An antisense oligonucleotide targeted at MAO-B attenuates rat striatal serotonergic neurotoxicity induced by MDMA.
The present study was designed to elucidate the role of dopamine (DA) metabolism in the serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA). An antisense (AS) oligonucleotide (ODN) sequence targeted at monoamine oxidase-B (MAO-B) was utilized to attenuate MAO-B activity prior to MDMA administration. Sprague-Dawley rats were surgically implanted with intracerebroventricular (icv) cannulae and received a continuous infusion of MAO-B AS-ODN via an osmotic minipump. Constant AS ODN infusion for 7 days at a rate of 0.5 microl/h (total daily dose 600 pmol) resulted in a 63% knockdown of MAO-B activity. MDMA (40 mg/kg, sc) produced a rise in body temperature within 1 h of MDMA administration and a reduction in striatal serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) levels 7 days later. Pretreatment with the MAO-B AS ODN prior to MDMA attenuated this reduction in serotonergic markers, yet had no effect on MDMA-induced hyperthermia. Furthermore, in vivo microdialysis revealed that previous AS ODN treatment failed to alter the acute DA release induced by MDMA (10 mg/kg, sc) within the striatum. These results indicate that MAO-B plays an integral role in the development of MDMA-induced neurotoxicity while not affecting MDMA-induced hyperthermia or acute DA release.
Falk
Erin M
EM
The Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, Ada 45810, USA.
Cook
Valerie J
VJ
Nichols
David E
DE
Sprague
Jon E
JE
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism* / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D012701:Serotonin; D008995:Monoamine Oxidase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine