Effects of harmine on dopamine output and metabolism in rat striatum: role of monoamine oxidase-A inhibition.
In vivo microdialysis was used to investigate the effects of acute injections of harmine on extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxindoleacetic acid (5-HIAA) in the striatum of awake rats. Administration of harmine in doses of 0.5, 2.5, and 10 mg/kg (i.p.) elicited a dose-dependent increase of the dopamine efflux to 152, 173, and 243% and a decrease in DOPAC to 52, 36, and 10%, and HVA to 67, 45, and 20% throughout, respectively; 5-HIAA concentrations were decreased to 81, 74, and 72% only. In contrast to D-amphetamine, which also increases dopamine release and decreases its metabolites, the stimulatory action of harmine on dopamine release in the striatum was totally abolished in the presence of tetrodotoxin (1 microM). Similar to monoamine oxidase (MAO)-A inhibitors, harmine potentiated the stimulatory effect of D-amphetamine (10 microM), infused by reverse microdialysis in the striatum, on dopamine release. Pre-treatment with the benzodiazepine receptor antagonist flumazenil (5 mg/kg, i.p.) did not modulate the effect of harmine on striatal dopamine release and metabolism. Administration of the reversible MAO-A inhibitor, moclobemide (20 mg/kg, i.p.), induced an increase in dopamine to 256% and a decrease in DOPAC, HVA, and 5-HIAA to 30, 24, and 62%, respectively, reproducing a pattern similar to that of harmine. Taken together, these results indicate that harmine affects the brain dopamine system probably by acting as a MAO-A inhibitor and not as an inverse agonist for the benzodiazepine receptors.
Iurlo
M
M
Department of Physiology and Pharmacology, Division of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Leone
G
G
Schilström
B
B
Linnér
L
L
Nomikos
G
G
Hertel
P
P
Silvestrini
B
B
Svensson
H
H
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D015314:Dialysis Solutions / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006247:Harmine / Q000494:pharmacology*; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism / Q000502:physiology*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D015314:Dialysis Solutions; D008996:Monoamine Oxidase Inhibitors; D006247:Harmine; D008995:Monoamine Oxidase; D004298:Dopamine