THE MAO-B INHIBITOR DEPRENYL, BUT NOT THE MAO-A INHIBITOR CLORGYLINE, POTENTIATES THE NEUROTOXICITY OF P-CHLOROAMPHETAMINE

被引:15
作者
BENMANSOUR, S
BRUNSWICK, DJ
机构
[1] UNIV PENN,SCH MED,DEPT PSYCHIAT,PHILADELPHIA,PA 19104
[2] DEPT VET AFFAIRS MED CTR,NEUROPSYCHOPHARMACOL UNIT,PHILADELPHIA,PA 19104
关键词
P-CHLOROAMPHETAMINE; NEUROTOXICITY; SEROTONIN UPTAKE SITE; MONOAMINE OXIDASE; PARGYLINE; DEPRENYL; CLORGYLINE;
D O I
10.1016/0006-8993(94)91796-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 [H-3]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.
引用
收藏
页码:305 / 312
页数:8
相关论文
共 45 条
[1]   ALPHA-METHYL-PARA-TYROSINE PARTIALLY ATTENUATES PARA-CHLOROAMPHETAMINE-INDUCED 5-HYDROXYTRYPTAMINE DEPLETIONS IN THE RAT-BRAIN [J].
AXT, KJ ;
SEIDEN, LS .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1990, 35 (04) :995-997
[2]   EFFECT OF ACUTE MONOAMINE DEPLETION ON 3,4-METHYLENEDIOXYMETHAMPHETAMINE-INDUCED NEUROTOXICITY [J].
BRODKIN, J ;
MALYALA, A ;
NASH, JF .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1993, 45 (03) :647-653
[3]   EFFECTS OF SELECTIVE MONOAMINE-OXIDASE INHIBITORS ON THE INVIVO RELEASE AND METABOLISM OF DOPAMINE IN THE RAT STRIATUM [J].
BUTCHER, SP ;
FAIRBROTHER, IS ;
KELLY, JS ;
ARBUTHNOTT, GW .
JOURNAL OF NEUROCHEMISTRY, 1990, 55 (03) :981-988
[4]   MONOAMINE-OXIDASE INHIBITORS INCREASE PREFERENTIALLY EXTRACELLULAR 5-HYDROXYTRYPTAMINE IN THE MIDBRAIN RAPHE NUCLEI - A BRAIN MICRODIALYSIS STUDY IN THE AWAKE RAT [J].
CELADA, P ;
ARTIGAS, F .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1993, 347 (06) :583-590
[5]   ENDOGENOUSLY PRODUCED 5,6-DIHYDROXYTRYPTAMINE MAY MEDIATE THE NEUROTOXIC EFFECTS OF PARA-CHLOROAMPHETAMINE [J].
COMMINS, DL ;
AXT, KJ ;
VOSMER, G ;
SEIDEN, LS .
BRAIN RESEARCH, 1987, 419 (1-2) :253-261
[6]   5,6-DIHYDROXYTRYPTAMINE, A SEROTONERGIC NEUROTOXIN, IS FORMED ENDOGENOUSLY IN THE RAT-BRAIN [J].
COMMINS, DL ;
AXT, KJ ;
VOSMER, G ;
SEIDEN, LS .
BRAIN RESEARCH, 1987, 403 (01) :7-14
[7]   STRUCTURE-MODULATED RECOGNITION OF SUBSTRATES AND INHIBITORS BY MONOAMINE OXIDASE-A AND OXIDASE-B [J].
DOSTERT, P ;
BENEDETTI, MS .
BIOCHEMICAL SOCIETY TRANSACTIONS, 1991, 19 (01) :207-211
[8]  
FEINGOLD E, 1986, EXPT BIOL MED, V11, P175
[9]   THE METABOLISM OF DOPAMINE BY BOTH FORMS OF MONOAMINE-OXIDASE IN THE RAT-BRAIN AND ITS INHIBITION BY CIMOXATONE [J].
FOWLER, CJ ;
BENEDETTI, MS .
JOURNAL OF NEUROCHEMISTRY, 1983, 40 (06) :1534-1541
[10]   HYPERTHERMIA INDUCED BY AMPHETAMINE, P-CHLOROAMPHETAMINE AND FENFLURAMINE IN RAT [J].
FREY, HH .
PHARMACOLOGY, 1975, 13 (02) :163-176