ergoline and alpha-methyltyrosine-methyl-ester

SCH 23390, a D-1 dopaminergic antagonist, was examined for its effects on the cholinergic system in rat brain. The compound raised the content of acetylcholine selectively in striatum and not in other brain areas including the hippocampus, nucleus accumbens, hemispheric residuum and midbrain-hindbrain, mirroring the action of dopaminomimetic drugs. That the increase in acetylcholine content reflected a depression of striatal cholinergic neuronal activity was substantiated by the drug's ability to inhibit sodium-dependent high affinity choline uptake, to reduce the electrically evoked release of [3H]acetylcholine from striatal slices in vitro and to reduce acetylcholine release from striatum in freely moving rats in vivo. The increase in striatal acetylcholine was prevented by the D-1 dopaminergic agonist, SK 38393-A, but not by the D-2 agonist, LY 171555. Inhibition of dopamine synthesis by DL alpha-methyltyrosine methyl ester HCI or the selective degeneration of nigrostriatal dopaminergic terminals by the neurotoxin 6-hydroxydopamine HBr prevented the acetylcholine increasing effect of SCH 23390 completely, suggesting that presynaptic dopamine is important in the action of the dopaminergic antagonist. In agreement with these findings, SCH 23390 amplified the action of amphetamine, a dopamine releaser, on striatal cholinergic neurons. Furthermore, blockade of D-2 receptors by pimozide or sulpiride did not suppress the cholinergic effect of SCH 23390. When combined with a subthreshold dose of LY 171555, SCH 23390 did not potentiate the action of the D-2 dopaminergic agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Amphetamine; Animals; Benzazepines; Choline; Corpus Striatum; Electric Stimulation; Ergolines; Female; Methyltyrosines; Quinpirole; Rats; Receptors, Dopamine; Receptors, Dopamine D1; Sodium; Synaptic Transmission; Tyrosine 3-Monooxygenase

The effects of various dopaminergic drugs on the spontaneous and veratrine-stimulated release of endogenous dopamine (DA) from superfused rat striatal slices have been examined using a high-sensitivity HPLC system. The DA uptake inhibitor nomifensine greatly increased both veratrine-stimulated and spontaneous DA release, whilst the effects of the more potent and selective inhibitor GBR 12921 were much smaller. The DA agonists pergolide and LY 171555 reduced both spontaneous and veratrine-stimulated DA release; conversely, the D-2 selective antagonist l-sulpiride stereospecifically increased spontaneous and veratrine-stimulated release, and blocked the effects of pergolide and LY 171555. Inhibition of DA synthesis did not directly influence the actions of either pergolide or sulpiride. These studies indicate that nomifensine may have a DA-releasing action in addition to its uptake blocking action, the regulation of endogenous DA release by D-2 autoreceptors shows properties similar to those reported previously for radiolabelled DA release, with the novel finding that spontaneous release is also regulated, the autoreceptors do not appear to selectively influence newly synthesised DA release.

Topics: Animals; Calcium; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Dopamine Antagonists; Ergolines; In Vitro Techniques; Male; Methyltyrosines; Nomifensine; Piperazines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Tetrodotoxin

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.

Topics: 3,4-Dihydroxyphenylacetic Acid; 5-Hydroxytryptophan; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Brain; Catecholamines; Dihydroxyphenylalanine; Ergolines; Lisuride; Male; Methyltyrosines; Rats; Rats, Inbred Strains; Receptors, Dopamine

Stereotyped responses to apomorphine, 2-bromo-alpha-ergocryptine (BEC) and lergotrile were compared in naive animals and after various pretreatments. Lergotrile was about half as effective as apomorphine in naive rats, while BEC produced intense stereotyped reactions only after pretreatment with p-chlorophenylalanine. Inhibitors of catecholamine biosynthesis (alpha-methyltyrosine and alpha-methyldopa) only impaired the response to BEC. Haloperidol, a dopamine antagonist, blocked the lergotrile-induced stereotypy within a few minutes, but had a rather slow effect on the response to BEC. It is concluded that lergotrile mainly activates dopamine receptors directly, similar to apomorphine. BEC, however, has a predominantly indirect effect, stimulating the formation and subsequent release of both dopamine and 5-hydroxytryptamine. The relationship of this difference in mechanism to the differences in structure is discussed.

Topics: Animals; Apomorphine; Bromocriptine; Drug Interactions; Ergolines; Fenclonine; Haloperidol; Humans; Male; Methyldopa; Methyltyrosines; Rats; Stereotyped Behavior; Stimulation, Chemical