Effect of 5-HT depletion by MDMA on hyperthermia and Arc mRNA induction in rat brain.
BACKGROUND
3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces an acute hyperthermic response and induces localised neuronal activation, which can be visualised via expression of immediate-early genes. The pharmacological and anatomical basis of these effects are unclear. At high doses, MDMA also causes selective neurotoxicity at serotonergic nerve terminals.


OBJECTIVE
We investigated the effect of 5-hydroxytryptamine (5-HT) depletion on the acute hyperthermic response to MDMA and the pattern of neuronal excitation indicated by Arc (activity-regulated cytoskeleton associated gene) in naive rats and following administration of MDMA at a neurotoxic dose.


METHODS
Expression of Arc mRNA was investigated by in situ hybridisation histochemistry using 35S-labelled oligonucleotide probe.


RESULTS
MDMA induced a significant hyperthermia together with increased Arc mRNA expression in cortical regions, caudate-putamen and CA1 hippocampus but not hypothalamus. At 21 days after a neurotoxic dose of MDMA, brain 5-HT and 5-HIAA levels were significantly reduced by 21-32%. In these animals, both the hyperthermic response and the pattern and extent of Arc mRNA expression induced by a subsequent dose of MDMA were unaltered. However, basal Arc expression was significantly increased in cortical regions and CA1 hippocampus.


CONCLUSIONS
We conclude that the acute hyperthermic response induced by MDMA is not attenuated by moderate depletion of 5-HT, further questioning mediation via a serotonergic mechanism. Arc mRNA induction by MDMA exhibits highly localised expression, which is not altered following 5-HT depletion. However, following a neurotoxic dose of MDMA, basal expression of Arc is increased, particularly in cortex and CA1, suggesting that mechanisms underlying synaptic plasticity might also be modified.
Beveridge
Thomas J R
TJ
School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
Mechan
Annis O
AO
Sprakes
Marie
M
Pei
Qi
Q
Zetterstrom
Tyra S C
TS
Green
A Richard
AR
Elliott
J Martin
JM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005334:Fever / Q000139:chemically induced / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D017403:In Situ Hybridization; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000633:toxicity*
D003598:Cytoskeletal Proteins; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012702:Serotonin Antagonists; C092069:activity regulated cytoskeletal-associated protein; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine