ergoline and 3-hydroxybenzylhydrazine

Using adrenal dopamine as indicator we have previously obtained evidence that quinpirole and several other agonists on dopamine D2-like receptors acutely stimulate the synthesis of adrenal catecholamines. In the present study we measured the effect of quinpirole and dopamine on the hydroxylation of tyrosine in the adrenals, using the method of DOPA (3,4-dihydroxyphenylalanine) accumulation following the administration of the inhibitor of aromatic L-amino acid decarboxylase NSD 1015 (3-hydroxybenzylhydrazyne). In view of the large amounts of catecholamines in the adrenal tissue samples, this necessitated a modification of the method for analysing DOPA. Both quinpirole and dopamine significantly enhanced the rate of DOPA accumulation in the adrenals, indicating stimulation of adrenal tyrosine hydroxylase. The effect of dopamine was blocked by domperidone, a dopamine D2 receptor antagonist that penetrates poorly into the central nervous system. Thus the effect of dopamine, which itself penetrates poorly into the central nervous system, was presumably mediated peripherally. Similarly epinine, i.e. the N-methyl derivative of dopamine, appeared to enhance adrenal catecholamine synthesis, as indicated by an elevated adrenal dopamine level. The data support the view that stimulation of peripherally located dopamine D2-like receptors can enhance the rate of adrenal catecholamine synthesis by stimulating the activity of tyrosine hydroxylase.

Topics: Adrenal Glands; Adrenal Medulla; Analysis of Variance; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Catecholamines; Chromatography, High Pressure Liquid; Deoxyepinephrine; Dihydroxyphenylalanine; Domperidone; Dopamine; Dopamine Agonists; Ergolines; Hydrazines; Hydroxylation; Injections, Subcutaneous; Male; Myocardium; Prosencephalon; Quinpirole; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tyrosine; Tyrosine 3-Monooxygenase

The aminoergolines SDZ-208-911, -208-912, and -212-327, weak partial D2 agonists with agonist/antagonist properties, are proposed as potential atypical antipsychotic agents with limited risk of extrapyramidal effects or hyperprolactinemia. The in vivo effects on dopamine (DA) metabolism in limbic (accumbens) and extrapyramidal (striatum) regions of rat brain were evaluated by measuring the accumulation of L-dihydroxyphenylalanine (DOPA) after inhibiting decarboxylation alone ("open-loop" model) or with added gamma-butyrolactone (GBL, autoreceptor model). All three aminoergolines markedly increased DOPA in both regions, dose-dependently, with only minor decreases when GBL was included, and so evidently lack appreciable agonist activity at D2-like autoreceptors and resemble typical neuroleptics in stimulating DA synthesis, without regional selectivity.

Topics: 4-Butyrolactone; Animals; Dihydroxyphenylalanine; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Extrapyramidal Tracts; Hydrazines; Limbic System; Male; Rats; Rats, Sprague-Dawley

A non-effective dose of exogenously applied L-dopa itself stereoselectively potentiates postsynaptic D2 receptor-mediated locomotor activities of rats. We further attempted to clarify whether or not endogenously released L-dopa tonically functions to potentiate activities of these receptors, simultaneously monitoring locomotor activities and basal release of L-dopa and dopamine during striatal microdialysis in conscious rats. Quinpirole (1 mg/kg, s.c.) alone, a selective D2 agonist, increased locomotor activities and decreased basal L-dopa and dopamine release 20-140 min after injection. Pretreatment with alpha-methyl-p-tyrosine (3 mg/kg, i.p.), a tyrosine hydroxylase inhibitor, decreased locomotor activities and further decreased L-dopa release without modification of dopamine release, compared to quinpirole alone, whereas 3-hydroxybenzylhydrazine (100 mg/kg, i.p.), a central dopa decarboxylase inhibitor, further increased locomotor activities and markedly increased L-dopa release without modification of dopamine release. Endogenously released L-dopa itself functions tonically to potentiate activities of postsynaptic D2 receptors relevant to locomotor movement of rats.

Topics: alpha-Methyltyrosine; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Dihydroxyphenylalanine; Dopamine; Dopamine Agents; Ergolines; Hydrazines; Male; Methyltyrosines; Microdialysis; Motor Activity; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Stereoisomerism; Tyrosine 3-Monooxygenase

We attempted to clarify whether or not under inhibition of central dopa decarboxylase non-effective i.p. doses of L-dopa potentiate D2 receptor-mediated locomotor activities without conversion to dopamine in normal and i.v.t. 6-hydroxydopamine-treated rats. In normal rats, only the highest dose of quinpirole, a selective D2 agonist, at ranges used (0.01-1 mg/kg, s.c.) slightly increased the total counts of locomotor activities for 140 min after injection. A simultaneously injected non-effective dose of L-DOPA (30 mg/kg) potentiated locomotor activities by quinpirole (0.1 and 1 mg/kg). L-dopa potentiated quinpirole (1 mg/kg)-induced locomotor activities 90 to 140 min after the injection with marked increase in basal release of L-DOPA without increase in dopamine release simultaneously monitored during striatal microdialysis, compared to quinpirole alone. D-dopa (30 mg/kg) produced no potentiation. In 6-hydroxydopamine-treated rats, a non-effective dose of L-dopa (10 mg/kg) also potentiated quinpirole (0.3 mg/kg)-induced locomotor activities. L-dopa acting on a recognition site for itself stereoselectively potentiates postsynaptic D2 receptor-mediated locomotor activities of rats.

Topics: Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Desipramine; Dopamine Agents; Ergolines; Hydrazines; Injections, Intraventricular; Levodopa; Male; Microdialysis; Motor Activity; Nerve Fibers; Oxidopamine; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Stereoisomerism

The effects of D2 dopamine (DA) receptor antagonism or stimulation by systemic haloperidol or quinpirole, respectively, on in vivo DA synthesis in 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated black mice were assessed by measuring the rate of dihydroxyphenylalanine (DOPA) accumulation following acute inhibition of L-aromatic amino acid decarboxylase with NSD-1015. 6-OHDA and MPTP caused partial lesions of nigrostriatal input to the striatum. Dopamine synthetic capacity was preserved relative to the severity of nigrostriatal lesion over a broad range of DA depletions. An exponential increase in fractional DA synthesis (the ratio DOPA/DA) was observed with increasing DA depletion, suggesting an elevation of the DA synthetic capacity per surviving DA terminal. In both lesioned rats and mice, haloperidol caused a significant increase in fractional DA synthesis above that induced by the lesion alone, while quinpirole significantly depressed fractional DA synthesis. Our results provide evidence that nigrostriatal terminals acquire increased DA synthetic capacity as nigrostriatal lesions exceed 90%, but that the increase in fractional DA synthesis observed in partially lesioned animals is not due to a loss of autoreceptor function. Pharmacological strategies to stimulate DA synthesis and release in moderately advanced Parkinson's disease should be pursued.

Topics: Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Ergolines; Haloperidol; Hydrazines; Kinetics; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning; Oxidopamine; Parkinson Disease, Secondary; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reference Values

The rate of brain monoamine synthesis was estimated in the rat by measuring the accumulation of dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) following inhibition of cerebral aromatic amino acid decarboxylase by NSD-1015 (475 mumol/kg, i.p., 30 min before decapitation). As expected, pretreatment with reserpine, (8.2 mumol/kg, s.c., -18 h) produced a marked and statistically significant increase in the DOPA accumulation in the ventral striatum and in the neocortex, whereas only minor changes were noted in 5-HTP accumulation in the same brain areas. The administration of terguride or quinpirole (30 mumol/kg, s.c., -65 min) resulted in both cases in an antagonism of the reserpine-induced increase in the DOPA accumulation. The effect was less marked in the neocortex than in the ventral striatum, but there was no difference between the effects produced by either compound. In contrast, the two drugs produced opposite effects on the 5-HTP accumulation in the ventral striatum as well as in the neocortex. Thus, there was a decrease and an increase in the 5-HTP accumulation by terguride and quinpirole administration, respectively. Together the results suggest that, in the reserpine treated rat, both terguride and quinpirole to the same degree stimulate dopamine receptors in the ventral striatum and noradrenaline receptors in the neocortex. To the extent that serotonin receptors in these two brain areas mediate the effects on 5-HTP accumulation of terguride and quinpirole, respectively, these receptors appear differently affected by the two compounds: stimulation by terguride and blockade by quinpirole.

Topics: Animals; Brain; Cerebral Cortex; Corpus Striatum; Dihydroxyphenylalanine; Dopamine Agents; Ergolines; Hydrazines; Lisuride; Male; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Serotonin; Reference Values; Reserpine; Serotonin

Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic L-amino acid decarboxylase by means of NSD-1015, 100 mg kg-1 intraperitoneally. In animals treated with reserpine, 5 mg kg-1 subcutaneously -18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT1A receptor agonist 8-OH-DPAT, 0.15-2.4 mumol kg-1, whereas the partial dopamine D2 receptor agonist (-)3-PPP, 2.5-10.0 mumol kg-1, or the full dopamine D2 receptor agonist quinpirole, 0.05-0.8 mumol kg-1, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mumol kg-1, but not by (-)pindolol, 8 mumol kg-1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (-)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5-Hydroxytryptophan; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Corpus Striatum; Depression, Chemical; Dihydroxyphenylalanine; Dopamine; Ergolines; Hydrazines; Limbic System; Male; Naphthalenes; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Reserpine; Serotonin; Tetrahydronaphthalenes; Tryptophan Hydroxylase; Tyrosine 3-Monooxygenase