Transdihydrolisuride, a partial dopamine receptor antagonist: effects on monoamine metabolism

The 9,10-transdihydro analogue of the dopaminergic ergot derivative lisuride, transdihydrolisuride (TDHL) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl in striatum (0.1-10 mg/kg i.p.), in the dopamine rich part of the limbic system (at 3 mg/kg i.p.) and in the neocortex (0.3-10 mg/kg i.p.). At a low dose (0.03 mg/kg) however, TDHL inhibited dopa accumulation in the limbic system. In gamma-butyrolactone-pretreated rats TDHL not only inhibited the accumulation of dopa in striatum and in the dopamine-rich part of the limbic system but also antagonized the inhibitory effect of lisuride on dopa accumulation. The accumulation of 5-hydroxytryptophan was reduced in striatum, in parts of the limbic system and neocortex only at high doses of TDHL (3 and 10 mg/kg i.p.). TDHL (0.03 or 3 mg/kg i.p.) did not change the alpha-methyl-p-tyrosine methylester HCl-induced disappearance of dopamine but accelerated the disappearance of noradrenaline at a dose of 3 mg/kg in all brain regions studied. The striatal level of dihydroxyphenylacetic acid was increased by TDHL dose dependently, the maximum effect being only half of that induced by haloperidol. TDHL (0.3 and 3 mg/kg i.p.) stimulated the accumulation of 3-methoxytyramine and normetanephrine following monoamine oxidase (MAO) inhibition with pargyline. The data suggest that TDHL is a mixed agonist-antagonist at central dopamine receptors. Under normal conditions the antagonistic component appears to predominate in the nigrostriatal and mesolimbic system. The stimulation of noradrenaline turnover was most likely due to an adrenoceptor antagonistic action of TDHL.