Effect of lisuride and other ergot derivatives on monoaminergic mechanisms in rat brain

Abstract

The effects of the ergot derivative lisuride hydrogen maleate on synthesis, turnover and receptor activity of monoamines were compared with those of LSD, methysergide, yohimbine and methiothepin. In the dopamine (DA) rich areas, c. striatum and mesolimbic forebrain, lisuride, (30-100 mug/kg) decreased the rate of dopa formation after inhibition of the aromatic amino acid decarboxylase with NSD 1015, 100 mg/kp i.p. After axotomy of the ascending monoaminergic fibers, lisuride (0.5 mg/kg) antagonized the accumulation of dopa in c. striatum and mesolimbic forebrain even on the lesioned side; haloperidol effectively counteracted this lisuride-induced decrease in dopa formation. In the predominantly noradrenaline (NA)-innervated neocortex, lisuride in doses of 0.3 and 1.0 mg/kg increased dopa accumulation. Methysergide, yohimbine and methiothepin also stimulated tyrosine hydroxylation. After inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine methylester HCl, lisuride decelerated DA disappearance and accelerated NA disappearance. 3-Methoxytryramine (3-MY) accumulating after inhibition of monoamine axidase with pargyline HCl (100 mg/kg) was used as an indicator of DA release. Lisuride and LSD, 50 mug/kg administered twice, reduced 3-MT formation while methysergide, 50 mg/kp i.p. had no effect on 3-MT accumulation. All compounds except methiothepin reduced 5-hydroxytryptophan (5-HTP) accumulation in whole brain after NSD 1015. In addition, lisuride caused an increase in 5-hydroxytryptamine (5-HT) and a decrease in 5-hydroxyindole acetic acid concentration. In spinal reserpinized rats, lisuride was indistinguishable from LSD in inducing extension and athetoid movements of the hind legs. The data support the view that lisuride stimulates pre- and postsynaptic DA and 5-HT receptors and suggest that lisuride blocks NA receptors in the central nervous system.