The MAO-B inhibitor deprenyl, but not the MAO-A inhibitor clorgyline, potentiates the neurotoxicity of p-chloroamphetamine.
The effect of co-administration of MAO inhibitors together with a low dose of the neurotoxic amphetamine p-chloroamphetamine (pCA) on neurotoxicity was examined. Neurotoxicity was assessed by measuring decreases in the binding of [3H]cyanoimipramine to serotonin uptake sites using quantitative autoradiography. By itself, a low dose of pCA (2 mg/kg) did not produce any alterations in radioligand binding, measured 7 days after drug administration. However, co-administration of the MAO-B selective inhibitor deprenyl (1 mg/kg) or the non-selective inhibitor pargyline (50 mg/kg) produced significant decreases in radioligand binding. Measurements of the effects of these drugs on body temperature ruled out the possibility that deprenyl and pargyline were increasing neurotoxicity by producing a drug-induced hyperthermia. In contrast to the effects of deprenyl and pargyline, co-administration of the MAO-A selective inhibitor clorgyline (1 mg/kg) did not alter binding. By themselves none of the MAO inhibitors produced neurotoxic effects. There are a number of possible explanations for these results. Administration of deprenyl or pargyline, together with pCA, itself a MAO-A inhibitor, will lead to inhibition of both MAO-A and MAO-B activities. This will likely lead to an enhanced release of dopamine and serotonin compared with the release following administration of pCA alone or pCA together with clorgyline. Elevation of the extracellular levels of either or both of these monoamines could lead to enhanced neurotoxicity. Whatever the mechanism involved, our results show that the co-administration of a type-B MAOI enhances the neurotoxic effects of pCA on serotonin neurons.
Benmansour
S
S
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia.
Brunswick
D J
DJ
D000818:Animals; D001345:Autoradiography; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology; D003010:Clorgyline / Q000633:toxicity*; D004357:Drug Synergism; D020120:Iodocyanopindolol; D008297:Male; D009411:Nerve Endings / Q000502:physiology; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects; D010293:Pargyline / Q000494:pharmacology; D010869:Pindolol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects; D012642:Selegiline / Q000633:toxicity*; D012701:Serotonin / Q000502:physiology; D010133:p-Chloroamphetamine / Q000633:toxicity*
D011985:Receptors, Serotonin; D012642:Selegiline; D012701:Serotonin; D010133:p-Chloroamphetamine; D020120:Iodocyanopindolol; D010293:Pargyline; D010869:Pindolol; D003010:Clorgyline