5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis

Eur Neuropsychopharmacol. 2014 Aug;24(8):1362-70. doi: 10.1016/j.euroneuro.2014.04.009. Epub 2014 May 10.

Abstract

Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150-290%) but remarkably increased 5-HT levels (540-900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

Keywords: 5-hydroxytryptamine; Amphetamines; Dopamine; Microdialysis; Monoamine oxidase.

Publication types

  • Comparative Study

MeSH terms

  • Amphetamines / pharmacology*
  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Central Nervous System Stimulants / pharmacology*
  • Chromatography, High Pressure Liquid
  • Dopamine / metabolism*
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism
  • Hydroxyindoleacetic Acid / pharmacology
  • Inhibitory Concentration 50
  • Male
  • Microdialysis
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology
  • Rats
  • Rats, Wistar
  • Serotonin / metabolism*
  • Time Factors

Substances

  • Amphetamines
  • Central Nervous System Stimulants
  • Serotonin
  • Hydroxyindoleacetic Acid
  • 4-methylthioamphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Dopamine