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 alpha2-adrenoceptor agonist, medetomidine. Medetomidine (3, 30 and 100 mug/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 mug/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 alpha2-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 alpha2-receptor mediated action of medetomidine. The turnover of 5-HT was also reduced by medetomidine in the nucleus raphe dorsalis, the Al-Cl area, locus coeruleus, nucleus tractus solitarius and the A5 area. The accumulation of DOPA was markedly inhibited in the Al-Cl area, nucleus tractus solitarius and nucleus raphe dorsalis, but not in locus coeruleus. In these brain stem areas the accumulation of DOPA mainly takes place in noradrenergic neurones and thus reflects the in vivo rate of synthesis of NA. It is concluded that in spite of the proven alpha2-adrenoceptor selectivity and specificity of medetomidine it has marked effects on the metabolism and turnover of other neurotransmitters in addition to NA. This is in agreement with the wide distribution of alpha2-adrenoceptors in the central nervous system. Furthermore, it suggests that important interactions take place between different monoaminergic neurones, reducing the in vivo selectivity of drug actions.