with Dunnett's correction for multiple comparisons. All compounds tested affected neurohypophysial hormone release, HMMA (4-hydroxy-3-methoxymethamphetamine) and DHA (3,4-dihydroxyamphetamine) being more active than MDMA, and DHMA (3,4-dihydroxymethamphetamine) being the least active. The effect on vasopressin release was greater than that on oxytocin. In the presence of HMMA the ratio test:control for basal release increased for vasopressin from 1.1+/-0.16 to 2.7+/-0.44 (s.e.m., P<0.05) at 10 nM and for oxytocin from 1.0+/-0.05 to 1.6+/-0.12 in the same hypothalami. For MDMA the ratio increased to 1.5+/-0.27 for vasopressin and to 1.28+/-0.04 for oxytocin for 10 nM. MDMA and its metabolites can stimulate both oxytocin and vasopressin release in vitro, the response being dose dependent for each drug with HMMA being the most potent.

Figure 1

MDMA and its metabolites.

Figure 2

Synthesis of HMMA, HMA and the corresponding catechol derivatives.

Figure 3

The effect of MDMA on (a) vasopressin and (b) oxytocin release from the isolated rat hypothalamus in vitro. Bars represent means±s.e.m.; ^*P<0.05 and ^**P<0.01 compared to control (Cont) or 40 mM potassium alone (K40) for the single drug. The vasopressin response to 500 nM (−)-MDMA was significantly less than that to 500 nM (+)- MDMA (P<0.05). There was a significant difference in the oxytocin response to the two enantiomers of MDMA (indicated by+ and- signs) and the response in the presence of HMMA was significantly greater than that seen with MDMA alone (P<0.01).

Figure 4

The effect of HMMA on (a) vasopressin and (b) oxytocin release from the isolated rat hypothalamus in vitro. Bars represent means±s.e.m.; ^*P<0.05 and ^**P<0.01 compared to control (Cont) or 40 mM potassium alone (K40) for the single drug. The vasopressin response to 1000 nM and 10 nM HMMA as well as the oxytocin response to 1000 nM HMMA was significantly less in the presence of MDMA (P<0.01).

Figure 5

The effect of MDA on (a) vasopressin and (b) oxytocin release from the isolated rat hypothalamus in vitro. Bars represent means±s.e.m. and ^*P<0.05 ^**P<0.01 compared to control (Cont) or 40 mM potassium alone (K40). The vasopressin response to 500 nM (−)-MDA was significantly less than that to 500 nM(+)-MDMA (P<0.05).

Figure 6

The effect of HMA, DHMA and DHA on (a) vasopressin and (b) oxytocin release from the isolated rat hypothalamus in vitro. Bars represent means±s.e.m.; ^*P<0.05 and ^**P<0.01 compared to the control values of 1.1±0.08.

Figure 7

The effect of HMA, DHMA and DHA on 40 mM KCl stimulated release of (a) vasopressin and (b) oxytocin from the isolated rat hypothalamus. Bars represent means±s.e.m.; ^*P<0.05 and ^**P<0.01 compared to the response to potassium alone.