A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice

Abstract

1. This study investigated whether the immediate and long-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in mouse brain are due to the parent compound and the possible contribution of a major reactive metabolite, 3,4-dihydroxymethamphetamine (HHMA), to these changes. The acute effect of each compound on rectal temperature was also determined. 2. MDMA given i.p. (30 mg kg(-1), three times at 3-h intervals), but not into the striatum (1, 10 and 100 microg, three times at 3-h intervals), produced a reduction in striatal dopamine content and modest 5-HT reduction 1 h after the last dose. MDMA does not therefore appear to be responsible for the acute monoamine release that follows its peripheral injection. 3. HHMA does not contribute to the acute MDMA-induced dopamine depletion as the acute central effects of MDMA and HHMA differed following i.p. injection. Both compounds induced hyperthermia, confirming that the acute dopamine depletion is not responsible for the temperature changes. 4. Peripheral administration of MDMA produced dopamine depletion 7 days later. Intrastriatal MDMA administration only produced a long-term loss of dopamine at much higher concentrations than those reached after the i.p. dose and therefore bears little relevance to the neurotoxicity. This indicates that the long-term effect is not attributable to the parent compound. HHMA also appeared not to be responsible as i.p. administration failed to alter the striatal dopamine concentration 7 days later. 5. HHMA was detected in plasma, but not in brain, following MDMA (i.p.), but it can cross the blood-brain barrier as it was detected in the brain following its peripheral injection. 6. The fact that the acute changes induced by i.p. or intrastriatal HHMA administration differed indicates that HHMA is metabolised to other compounds which are responsible for changes observed after i.p. administration.

Figure 1

Postulated pathways of MDMA metabolism (adapted from Green et al., 2003). Only structures considered in this paper are shown. MDMA: 3,4-methylenedioxymethamphetamine; HHMA: 3,4-dihydroxymethamphetamine; MDA: 3,4-methylenedioxyamphetamine; HMMA: 4-hydroxy-3-methoxymethamphetamine; HMA: 4-hydroxy-3-methoxyamphetamine.

Figure 2

Immediate effects induced by repeated administration of MDMA, given intraperitoneally (30 mg kg⁻¹) or intrastriatally (1, 10 and 100 μg) on the concentrations of dopamine (a, d) and DOPAC acid (b, e) in striatum and of 5-HT in striatum, hippocampus and cortex (c, f). Each dose was injected three times at 3-h intervals and mice killed 1 h after last injection. The results are shown as mean±s.e.m. (n=5–9). Differences from saline: ^*P<0.05, ^**P<0.01, ^***P<0.001. Differences from the corresponding ipsi- and contralateral side of saline-treated animals: ^ΔP<0.05, ^ΔΔΔP<0.001.

Figure 3

Long-term effects induced by repeated administration of MDMA, given intraperitoneally (30 mg kg⁻¹) or intrastriatally (1, 10 and 100 μg) on the concentrations of dopamine (a, d) and DOPAC acid (b, e) in striatum and of 5-HT in striatum, hippocampus and cortex (c, f). Each dose was injected three times at 3-h intervals and mice killed 7 days after last injection. The results are shown as mean±s.e.m. (n=6–9). Difference from saline: ^***P<0.001. Difference from the corresponding ipsilateral side of saline-treated animals: ^ΔP<0.05.

Figure 4

Immediate effects induced by repeated administration of HHMA, given intraperitoneally (30 mg kg⁻¹) or intrastriatally (1, 10 and 100 μg) on the concentrations of dopamine (a, d) and DOPAC acid (b, e) in striatum and of 5-HT in striatum, hippocampus and cortex (c, f). Each dose was injected three times at 3-h intervals and mice killed 1 h after last injection. The results are shown as mean±s.e.m. (n=5–9). Difference from saline: ^*P<0.05. Differences from the corresponding ipsilateral side of saline-treated animals: ^ΔP<0.05, ^ΔΔΔP<0.001. Differences from the corresponding contralateral side of HHMA-treated animals: ^fP<0.05, ^fffP<0.001.

Figure 5

Long-term effects induced by repeated administration of HHMA, given intraperitoneally (30 mg kg⁻¹) or intrastriatally (1, 10 and 100 μg) on the concentrations of dopamine (a, d) and DOPAC acid (b, e) in striatum and of 5-HT in striatum, hippocampus and cortex (c, f). Each dose was injected three times at 3-h intervals and mice killed 7 days after last injection. The results are shown as mean±s.e.m. (n=5–10). Difference from the corresponding ipsilateral side of saline-treated animals: ^ΔP<0.05.

Figure 6

Rectal temperature of animals injected with MDMA or HHMA, intraperitoneally (30 mg kg⁻¹) or intrastriatally (100 μg) three times at 3-h intervals. Each value is the mean±s.e.m. of 12–18 mice. Intraperitoneal administration of MDMA or HHMA significantly increased the temperature compared to saline treatment (F(1,26)=218.8, P<0.001 and F(1,26)=11.16, P<0.001, respectively).

Figure 7

Plasma and striatal levels of MDMA and HHMA and metabolites 1 h after intraperitoneal injection of (a, b) MDMA (30 mg kg⁻¹) or (c, d) HHMA (30 mg kg⁻¹). The absence of bar for a given compound means that it was not detected.