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Acceleration of serotonin transporter transport-associated current by 3,4-methylenedioxymethamphetamine (MDMA) under

Yosuke Yamauchi1, Takaya Izumi, Kazuhiro Unemura

  • 1Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

Neuroscience Letters
|October 24, 2007
PubMed

Insights

Acidic conditions enhance the effects of 3,4-Methylenedioxymethamphetamine (MDMA) on the serotonin transporter (SERT). This suggests MDMA

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • 3,4-Methylenedioxymethamphetamine (MDMA) is known to release serotonin (5-HT) via the serotonin transporter (SERT).
  • Increased central nervous system (CNS) lactate levels, indicated by a rise in H+ concentration, have been observed with MDMA use.
  • The functional states of SERT and their modulation by pH are not fully understood.

Purpose of the Study:

  • To investigate the impact of physiological changes in H+ concentration (acidity) on SERT function.
  • To determine how altered pH affects the transport kinetics and substrate binding of SERT.
  • To elucidate the mechanism underlying MDMA's interaction with SERT under varying pH conditions.

Main Methods:

  • Expression of SERT in Xenopus oocytes to study transporter function.
  • Electrophysiological recordings to measure transport-associated currents and leak currents.
  • Dose-response experiments using various SERT substrates (5-HT, MDMA, dopamine, norepinephrine) at different pH levels (7.4 and 6.4).
  • Kinetic analysis to determine Km (Michaelis-Menten constant) and Ki (inhibition constant) values.

Main Results:

  • SERT substrates exhibited a rank order of potency of 5-HT > MDMA > dopamine >> norepinephrine for transport-associated currents at pH 7.4.
  • A transient Na+ leak current, inhibited by SERT substrates and citalopram, was observed in the absence of transport substrates.
  • At pH 6.4, the Km for MDMA transport was reduced threefold, indicating enhanced transport, while Km for 5-HT and dopamine remained unchanged.
  • The Ki values for the inhibition of the transient leak current by substrates and citalopram were unaffected by the pH change, suggesting binding affinity is preserved.

Conclusions:

  • The affinity of MDMA and other substrates for SERT binding sites is not significantly altered by acidic conditions.
  • Acidic conditions (lower pH) enhance the transport activity of MDMA through the serotonin transporter.
  • These findings suggest that the psychostimulant and neurochemical effects of MDMA may be potentiated in environments with increased H+ concentration.

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