ergoline and quinelorane

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.

Topics: Animals; Antiparkinson Agents; Apomorphine; Azepines; Benzothiazoles; Cabergoline; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Ergolines; Indoles; Injections, Intraventricular; Male; Mice; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pramipexole; Quinolines; Receptors, Dopamine D2; Tetrahydronaphthalenes; Thiophenes

Central cardiovascular effects of the dopamine D2 receptor agonist quinpirole were studied in conscious rats. The i.v. injection of 0.3 mg/kg of quinpirole in spontaneously hypertensive rats (SHR) caused a rapid but short-lasting increase in blood pressure. Heart rate showed little change. Pretreatment with the centrally acting selective dopamine D2 receptor antagonist raclopride, but not the D1 antagonist SCH23390, completely prevented the rise in blood pressure. A second injection of quinpirole, 30 min after the first injection, induced little change in blood pressure, although at 4 or 24 hr after quinpirole treatment, we observed partial and complete recovery of the pressor response, respectively. This pattern of desensitization was similar to that seen after administration of the dopamine D2 receptor agonists N-propylnorapomorphine (0.3 mg/kg) or quinelorane (0.1 mg/kg), and was similar in spontaneously hypertensive rats, Wistar Kyoto and Sprague-Dawley rats. At 30 min after treatment with quinpirole, the hypotension induced by i.v. injection of clonidine (0.01 mg/kg) or of 8-hydroxy-dipropylaminotetralin (0.1 mg/kg) was markedly reduced when compared to that in saline-pretreated spontaneously hypertensive rats, suggesting a prolonged effect of quinpirole at the level of sympathetic regulation. The rapid fall in blood pressure caused by i.v. injection of the ganglion blocker pentolinium (10 mg/kg) was slightly, but significantly enhanced by treatment with quinpirole, which suggests an overall prolonged increase in resting sympathetic vasomotor tone. This would be difficult to reconcile with an inhibition of the action of sympatholytic drugs, unless it is hypothesized that the increase in sympathetic vasomotor tone was differential between different sympathetic beds or different neuronal populations in the brain. This may prohibit any additional pressor responses and, through a central feedback mechanism, may inhibit the action of sympatholytic drugs. No evidence was found for lasting changes in circulating levels of vasopressin, angiotensin or atrial natriuretic factor, nor were there changes in hematocrit. Cardiac sympathetic tone appeared to be enhanced, although vagal tone was normal and no major changes in baroreflex sensitivity were observed.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Benzazepines; Blood Pressure; Brain; Clonidine; Dopamine Agonists; Ergolines; Heart Rate; Male; Quinolines; Quinpirole; Raclopride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Salicylamides; Species Specificity

Topics: Animals; Apomorphine; Corpus Striatum; Dopamine; Dopamine Agonists; Ergolines; Male; Mice; Mice, Inbred Strains; Microdialysis; Neurons; Nucleus Accumbens; Oxazines; Quinolines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Tetrahydronaphthalenes

The potencies for in vivo inhibition of substantia nigra pars compacta dopamine single cell firing were determined for apomorphine, BHT 920, N-0923, (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT), (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), pramipexole, quinelorane, quinpirole, RU 24926, U-86170, and U-91356. Significant correlation was obtained between the potencies of these 11 highly efficacious dopamine receptor agonists and the in vitro binding affinities at dopamine D3 receptors, but not at dopamine D2L receptors. These results support a functional role for the dopamine D3 receptor subtype in the autoreceptor-mediated regulation of dopamine cell activity, while a role for dopamine D2 receptors awaits further analysis. In addition, the results demonstrate the limitations of using currently available dopamine receptor agonists to delineate relative in vivo roles for the dopamine D2 and D3 receptor subtypes.

Topics: Aminoquinolines; Animals; Apomorphine; Azepines; Benzothiazoles; Binding, Competitive; CHO Cells; Cricetinae; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Imidazoles; Male; Neurons; Phenethylamines; Piperidines; Pramipexole; Quinolines; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Structure-Activity Relationship; Substantia Nigra; Tetrahydronaphthalenes; Thiazoles; Thiophenes; Transfection

High doses of dopamine D2 receptor agonists produce hyperactivity in rodents whereas low doses suppress activity. In this study, low doses of a range of dopamine agonists were examined for their effects on locomotor activity in rats. All agonists caused a dose-related hypolocomotor effect with a rank order of potency of quinelorane > (-)-quinpirole > 7-OHDPAT > PBTO. (-)-Sulpiride (1.6-160 mumol/kg), a neuroleptic with atypical properties caused a dose-related reversal of the hypolocomotor effect produced by all four agonists whereas the typical neuroleptic haloperidol (0.005-0.16 mumol/kg) did not reverse hypolocomotion. Neither sulpiride (5-16 mumol/kg) nor haloperidol (0.005-0.16 mumol/kg) affected locomotor activity per se, although haloperidol (1.6-5 mumol/kg) did reduce locomotor activity. The different behavioural profiles shown by (-)-sulpiride and haloperidol in these tests may reflect some of the clinical characteristics of these neuroleptics. The question of whether these effects can be ascribed to differential actions at dopamine receptor subtypes will only be answered when more selective dopamine receptor antagonists are developed.

Topics: Animals; Apomorphine; Benzopyrans; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Haloperidol; Male; Motor Activity; Oxazines; Quinolines; Quinpirole; Rats; Rats, Sprague-Dawley; Sulpiride; Tetrahydronaphthalenes

The effects of piribedil and the selective D2 dopamine agonists, quinpirole and quinelorane, on the synthesis and metabolism of dopamine, within tuberoinfundibular neurons, were studied. The synthesis and metabolism of dopamine within these hypothalamic neurons were assessed by measuring the accumulation of DOPA after inhibition of DOPA decarboxylase and the concentration of DOPAC in the median eminence. Quinpirole (0.1-2.5 mg/kg, i.p.) produced a dose-related increase in accumulation of DOPA and concentrations of DOPAC in the median eminence. The increased accumulation of DOPA after administration of quinpirole was evident for at least 4 hr. The accumulation of DOPA in the median eminence also was enhanced after the administration of quinelorane (0.025 mg/kg, i.p.) and piribedil (50 mg/kg, i.p.). The stimulatory effect of quinpirole on accumulation of DOPA in the median eminence was antagonized by haloperidol (1 mg/kg, i.p.) but not by SCH 23390 (0.5 mg/kg, i.p.). Although D2 agonists have been shown to acutely suppress the synthesis and metabolism of dopamine in nigrostriatal and mesocorticolimbic dopamine neurons, it is apparent that activation of D2 receptors enhanced the synthesis and metabolism of dopamine within tuberoinfundibular neurons in the hypothalamus.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Arcuate Nucleus of Hypothalamus; Benzazepines; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Dopamine; Dopamine Agents; Ergolines; Haloperidol; Male; Neurons; Quinolines; Quinpirole; Rats; Rats, Inbred Strains

1. The ability of the selective dopamine receptor agonists, fenoldopam and SKF38393 (D1) and quinpirole and LY163502 (D2), to mimic the effect of dopamine on cockroach salivary gland acinar cells has been investigated. 2. Intracellular recordings of the membrane potential established that all the agonists mimicked dopamine (i.e. they induced a hyperpolarization which was occasionally followed by a depolarization), whether applied by addition to the superfusate or locally by pressure ejection. 3. The rank order of potency of the agonists to induce a hyperpolarization was (equipotent molar ratio relative to dopamine in parentheses): dopamine (1) much much greater than fenoldopam (1000) greater than SKF38393 (3500) greater than LY163502 (13750) greater than quinpirole (35000). 4. The agonists also elicited secretion from the salivary gland when superfused onto the preparation. SKF38393 and quinpirole did not induce the same maximum rate of secretion as dopamine. The rank order of potency of the agonists was (minimum effective concentration in parentheses): dopamine (0.03 microM) much much greater than fenoldopam (4.8 microM) greater than SKF38393 (40.8 microM) greater than quinpirole (132 microM). 5. Both the hyperpolarizing and secretory responses to all the agonists were antagonized by the selective D1 antagonist, (+)-SCH23390, but not the selective D2 antagonist, (+/-)-sulpiride. 6. These results support the idea that the same receptors mediate both the hyperpolarizing and secretory responses, and that they are similar to the mammalian D1 receptor.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Cockroaches; Dopamine Agents; Electrophysiology; Ergolines; Fenoldopam; In Vitro Techniques; Membrane Potentials; Quinolines; Quinpirole; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Salivary Glands; Sulpiride

Systemic administration of direct and indirect dopamine agonists resulted in increased extracellular ascorbic acid levels in the striatum and, to a lesser degree, in the nucleus accumbens as measured by in vivo voltammetry. Intraperitoneal d-amphetamine sulfate (5mg/kg) increased ascorbate concentrations in striatal extracellular fluid. Amphetamine also increased extracellular ascorbate levels in the nucleus accumbens although more gradually and to a lesser extent. Intraperitoneal phenethylamine hydrochloride (20 mg/kg) following pargyline hydrochloride pretreatment (20 mg/kg) increased extracellular ascorbate levels in the striatum significantly above the small increase seen in the nucleus accumbens. The direct acting dopamine agonists Ly-141865 and Ly-163502 when given i.p. at 1 mg/kg, resulted in increased extracellular ascorbate concentrations in both brain areas, again with a significantly greater effect in the striatum. These results indicate that brain extracellular ascorbate levels can be modulated by dopaminergic neuro-transmission and that this modulation is quantitatively different in different dopamine-containing brain structures.

Topics: Animals; Ascorbic Acid; Corpus Striatum; Dextroamphetamine; Dopamine Agents; Ergolines; Extracellular Space; Male; Nucleus Accumbens; Phenethylamines; Quinolines; Quinpirole; Rats; Rats, Inbred Strains

Quinelorane (LY163502) has the endocrine, neurochemical and behavioral profile of a potent and highly selective D2-dopaminergic agonist. The administration of quinelorane produced dose-related decreases in serum prolactin concentration of reserpinized, male rats and increases in serum corticosterone concentration of male rats. The minimum effective doses (MED) for these effects were 10 and 30 micrograms/kg i.p., respectively. Quinelorane induced increases in 3-methoxy-4-hydroxyphenylglycol-sulfate levels in the brain stem (MED, 30 micrograms/kg i.p.) and decreases in hypothalamic epinephrine levels (MED, 100 micrograms/kg i.p.) in male rats as determined by high-pressure liquid chromatography with electrochemical detection methods. Quinelorane induced increases in extracellular ascorbic acid as determined by in vivo voltammetry in the nucleus accumbens and striatum of male rats. Quinelorane produced concentration-dependent suppression of K+-evoked release of acetylcholine from superfused caudate slices, with an IC50 of approximately 10(-8)M. Quinelorane administration produced dose-related increases in compulsive, contralateral turning in male rats with unilateral nigrostriatal lesions and increases in locomotor activity and stereotypic behavior in male rats. In dogs, quinelorane administration produced dose-related increases in emetic response with an ED50 of 7 micrograms/kg i.v. Quinelorane administration also produced dose-related decreases in the striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic (MED, 1 microgram/kg i.p. for both metabolites) as determined by high-pressure liquid chromatography with electrochemical detection methods and decreases in extracellular concentrations of homovanillic acid in the nucleus accumbens and striatum as determined by in vivo voltammetry., Quinelorane produced concentration-dependent decreases in K+-evoked dopamine release from superfused striatal slices (IC50 = 3 X 10(-9) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Animals; Biogenic Amines; Brain; Corticosterone; Dopamine; Dose-Response Relationship, Drug; Emetics; Ergolines; Male; Motor Activity; Pergolide; Prolactin; Quinolines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Reference Values; Stereotyped Behavior

Four daily injections of pergolide, an ergoline dopamine agonist, made male rats tolerant to the corticosterone-elevating effects of an acute injection of pergolide on the fifth day. This tolerance occurred not only to acute treatment with pergolide, but also to other dopamine agonists differing in structure, potency and receptor subtype selectivity. Plasma corticosterone was elevated following administration of opioid or serotonin agonists in both vehicle- and pergolide-pretreated rats. The current findings strengthen the conclusion that tolerance to the acute elevation of corticosterone by pergolide is not due to impairment of pituitary-adrenocortical function but instead to changes in dopamine receptors that initiate the response.

Topics: Animals; Corticosterone; Dopamine; Dopamine Agents; Ergolines; Male; Oxazines; Pergolide; Pharmaceutical Vehicles; Quinolines; Quinpirole; Rats; Rats, Inbred Strains

LY163502, a partial ergoline and a trans-levorotatory enantiomer, does not stimulate adenylate cyclase in striatal membranes but inhibits 50% binding of 3H-apomorphine, 3H-pergolide and 3H-spiperone at 10, 13 and 151 nM (IC50), respectively. The racemic mixture (LY137157) is less effective, with 3, 2.7 and 1.4 times higher IC50 values, respectively, whereas the dextrorotatory isomer (LY175877) is inactive. LY163502 inhibits binding of 3H-clonidine with an IC50 value of 2600 nM, but not the binding of 3H-WB4101, 3H-dihydroalprenolol, 3H-serotonin, 3H-quinuclidinyl benzilate and 3H-pyramilamine or the uptake of serotonin, norepinephrine or dopamine, suggesting selective affinity toward dopamine receptors in vitro. Both LY163502 and LY137157 elevate striatal acetylcholine (Ach) levels. The elevation of Ach levels by LY163502 is reversed by dopamine antagonists haloperidol, cis-flupenthixol and metoclopramide. Therefore, the levorotatory enantiomer exhibits pharmacology of a D2 type of dopamine agonist.

Topics: Acetylcholine; Adenylyl Cyclases; Animals; Apomorphine; Clonidine; Corpus Striatum; Dopamine; Dopamine Antagonists; Enzyme Activation; Ergolines; Pergolide; Quinolines; Rats; Receptors, Dopamine; Spiperone