dironyl and alpha-methyltyrosine-methyl-ester

In adult rats, the partial D(2)-like agonist terguride acts as an antagonist at normosensitive D(2)-like post-synaptic receptors, while it acts as an agonist at the same receptors during states of low dopaminergic tone.. The purpose of the present study was to determine whether partial D(2)-like agonists exhibit both antagonistic and agonistic actions during the preweanling period.. In experiments 1 and 2 (examining the agonistic actions of terguride), preweanling rats were either given an escalating regimen of amphetamine to induce a state of amphetamine withdrawal or pretreated with the tyrosine hydroxylase inhibitor AMPT. Distance traveled was measured after rats were injected with saline, terguride (0.4-1.6 mg/kg), or the full D(2)-like receptor agonist NPA (0.01 mg/kg). In experiment 3 (examining the antagonistic actions of terguride), preweanling rats were pretreated with terguride 30 min before they were tested with saline, NPA (0.05 mg/kg), or amphetamine (1.5 mg/kg).. NPA had an exaggerated locomotor activating effect when tested under conditions of amphetamine withdrawal, while the partial D(2)-like agonist did not enhance distance traveled under any circumstance. Similarly, NPA increased and terguride did not affect the distance-traveled scores of AMPT-pretreated rats. In experiment 3, terguride pretreatment significantly reduced the distance traveled of amphetamine-treated and NPA-treated rats.. The behavioral evidence indicates that, during the preweanling period, terguride antagonizes D(2)-like post-synaptic receptors in a state of high dopaminergic tone; however, there is no evidence that terguride is capable of stimulating D(2)-like post-synaptic receptors during states of low dopaminergic tone.

Topics: Animals; Animals, Newborn; Apomorphine; Body Weight; Corpus Striatum; Dextroamphetamine; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Hyperkinesis; Lisuride; Methyltyrosines; Motor Activity; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Substance Withdrawal Syndrome; Tyrosine 3-Monooxygenase

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