Inhibition of MAO-A fails to alter cocaine-induced increases in extracellular dopamine and norepinephrine in rat nucleus accumbens.
Monoamine oxidase (MAO) inhibitors are being investigated as possible medications for cocaine dependence, but there are potential problems with this approach. In the present study, we tested the hypothesis that inhibition of catecholamine metabolism with the MAO-A inhibitor, clorgyline, might enhance cocaine-induced increases in extracellular dopamine and norepinephrine in rat nucleus accumbens. Male rats were pretreated with clorgyline (1 mg/kg, s.c.) or its saline vehicle (1 ml/kg, s.c.), and microdialysis probes were inserted into previously implanted guide cannulae. After overnight perfusion of the probes in situ, rats received an acute challenge injection of either cocaine (1 mg/kg, i.v.) or its saline vehicle (1 ml/kg, i.v.). Clorgyline pretreatment alone caused significant elevations in basal levels of dialysate norepinephrine but not dopamine. Cocaine administration elicited significant increases in extracellular dopamine and norepinephrine in all groups of rats, and this effect was not altered by clorgyline pretreatment. The 1 mg/kg dose of clorgyline decreased dopamine metabolites in postmortem brain tissue by more than 80%. Our data are consistent with clinical studies that demonstrate pretreatment with the MAO-B selective inhibitor, selegeline, fails to alter cocaine-induced subjective effects in human drug users. Moreover, these findings suggest that adverse consequences related to altered catecholamine transmission would not occur if patients taking phenelzine, a non-selective MAO inhibitor, relapsed and used cocaine.
Clinical Psychopharmacology Section, Intramural Research Program, NIDA, NIH, P.O. Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
J P
JP
Pepper
M H
MH
Baumann
M
M
Ayestas
R B
RB
Rothman
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003010:Clorgyline / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase; D003042:Cocaine; D003010:Clorgyline; D004298:Dopamine; D009638:Norepinephrine