Administration of neurotoxic doses of MDMA reduces sensitivity to ethanol and increases GAT-1 immunoreactivity in mice striatum.
BACKGROUND
Mice with reduced dopamine activity following neurotoxic doses of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') consume more ethanol (EtOH) and show greater preference for EtOH. In keeping with human studies and other animal models where alcohol consumption and preference are also high, MDMA treatment will reduce sensitivity to certain physiological effects of EtOH.


OBJECTIVE
We have examined the sensitivity to the acute effects of EtOH in MDMA-lesioned mice and the effects of EtOH on striatal gamma-aminobutyric acid (GABA) accumulation and expression of GABA subtype-1 transporter (GAT-1).


METHODS
C57BL/6J mice were injected with neurotoxic MDMA (30 mg/kg, three times, every 3 h, i.p.). Seven days later, mice were given EtOH (3 g/kg, i.p.) to determine the loss of righting response and the development of rapid tolerance to the hypothermic effect of EtOH. The effect of EtOH on the striatal accumulation of GABA after inhibiting GABA transaminase and on GAT-1 immunoreactivity was also determined.


RESULTS
Mice pre-treated with a neurotoxic dose of MDMA were less sensitive to the sedative-hypnotic effect of acute EtOH and exhibited alterations in the development of rapid tolerance to the hypothermic effect of EtOH. These animals showed an increase in striatal GAT-1 immunoreactivity. EtOH reduced GABA concentration in the striatum of non-lesioned mice, an effect not observed in MDMA-lesioned mice.


CONCLUSIONS
These findings indicate that mice with a MDMA-induced dopaminergic lesion show increased expression of striatal GAT-1 that may contribute to the lower sensitivity to EtOH-induced sedative effects and the resistance to the development of rapid tolerance to hypothermia produced by EtOH.
Izco
María
M
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
Gutierrez-Lopez
Maria Dolores
MD
Marchant
Ivanny
I
O'Shea
Esther
E
Colado
Maria Isabel
MI
D000428:Alcohol Drinking; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004361:Drug Tolerance; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D018490:Serotonin Agents / Q000633:toxicity; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism
D050485:GABA Plasma Membrane Transport Proteins; D018490:Serotonin Agents; C493414:Slc6a1 protein, mouse; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine