Effect of acute brain tyrosine depletion on MDMA-induced changes in brain 5-HT.
The mechanism by which 3,4-methylenedioxymethamphetamine (MDMA) produces 5-hydroxytryptamine (5-HT, serotonin) neurotoxicity has been suggested to involve an acute release of tyrosine and its non-enzymatic conversion to dopamine. To determine whether brain tyrosine availability is important in MDMA-induced neurotoxicity, brain tyrosine was acutely depleted with a tyrosine-free amino acid mixture (1 g/kg intraperitoneal; twice 1 h apart) which was administered prior to an injection of MDMA (12.5 mg/kg intraperitoneal). A small increase in both the hippocampal and striatal tyrosine concentration occurred in control rats treated with MDMA. The tyrosine-free amino acid mixture significantly decreased tyrosine levels by more than 50% in both brain regions 2 h after injection of either MDMA or saline. MDMA significantly reduced brain 5-HT content 2 h later, but this was of a similar magnitude in control and tyrosine-depleted groups. The long-term neurotoxic 5-HT loss in the hippocampus induced two weeks after MDMA administration was unaltered by the tyrosine-free amino acid mixture. Striatal dopamine content was unaffected by acute MDMA in all groups, while the tyrosine-free amino acid mixture given with MDMA significantly decreased striatal dopamine content 2 weeks later. The tyrosine-free amino acid mixture given alone had no affect on rectal body temperature but attenuated the duration of MDMA-induced hyperthermia. The results confirmed the ability of systemic MDMA to acutely increase brain tyrosine content, but also indicated that a marked acute reduction of brain tyrosine does not directly affect either immediate 5-HT release (as measured by tissue depletion) or long-term hippocampal serotonergic neurotoxicity produced by MDMA.
Rodsiri
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R
School of Biomedical Sciences, Institute of Neuroscience, University of Nottingham, Nottingham, UK.
Green
A R
AR
Marsden
C A
CA
Fone
K C F
KC
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005334:Fever / Q000139:chemically induced; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity; D013997:Time Factors; D014443:Tyrosine / Q000172:deficiency / Q000378:metabolism*
D018490:Serotonin Agents; D012701:Serotonin; D014443:Tyrosine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine