Reduced turnover of dopamine and 5-hydroxytryptamine in discrete dopaminergic, noradrenergic and serotonergic rat brain areas after acutely administered medetomidine, a selective alpha 2-adrenoceptor agonist.
Monoamine metabolism and turnover were investigated in discrete dopaminergic, noradrenergic and serotonergic brain areas in the rat after acute administration of the selective alpha 2-adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 micrograms/kg subcutaneously) was given 90 min. before decapitation and discrete brain nuclei were punched from frozen brain slices for the analysis of concentrations of noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). In a separate experiment, the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) was measured after inhibition of L-aromatic amino acid decarboxylase by NSD 1015: medetomidine (3, 10 and 100 micrograms/kg subcutaneously) was given 60 min. before NSD 1015 (100 mg/kg intraperitoneally), and the rates of DOPA and 5-HTP accumulation were determined over 30 min. Finally, the antagonistic effect of idazoxan (1 mg/kg subcutaneously), a selective alpha 2-adrenoceptor blocking agent, on the medetomidine-induced changes in monoamine metabolism was investigated. Medetomidine markedly decreased the metabolism and turnover of DA in the nucleus caudatus, but not in the nucleus accumbens or substantia nigra. In all dopaminergic areas, the turnover of 5-HT was markedly inhibited by medetomidine. These effects were significantly counteracted by idazoxan pretreatment demonstrating the alpha 2-receptor mediated action of medetomidine. The turnover of 5-HT was also reduced by medetomidine in the nucleus raphe dorsalis, the A1-C1 area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the A1-C1 area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus.(ABSTRACT TRUNCATED AT 250 WORDS)
Koulu
M
M
Department of Pharmacology, University of Turku, Finland.
Pesonen
U
U
Koskinen
S
S
Scheinin
H
H
Virtanen
R
R
Scheinin
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D015306:Biogenic Monoamines; D004146:Dioxanes; D006834:Hydrazines; D007093:Imidazoles; D011941:Receptors, Adrenergic; C004297:3-hydroxybenzylhydrazine; D020926:Medetomidine; D019329:Idazoxan