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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.

Non-ergot-type dopamine receptor agonists such as ropinirole are used for the treatment of Parkinson disease, but they occasionally show serious side effects including sleep attacks and daytime sleepiness. These symptoms are reminiscent of narcolepsy, a major sleep disorder. Because narcolepsy is thought to result from deficiency of a hypothalamic neuropeptide orexin, we examined whether ropinirole affected the integrity of orexin-containing neurons, using organotypic slice culture of rat hypothalamus. Application of ropinirole induced a significant decrease in the number of orexin-immunoreactive neurons. The same treatment showed no significant effect on the number of melanin-concentrating hormone-immunoreactive neurons. The decrease of orexin-immunoreactive neurons was reversible after washout of ropinirole and was not accompanied by induction of cell death. Antagonism of dopamine D(2) receptors and of serotonin 5-HT(1A) receptors attenuated the effect of ropinirole, suggesting involvement of these receptors in depletion of orexin. On the other hand, a moderate concentration of N-methyl-d-aspartate that excited orexin neurons counteracted the effect of ropinirole on the number of orexin-immunoreactive neurons. These results suggest that ropinirole can cause deficiency of orexin by inhibiting excitatory activities of orexin neurons, which may be relevant to the adverse actions of this drug on sleep and wakefulness.

B-HT 920 at low doses inhibited the accumulation of DOPA following treatment with reserpine and a DOPA decarboxylase inhibitor in the dopamine-, but not in the noradrenaline-predominant regions of the rat brain. B-HT 933 selectively inhibited this DOPA accumulation in the noradrenaline-predominant regions. These effects of B-HT 920 and B-HT 933 were completely antagonized by haloperidol and yohimbine, respectively. The rat motor activity was reduced by B-HT 920 and it was restored following apomorphine. B-HT 933 decreased the motor activity by a yohimbine-sensitive mechanism. The results indicate that B-HT 920 can selectively and potently stimulate the dopamine autoreceptors whereas B-HT 933 can selectively stimulate the noradrenaline autoreceptors.

Parkinson's disease (PD) is characterized by loss of nigral dopaminergic (DAergic) neurons and presence of Lewy bodies, whose major component is alpha-synuclein. We had previously generated transgenic mice termed Syn130m that express truncated human alpha-synuclein (amino acid residues 1-130) in DAergic neurons. Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta. Subsequently, the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly. In the present study, we investigated behavioral responses of Syn130m mice to L-DOPA and DA receptor agonists. Administration of L-DOPA dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice. Similarly, D(2) agonists, quinpirole and talipexole, and a D1/D2 agonist, pergolide, were effective against the reduction. Syn130m mice also showed significant reduction in exploratory behavior compared with non-Tg littermates when they were placed in a novel environment, but this abnormality was ameliorated by treatment with pergolide. These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content. On the other hand, the expression of postsynaptic D(2)-like receptors (DRD2) in the striatum was not increased in Syn130m mice, although the low striatal DA level is known to induce compensatory expression of DRD2. Because the abnormalities could be rectified by treatment with DA receptor agonists, it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease.

We investigated by means of behavioral and neurochemical studies the effects of either D 1 or D 2 agonist on excessive dopamine release and hyperactivity induced by the microinjection of Bay K 8644, and an L-type Ca 2+ channel stimulant, into the rat caudate putamen under a novel environmental condition. Hyperactivity (locomotor activity and rearing counts) and significant increases in extracellular dopamine levels induced by Bay K 8644 were concomitantly observed. D 1 agonist, SKF81297, administered into the caudate putamen did not block Bay K 8644-induced hyperactivity measured by monitoring both animal activity and increases in extracellular dopamine levels detected by microdialysis. Pretreatment with the D 2 agonists, bromocriptine, talipexole and pramipexole, into the caudate putamen significantly blocked Bay K 8644-induced hyperactivity for 45 min after Bay K 8644 administration, although the single administration of these agonists significantly potentiated locomotor activity and rearing behavior. Furthermore, these agonists significantly suppressed Bay K 8644-induced extracellular dopamine levels. Our results indicate that these D 2 agonists (1) act on postsynaptic neuronal D 2 receptors under conditions of normal or low dopamine release in the caudate putamen, and (2) act on presynaptic D 2 receptors (autoreceptors) when excessive levels of dopamine are released or hyperdopamine neuronal activity is induced. Consequently, the effect of D 2 agonists in the clinical treatment of Parkinson’s disease may be due to stimulation of postsynaptic D 2 receptors rather than presynaptic autoreceptors.

Because little comparative information is available concerning receptor profiles of antiparkinson drugs, affinities of 14 agents were determined at diverse receptors implicated in the etiology and/or treatment of Parkinson's disease: human (h)D(1), hD(2S), hD(2L), hD(3), hD(4), and hD(5) receptors; human 5-hydroxytryptamine (5-HT)(1A), h5-HT(1B), h5-HT(1D), h5-HT(2A), h5-HT(2B), and h5-HT(2C) receptors; halpha(1A)-, halpha(1B)-, halpha(1D)-, halpha(2A)-, halpha(2B)-, halpha(2C)-, rat alpha(2D)-, hbeta(1)-, and hbeta(2)-adrenoceptors (ARs); and native histamine(1) receptors. A correlation matrix (294 pK(i) values) demonstrated substantial "covariance". Correspondingly, principal components analysis revealed that axis 1, which accounted for 76% variance, was associated with the majority of receptor types: drugs displaying overall high versus modest affinities migrated at opposite extremities. Axis 2 (7% of variance) differentiated drugs with high affinity for hD(4) and H(1) receptors versus halpha(1)-AR subtypes. Five percent of variance was attributable to axis 3, which distinguished drugs with marked affinity for hbeta(1)- and hbeta(2)-ARs versus hD(5) and 5-HT(2A) receptors. Hierarchical (cluster) analysis of global homology generated a dendrogram differentiating two major groups possessing low versus high affinity, respectively, for multiple serotonergic and hD(5) receptors. Within the first group, quinpirole, quinerolane, ropinirole, and pramipexole interacted principally with hD(2), hD(3), and hD(4) receptors, whereas piribedil and talipexole recognized dopaminergic receptors and halpha(2)-ARs. Within the second group, lisuride and terguride manifested high affinities for all sites, with roxindole/bromocriptine, cabergoline/pergolide, and 6,7-dihydroxy-N,N-dimethyl-2-ammotetralin (TL99)/apomorphine comprising three additional subclusters of closely related ligands. In conclusion, an innovative multivariate analysis revealed marked heterogeneity in binding profiles of antiparkinson agents. Actions at sites other than hD(2) receptors likely participate in their (contrasting) functional profiles.

The atypical antipsychotic olanzapine (2.5-20 mg/kg) produced hypothermia in rats. The decrease in rectal temperature caused by olanzapine (2.5-20 mg/kg) was blocked by the selective dopamine D 2 receptor antagonist pimozide (0.5 and I mg/kg) but not by the dopamine D 1 receptor antagonist SCH 23390 (0.5 and I mg/kg). The dopamine D 1 /D 2 receptor agonist apomorphine (3 mg/kg) and the selective dopamine D 2 receptor agonist talipexole (0.5 mg/kg) produced hypothermia in rats. Olanzapine (10 and 20 mg/kg) significantly blocked hypothermia produced by both apomorphine and talipexole while the lower doses (2.5 and 5 mg/kg) of olanzapine failed to block it. The present results demonstrate that olanzapine behaves as a partial agonist at brain DA D 2 receptor populations involved in thermoregulation in the rat.

1. Effects of anti-Parkinsonian drugs on neurobehavioural changes induced by bilateral lesions of dopaminergic neurons were investigated in rats. 2. Dopaminergic neurons in rats were lesioned bilaterally by injection of 6-hydroxydopamine (6-OHDA; 8 μg) into the medial forebrain bundle at the level of the posterolateral hypothalamus. As a result, a decrease in locomotor activity and marked catalepsy and prolongation of grasping time were observed. 3. Levodopa, talipexole, bromocriptine and theophylline dose-dependently antagonized the decrease in locomotor activity induced by bilateral 6-OHDA lesions. These drugs also showed antagonistic effects on the appearance of catalepsy and prolongation of grasping time induced by bilateral 6-OHDA lesions. In contrast, trihexyphenidyl showed no antagonizing effect on the neurobehavioural changes induced by 6-OHDA lesions at any concentration tested. 4. Combined treatment with levodopa and talipexole antagonized the neurobehavioural changes induced by bilateral 6-OHDA lesions, whereas no marked changes were observed when either drug was administered separately. The same findings were noted with the simultaneous use of either levodopa (2 mg/kg) and theophylline (2 mg/kg) or talipexole (0.005 mg/kg) and theophylline (2 mg/kg). 5. These results indicate that this model may be useful for estimating the effects of drugs in the treatment of Parkinson's disease.

The effect of protection of dopaminergic neurons by talipexole, a dopamine (DA) agonist, is investigated on a methamphetamine (MA)-induced parkinsonism model of mice (C57BL/6N). The reduction of tyrosine hydroxylase activity in the striatum 72 h after MA (5 mg/kg every 2 h, four times) treatment was attenuated by the administration of talipexole (0.25 mg/kg or 1.0 mg/kg) prior to the administration of MA. In an in vitro experiment, talipexole inhibited the adduction reaction of hydroxyl radicals to salicylate. Taken together, these data suggest that the protective effect of talipexole on DA neurons is, in part, caused by the hydroxyl radical-scavenging action of the drug.

The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg kg ), quinelorane (0.01 mg kg ), quinpirole (0.04 mg kg ), pramipexole (0.09 mg kg ), roxindole (0.04 mg kg ), talipexole (0.04 mg kg ), (±)-7-OH-DPAT (0.05 mg kg ), (±)-PPHT (0.03 mg kg ), (−)-TNPA (0.06 mg kg ), PD128907 (0.13 mg kg ). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(−)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs.

The stimulating effect of antiparkinsonian drugs, talipexole and bromocriptine, on the striatal postsynaptic dopamine receptors were studied by measuring contralateral rotational behavior in rats. The nigro-striatal dopamine system of rats was degenerated by unilateral injection of 6-hydroxydopamine (6-OHDA, 8 micrograms/rat) into substantia nigra. By subcutaneous administration, talipexole at 0.16 mg/kg and bromocriptine at 10.24 mg/kg induced significantly increased rotational behavior to the contralateral direction to the lesioned side. The onset of the effect was 30 min for talipexole and 90 min for bromocriptine. By intragastric administration, talipexole at 0.4 mg/kg and bromocriptine at 20.48 mg/kg significantly increased the rotational behavior, and the onset of the effect was 60 min for talipexole and 180 min for bromocriptine. Rotational behavior induced by talipexole was suppressed by a D2 antagonist, sulpiride (40 mg/kg, s.c.), but not by a D1 antagonist, SCH23390 (1 mg/kg, s.c.). In contrast, rotational behavior induced by bromocriptine was suppressed by both sulpiride and SCH23390. These results indicated that when the nigrostriatal dopaminergic functions are disrupted, talipexole stimulates the striatal postsynaptic dopamine receptors at much lower doses than bromocriptine. Also it was indicated that the stimulating effect of talipexole is solely mediated by dopamine D2 receptors, whereas the effect of bromocriptine is mediated by both D1 and D2 receptors.

The effects of two predominant dopamine D2-like receptor agonists, talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine dihydrochloride, B-HT 920 CL2) and pramipexole (S(-)2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzothiazole dihydrochloride, SND 919 CL2Y), were studied alone and in combination with the selective dopamine D1-like receptor agonist chloro-APB ((+/-)6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-benz azepine hydrobromide, SKF 82958) in five chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotation in a dose-dependent manner up to 32 microg/kg, i.m. Talipexole was more potent than pramipexole (10 vs. 32 microg/kg, i.m.), but pramipexole was more efficacious in producing contraversive rotational behavior and significant hand movements in the afflicted limb. Larger doses of chloro-APB also produced contraversive rotation. Combinations of each dopamine D2-like receptor agonist in a median effective dose with chloro-APB (23.4 and 74.8 microg/kg, i.m.) had synergistic effects, producing either addition or potentiation, depending upon the dose used. The effects noted with these combinations were less than the effect of a large dose (100 microg/kg) of pramipexole. Talipexole, in the largest dose studied (100 microg/kg, i.m.), produced sedation which was not seen with the same dose of pramipexole. No significant extrapyramidal side effects were noted with either agent.

The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.

1. 1. Talipexole showed moderate displacement activity of 3 H-GR 65630 binding to 5-HT 3 receptors in both rat cortical and intestinal membrane fractions with Ki values of 0.35 μM and 0.22 μM, respectively. 2. 2. Bromocriptine failed to displace the binding activity in either experimental system even at a concentration of 10 μM. 3. 3. Both talipexole and tropisetron were found to significantly inhibit 5-HT 3 receptor-mediated effects of 5-HT in isolated guinea-pig ileum or atrium; however, the effect of talipexole was weaker than that of tropisetron. 4. 4. Bromocriptine, in contrast, had no antagonistic effects on 5-HT 3 receptor-mediated activity in guinea-pig ileum or atrium. 5. 5. It was concluded that talipexole might act as an antagonist on 5-HT 3 receptors in both brain and intestinal tissues.

Possible involvement of catecholamine receptor activities in modulating the incidence of yawning, which involves activation of dopaminergic-cholinergic linked neuronal mechanism, was investigated in rats. Subcutaneous injection of talipexole (B-HT 920), a selective dopamine D2-receptor-agonist, elicited yawning behavior. This behavior was increased by prazosin and bunazosin, alpha 1-adrenoceptor antagonists, and by pindolol, a beta-adrenoceptor antagonist. The yawning induced by physostigmine, an anticholinesterase agent, and pilocarpine, a direct muscarinic receptor agonist, was increased by pindolol, but was unaffected by prazosin and bunazosin. In addition, the yawning induced by the dopaminergic agonists, but not by the cholinergic agonists, was markedly suppressed by ST587, an alpha 1-adrenoceptor agonist. All the yawning responses to dopaminergic and cholinergic agents were reduced not only by scopolamine, a muscarinic receptor antagonist, but also by idazoxan, rauwolscine, and yohimbine, alpha 2-adrenoceptor antagonists. The results suggest that catecholamine receptor activities seem to play different roles in inhibitory modulation of the occurrence of yawning caused by dopaminergic and cholinergic stimulation.

The present experiments were performed to examine the behavioral effects of OPC-14597, which acts on dopamine receptors in rats. OPC-14597 administered subcutaneously (SC) at doses of 0.1–5 mg/kg elicited yawning, as did OPC-4392 (0.5–2 mg/kg, SC) and (−)-3-PPP (2.5–10 mg/kg, SC). These yawning responses were blocked by intraperitoneal (IP) pretreatment with haloperidol (0.5 mg/kg) but were increased by pindolol (20 mg/kg, IP) or reserpine (5 mg/kg, IP), which per se did not elicit yawning. The yawning induced by talipexole, a selective dopamine D 2 receptor agonist, was inhibited by OPC-14597 (0.5–5 mg/kg, SC) and (−)-3-PPP (10 mg/kg, SC). Apomorphine (0.5 mg/kg, SC), a dopamine D 1 D 2 receptor agonist, elicited stereotypy such as sniffing and licking but OPC-14597 (5–20 mg/kg, SC) did not induce this behavior. The stereotypy induced by apomorphine was inhibited not only by haloperidol (0.5 mg/kg, IP) and (−)-3-PPP (10 mg/kg, SC) but also by OPC-14597 (5–20 mg/kg, SC), without being affected by OPC-4392 (2 mg/kg, SC). In 6-hydroxydopamine (6-OHDA)-treated rats, apomorphine (0.5 mg/kg, SC) elicited rotation behavior whereas OPC-14597, OPC-4392 and (−)-3-PPP did not produce this behavior. These findings suggest that OPC-14597 provokes yawning without causing stereotypy and rotation but markedly antagonizes the talipexole-induced yawning and apomorphine-induced stereotypy, and that OPC-14597 thus exerts partial agonistic effects on yawning behavior but antagonistic effects on stereotypy in rats.

Objectives: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. Methods: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. Results: Talipexole induced mild hypothermia (35.1 ± 1.1 to 36.0 ± 0.5°C) for Conclusion: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug-induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke.

Electrophysiological studies using rats anesthetized with chloral hydrate were performed to elucidate whether or not intravenously injected talipexole acted as a D2 receptor agonist on the striatal neurons in comparison with the action of bromocriptine. The activities of the striatal neurons were extracellularly recorded using a glass microelectrode attached along a seven-barreled micropipette, each barrel of which was filled with talipexole, bromocriptine, SCH23390 (D1 antagonist), domperidone (D2 antagonist), glutamate or 2 M NaCl. These drugs were iontophoretically applied to the immediate vicinity of the target neuron being recorded. The effects of talipexole and bromocriptine were examined on the neurons, whose spikes (induced by the stimulation of the substantia nigra pars compacta) were inhibited by the iontophoretic application of domperidone. Iontophoretic application of talipexole or bromocriptine increased spontaneous firing of these neurons and this increase in firing was also inhibited by iontophoretically applied domperidone. In the same neurons, intravenously administered talipexole (0.01, 0.02 and 0.04 mg/kg) dose-dependently increased firing, and this increase was inhibited by microiontophoretically applied domperidone, but not by SCH23390. On the other hand, the intravenous injection of bromocriptine (0.1, 0.2 and 0.4 mg/kg) also increased the firing rate. However, the increase was not dose-dependent and fluctuated; the firing transiently decreased during the increase in firing with intravenously administered bromocriptine. However, the bromocriptine-induced increase in firing was also suppressed by domperidone, and decrease in firing was inhibited by SCH23390. These findings suggest that talipexole acts as a D2 agonist on the striatal neurons receiving input from substantia nigra pars compacta and increases firing when intravenously applied. However, intravenously administered bromocriptine appears to act as both a D2 agonist and probably as a D1 agonist on the striatal neurons to increase and decrease firing, respectively.

Transfection of a human dopamine D3 receptor cDNA in a neuroblastoma-glioma hybrid cell line (NG 108-15) provided clonal cell lines stably expressing up to 600 fmol per mg protein of [125I]iodosulpiride binding sites. Dopamine and several agonists distinguished two receptor-affinity states in membranes. In the case of dopamine, the high-affinity state (Ki = 0.9 nM, 30% of total binding) was completely converted into a low-affinity state (Ki = 57 nM) in the presence of 10 microM guanosine-5'-O-(3-thiotriphosphate). In addition to these two sites, a site with a very low affinity for dopamine was evidenced in whole cells. The dopamine D3 receptor mediated two responses: c-fos activation, as measured by the appearance of Fos-like immunoreactivity, and increased mitogenesis, as measured by incorporation of [3H]thymidine. The Fos-like immunoreactivity appeared within 30 min, lasted 2 h and was blocked by the partially selective dopamine D3 receptor compound (+)-UH 232 (cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin). The mitogenic effect, which occurred after a lag time (over 2 h stimulation), was produced with subnanomolar potency and full intrinsic activity by several compounds previously identified as dopamine D2 receptor agonists, e.g. quinpirole, (+)-7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and RU 24926 (N-n-propyl-di-beta(3-hydroxyphenyl)-ethylamine), and was reversibly blocked by (+)-UH 232 (Ki = 9 nM). Talipexole (B-HT 920, 5-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin) was identified as a partial agonist at the dopamine D3 receptor. Dopamine D3 receptor-mediated mitogenesis was potentiated by a phorbol ester and was abolished by pretreatment with pertussis toxin. A mitogenic effect of same amplitude was elicited by bradykinin or carbachol, both acting through constitutive receptors. Bradykinin markedly activated inositol phosphate turnover, and had no effect on forskolin-stimulated cyclic AMP accumulation. Carbachol inhibited forskolin-stimulated cyclic AMP accumulation and had no effect on inositol-phosphate turnover. Quinpirole had no effect on any of these second messenger pathways. Thus, in transfected NG 108-15 cells, the dopamine D3 receptor is coupled to a pertussis toxin-sensitive G protein and mediates two possibly unrelated biological effects, through initial biochemical events that remain to be identified.

An electrophysiological study using cats anesthetized with α-chloralose was performed to elucidate whether or not talipexole (B-HT 920 CL 2 : 6-allyl-2-amino -5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5 -d] -azepinedihydrochroride), a dopamine D 2 agonist, acts on postsynaptic dopamine receptors in the caudate nucleus (CN) neurons receiving excitatory input from the pars compacta of substantia nigra (SN). Extracellular neuron activities were recorded in the CN using a glass-insulated silver wire microelectrode attached along a seven-barreled micropipette, each of which was filled with talipexole, quinpirole (dopamine D 2 agonist), domperidone (dopamine D 2 antagonist), glutamate and 2M NaCl. These drugs were microiontophoretically applied to the immediate vicinity of the target neuron. In the same neurons in which the spikes elicited by the SN stimulation were blocked by microiontophoretically applied domperidone, microiontophoretic application of talipexole and quinpirole induced a dose-dependent increase in spontaneous firing. This increase in firing by talipexole and quinpirole was blocked during simultaneous application of domperidone, although glutamate-induced firing remained unaffected by domperidone. In the CN neurons, in which the SN stimulation-induced spikes were not blocked by domperidone, spontaneous firing was not affected by talipexole or quinpirole. These findings suggest that talipexole activates CN neurons receiving a dopaminergic input from SN via D 2 receptors, as does quinpirole.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.5 mg/animal i.v. once or twice) to common marmosets induced persistent parkinsonian motor deficits. The postsynaptic dopamine D2 receptor agonist properties of talipexole (B-HT 920, 2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine), which is believed to be a dopamine autoreceptor agonist, were examined using normal and MPTP-treated marmosets and were compared to these properties of bromocriptine, a selective dopamine D2 receptor agonist. Talipexole (20-160 micrograms/kg i.p.) dose dependently increased motor activity and reversed the akinesia and incoordination of movement in MPTP-treated marmosets. In normal marmosets, higher doses of talipexole (80-160 micrograms/kg i.p.) produced a dose-dependent increase in motor activity, while the lowest dose (20 micrograms/kg i.p.) depressed this activity. These data for talipexole were very similar to those for bromocriptine. Talipexole had, however, several properties different from those of bromocriptine; it had a rapid onset of antiparkinsonian activity compared to bromocriptine; it had more than 25 times as much activity potency as bromocriptine; a dose of talipexole (80 micrograms/kg i.p.) sufficient to produce the activity did not induce emesis as strongly as an insufficient dose of bromocriptine (0.5 mg/kg i.p.). These results suggest that talipexole has postsynaptic dopamine D2 receptor agonist properties and that these properties of talipexole may be favorable in the treatment of Parkinson's disease.

Talipexole is a non-ergot dopamine (DA) agonist that has been used in the treatment of Parkinson's disease. In the present study, we examined the effect of talipexole on paraquat (PQ)-induced N27 cell death and the intracellular pathways involved in this effect. Pretreatment of N27 cells with talipexole (1 mM) resulted in significant protection against paraquat-induced cell death. In N27 cells, talipexole inhibited paraquat-induced apoptotic hallmarks such as cytochrome c release, caspase-3 activation, chromatin condensation and externalization of phosphatidilserine. Talipexole pretreatment prevents the reduction in the anti-apoptotic Bcl-xL protein and increases in the pro-apoptotic form of Bak and p-Bad, both induced by PQ. Finally, we also observed that talipexole abrogates the activation of cell death pathways JNK1/2 and p38 produced by PQ, and increases the phosphorylated (active) forms of the pro-survival pathways ERK1/2 and Akt. These results reveal that talipexole exerts a neuroprotective effect in a mesencephalic cell line exposed to the neurotoxin PQ, which is related to the etiology of Parkinson's disease.

The present experiments were performed to investigate the potential role of central adrenergic neurons in regulating occurrence of yawning in rats. Intraperitoneal injection of tacrine (THA) or 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate HCl (NIK-247), cholinesterase inhibitors, induced yawning, which was markedly increased by pretreatment with the beta-adrenoceptor antagonist, pindolol. The yawning evoked by tacrine or NIK-247 given alone or in combination with pindolol was inhibited by pretreatment with scopolamine but not by mecamylamine or spiperone. Treatment with tacrine or NIK-247 increased acetylcholine content of the striatum, but this effect was not enhanced by pindolol, which per se did not affect basal acetylcholine content. Moreover, pretreatment with the central adrenaline synthesis inhibitors, (+-)-2,3-dichloro-alpha-methylbenzylamine HCl (LY-78335) and 2-cyclooctyl-2-hydroxyethylamine HCl (UK-1187A), increased tacrine-induced yawning. Subcutaneous injection of talipexole (B-HT 920), a dopamine D2 receptor agonist, evoked yawning, which was also increased by pindolol, LY-78335, and UK-1187A. These receptors antagonists and synthesis inhibitors per se did not cause yawning responses. The results suggest that the beta-adrenoceptor blockade and the inhibition of adrenaline synthesis facilitate the occurrence of yawning induced by cholinergic and dopaminergic agonists, and thus the central adrenergic neuronal systems may be implicated in the regulation of yawning responses.

Alterations in cortical EEG activity in male rats produced by putative agonists at dopamine (DA) autoreceptors and by antagonists at postsynaptic DA receptors were compared in order to study, whether an impairment in dopaminergic neurotransmission via two different mechanisms might result in similar or different effects. Simultaneously to the EEG recordings, gross behaviour was observed. Putative agonists at DA autoreceptors (apomorphine 0.05 mg/kg, quinpirole 0.05 mg/kg, or talipexole 0.02 mg/kg s.c.) produced increases in the power iin all of the frequency bands, except beta-2, with the most pronounced increase in the delta band. These EEG alterations were accompanied by hypokinesia, ptosis and yawning. In contrast, antagonists at DA receptors (haloperidol 0.1 mg/kg i.p., D2 blocker) or SCH 23390 (0.2 mg/kg i.p., D1 blocker) led to little increases in the delta band, but more pronounced increases in the alpha-2 band. Behavioural signs were hypokinesia, but little ptosis and yawning. The combination of both blockers produced, in addition, strong increases in the delta band and behavioural signs of ptosis and yawning. These results suggest that activation of putative dopamine autoreceptors produced EEG patterns and behavioural patterns different from those produced by blockade of either D1 or D2 postsynaptic dopamine receptors. In contrast, the effects following a stimulation of putative DA autoreceptors, which are expected to decrease the release of the agonist and its action at postsynaptic D1 and D2 receptors, were very similar to those found after a combined blockade of both types of postsynaptic dopamine receptors.

The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat.

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded inconsistent results. In order to reduce the excess of central dopaminergic activity postulated by the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in open clinical trials in positive schizophrenic symptomatology. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of positive psychotic symptoms. In negative schizophrenic symptomatology, a dopamine deficit rather than an excess has been hypothesized. Current evidence from pilot studies suggests that dopamine autoreceptor agonists like roxindole may produce a minor to moderate improvement of symptoms like affective flattening, depressed mood, alogia, and avolition, possibly by stimulation of supersensitive postsynaptic dopamine receptors. For certain subgroups of depression, a reduction of functional dopamine activity has been postulated. In an open pilot study in patients with a major depression, roxindole demonstrated antidepressive properties comparable to those of standard antidepressants, justifying further double-blind controlled trials against reference drugs.

Brain cortex slices were preincubated with 3H-noradrenaline and superfused with physiological salt solution containing desipramine. We studied the inhibition of the electrically evoked tritium overflow caused by histamine in the presence of α-adrenoceptor ligands (mouse and rat brain cortex), and the inhibition caused by talipexole (the former B-HT 920) in the presence of H3-receptor ligands (mouse brain cortex). In mouse brain cortex slices, the inhibitory effect of histamine on the tritium overflow evoked by 36 pulses, 0.3 Hz was not changed by the α1-adrenoceptor antagonist prazosin, but increased by the α2-adrenoceptor antagonist rauwolscine. When the current strength or the duration of electrical pulses was reduced to compensate for the increase in evoked tritium overflow produced by rauwolscine, the latter still. enhanced the effect of histamine. The histamine-induced inhibition of tritium overflow evoked by 360 pulses, 3 Hz was not affected by the α1-adrenoceptor agonist phenylephrine but attenuated by the α2-adrenoceptor- agonist talipexole. Finally, the inhibition by histamine of the tritium overflow evoked by 3 pulses, 100 Hz was attenuated by talipexole but not affected by rauwolscine. Conversely,. the inhibitory effect of talipexole on tritium overflow elicited by 360 pulses, 3 Hz was slightly attenuated by the H3-receptor agonist R-(−)-α-methylhistamine but not, affected by the H3- receptor antagonist thioperamide. In rat brain cortex slices, histamine only tended to inhibit tritium overflow evoked by 360 pulses, 3 Hz, both in the absence of α-adrenoceptor antagonists and in the presence of prazosin. However, histamine markedly inhibited the evoked overflow in the presence of rauwolscine. Again, enhancement of the histamine-induced inhibition also occurred when the current strength or the duration of pulses was reduced in order to compensate for the increase in evoked tritium overflow produced by rauwolscine. The results suggest that the α2-autoreceptors and the H3-heteroreceptors at the noradrenergic nerve endings in the brain of mouse and rat interact with each other. Activation of the α2-autoreceptors decreases, whereas blockade of the activated (but not of the non-activated) α2-autoreceptors increases, the inhibitory effect of histamine. Activation of the H3-heteroreceptors slightly decreases, whereas blockade of the H3-receptors fails to affect, the inhibitory effect of talipexole.

A microiontophoretic study using rats anesthetized with chloral hydrate and immobilized with gallamine triethiodide was carried out to compare the effect of talipexole (B-HT 920 CL 2 :2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine-dihydrochloride), a dopamine autoreceptor agonist, on dopaminergic neurons in the ventral tegmental area (VTA) to non-dopaminergic neurons in the VTA. VTA neurons were classified into two types according to the responses to antidromic stimulation of the nucleus accumbens (Acc) : type I neurons with a long spike latency (8.69 ± 0.24 msec) upon Acc stimulation and low spontaneous firing rate (6.80 ± 1.34 /sec), and type II neurons with a short latency (2.76 ± 0.20 msec) and high spontaneous firing rate (26.77 ± 7.05 /sec), probably corresponding to dopaminergic and non-dopaminergic neurons, respectively. In type I neurons, microiontophoretic application of talipexole and dopamine inhibited antidromic spike generation elicited by Acc stimulation, and talipexole-induced inhibition was antagonized by domperidone (dopamine D-2 antagonist). In type II neurons, however, the antidromic spikes were not affected by either talipexole or dopamine. Furthermore, spontaneous firing was also inhibited by iontophoretically applied talipexole and dopamine in most type I neurons, but rarely affected by either drug. Inhibitory effects of talipexole were antagonized by domperidone. These results suggest that talipexole acts on dopamine D-2 receptors, thereby inhibiting the dopaminergic neurons in the VTA.

To investigate whether dopamine agonists induce neurite outgrowth, we examined the effects of dopamine D2 receptor agonists such as bromocriptine, talipexole, and pramipexole in PC12 cells, a well-studied model of neurite outgrowth. Bromocriptine significantly induced neurite outgrowth in a concentration-dependent manner. Neither talipexole nor pramipexole induced neurite outgrowth. Domperidone and sulpiride, dopamine D2 receptor antagonists, did not have any effect on the bromocriptine-induced neurite outgrowth. These results suggest that the stimulation of dopamine D2 receptors would not affect neurite outgrowth in nerve regeneration. Next, we investigated how bromocriptine-induced neurite outgrowth. Bromocriptine is not only a dopamine D2 receptor agonist but also an ergot alkaloid. We examined the involvement of the structure of ergot alkaloids in the effect of bromocriptine. Ergot alkaloids have been divided into two groups: amino acid ergot alkaloids, including bromocriptine, and amine ergot alkaloids. Amino acid ergot alkaloids, such as ergocornine and ergotamine, induced neurite outgrowth, but amine ergot alkaloids, including ergometrine and methylergometrine, did not. These results indicate that the structure of amino acid ergot alkaloids is important for the effect of bromocriptine. Moreover, the effect of bromocriptine was inhibited by a src inhibitor and a mitogen-activated protein kinase kinase (MEK) inhibitor. Taken together, bromocriptine-induced neurite outgrowth via src and the MEK/extracellular signal-regulated kinase 1/2 signaling pathway in PC12 cells.

In a dialysis procedure not requiring perfusate addition of acetylcholinesterase inhibitors to "boost" basal levels of acetylcholine (ACh), the influence of the antiparkinson agent piribedil upon levels of ACh in frontal cortex and dorsal hippocampus of freely moving rats was compared with those of other antiparkinson drugs and selective ligands at alpha(2)-adrenoceptors (ARs). Suggesting a tonic, inhibitory influence of alpha(2A)-ARs upon cholinergic transmission, the alpha(2)-AR agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline tartrate (UK14,304), and the preferential alpha(2A)-AR agonist guanabenz reduced levels of ACh. They were elevated by the antagonists 2(2-methoxy-1,4 benzodioxan-2-yl)-2-imidazoline HCl (RX821002) and atipamezole and by the preferential alpha(2A)-AR antagonist 2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole (BRL44008). In contrast, trans-2,3,9,13b-tetrahydro-1,2-dimethyl-1H-dibenz[c,f]imidazo[1,5-a]azepine (BRL41992) and prazosin, preferential alpha(2B/2C)-AR antagonists, were inactive. The dopaminergic agonist and antiparkinson agent piribedil, which behaves as an antagonist at alpha(2)-ARs, dose dependently increased extracellular levels of ACh. This action was absent upon pretreatment with a maximally effective dose of RX821002. On the other hand, a further dopaminergic agonist and antiparkinson agent, talipexole, which possesses agonist properties at alpha(2)-ARs, dose dependently reduced levels of ACh. This action was also blocked by RX821002. In contrast to piribedil and talipexole, quinelorane, which interacts with dopaminergic receptors but not alpha(2)-ARs, failed to affect ACh levels. Finally, in analogy to the frontal cortex, piribedil likewise elicited a dose-dependent increase in extracellular levels of ACh in the dorsal hippocampus. In conclusion, in distinction to talipexole and quinelorane, and reflecting its antagonist properties at alpha(2A)-ARs, piribedil reinforces cholinergic transmission in the frontal cortex and dorsal hippocampus of freely moving rats. These actions may be related to its facilitatory influence upon cognitive function.

The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D(2SHORT(S)), hD(2LONG(L)), hD(3), and hD(4.4) receptors and at halpha(2A)-, halpha(2B)-, halpha(2C)-, and halpha(1A)-adrenoceptors (ARs). As determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D(2)-like" sites. However, at hD(2S) receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E(max)100%); TL99, talipexole, and apomorphine were highly efficacious (79-92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40-55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD(2L) receptors, with terguride and roxindole acting as antagonists. At hD(3) receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD(4) receptors, highest efficacies (approximately 70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD(2S) versus hD(2L) sites were highly correlated (r = 0.79), they correlated only modestly to hD(3)/hD(4) sites (r = 0.44-0.59). In [(35)S]GTPgammaS studies of halpha(2A)-ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at halpha(2B)- and halpha(2C)-ARs. Using [(3)H]phosphatidylinositol depletion, roxindole, bromocriptine, lisuride, and terguride displayed potent antagonist properties at halpha(1A)-ARs. In conclusion, antiparkinson agents display diverse agonist and antagonist properties at multiple subtypes of D(2)-like receptor and alpha(1)/alpha(2)-AR, actions, which likely contribute to their contrasting functional profiles.

Variations in the measurement of ligand's intrinsic activity between receptor subtypes is a common consequence of unequal receptor:G protein density ratios. We have investigated ligand activation at the alpha2-adrenoceptor (alpha2-AR) subtypes under defined expression conditions of one receptor molecule for one Galpha protein molecule using fusion proteins. Fusion between either a wt alpha2C AR or a mutant Thr382Lys alpha2C AR and a chimeric Galphaq/il protein displayed robust, transient (-)-adrenaline-mediated Ca2+ responses with similar potencies (pEC50: 7.78 and 7.66) and kinetic properties. A comparison of the intrinsic activities of alpha2 AR agonists found d-medetomidine to be the only compound with an efficacy similar to that of (-)-adrenaline. The Ca2+ responses as mediated by UK 14304, oxymetazoline and clonidine became more potent and efficacious at the Thr381Lys alpha2C AR, whereas the response as mediated by talipexole displayed a higher potency with an unaltered maximal response. Whereas only small differences in ligand's intrinsic activities between the wt alpha2A, alpha2B and alpha2C AR fusion proteins were observed with most ligands, oxymetazoline was virtually silent at the alpha2A AR while active as a partial and apparently full agonist at the alpha2C AR and alpha2B AR, respectively. The mutant alpha2 AR subtypes could be differentiated using the apparent positive efficacy of ligands that used to be defined as antagonists. The following rank order of maximal responses was observed for the Thr381Lys alpha2C AR: idazoxan approximately equals SKF 86466atipamezoledexefaroxan; Thr373Lys alpha2A AR: SKF 86466idazoxan = atipamezoledexefaroxan; and Thr370Lys alpha2B AR: atipamezoleidazoxan dexefaroxan. RX 811059 (10 microM) was the only compound to be completely silent at both the wt and mutant alpha2 AR subtypes. In conclusion, silent alpha2 AR ligands are probably rare in these specified alpha2 AR systems. Most antagonists may actually possess partial agonist properties at the alpha2 AR subtypes, which are facilitated by the same mutation in the distal portion of their third intracellular loop.

Treatment of rats for 4 days with the antiparkinsonian drugs, talipexole and pramipexole, markedly increased Bcl-2 immunoreactivity in neuronal dendritic processes in both cerebral cortex and hippocampus, but treatment for 1 day with either of these drugs did not. Repeated administration of talipexole or pramipexole may have neuroprotective effect in neurodegenerative disorders.

The planarian, a flatworm, has a high potential for regeneration, and dopamine plays a key role in its behavior. Planarians treated with MPTP underwent autolysis and individual death in a concentration-dependent manner. When the planarian body was cut into anterior, middle and posterior pieces, each piece subsequently regenerated and reorganized to form a new individual within approximately 10 days. The anterior piece was significantly more sensitive than the middle and posterior pieces to MPTP cytotoxicity. Concomitant treatment with talipexole, an anti-parkinsonian drug, inhibited MPTP-induced autolysis and individual death in a concentration-dependent manner. Pramipexole showed a similar protective effect. In addition, post-treatment with talipexole at 1 hr after MPTP completely inhibited MPTP-induced individual death. Although MPTP treatment caused 30% of the planarians to undergo autolysis and individual death within 12 hr, post-treatment with talipexole even at 12 hr completely rescued the remaining 70% of the planarians from death. These results suggest that the MPTP-treated planarian may be useful as a novel parkinsonian model in which talipexole has a protective effect even in the case of post-treatment.

The effects of talipexole on functional motor improvement in comparison with contraversive circling were studied in five chronic (5-7 years post MPTP-lesioned) hemiparkinsonian Macaca nemestrina monkeys. Talipexole induced contraversive rotations in a dose of 32 microg/kg for about 1 hr after i.m. injection. Larger doses (56 and 100 microg/kg, i.m.) produced less effect due to sedation. Three different rating scales were used to assess functional improvement, including a clinical parkinsonism rating scale, volitional responses to fruit presentations, and number of significant hand movements. The optimal dose of talipexole was 32 microg/kg, i.m. Functional improvement by talipexole, including clinical parkinsonian rating scales and significant hand movements, as well as contraversive circling in hemiparkinsonian monkeys, confirm that this chronic animal model is useful in preclinical testing of drugs for the treatment of human parkinsonism.

Previous study has shown that alpha2D-adrenoceptors are involved in modulation of peristalsis in the rat ileum. The aim of the present study was to determine the tissue location of alpha-adrenoceptors in the rat ileum by using a recently devised method. The pre-synaptic alpha-adrenoceptors were characterised by measuring the potencies of agonists to inhibit transmurally-evoked (1 ms pulses, 10 Hz, 8-10 s trains) contractions of the longitudinal and circular muscles and the affinities of antagonists. Post synaptic alpha-adrenoceptors were identified by screening agonists and antagonists in carbachol-contracted tissues. In the circular muscle the order of potencies for inhibiting transmurally-induced contraction was: clonidineor = oxymetazolineor = UK 14,304or = guanfacinetalipexolephenylephrineazepexole. The potency ratios relative to clonidine correlated to those previously derived using the rat ileum peristaltic reflex preparation. Most of the alpha-adrenoceptor agonists, however, caused only small inhibitions of the longitudinal muscle contraction in response to transmural stimulation, except phenylephrine and azepexole. RX 821002, yohimbine, rauwolscine, BRL 44408, phentolamine, idazoxan, ARC 239, and prazosin inhibited the effect of clonidine on the circular muscle response with apparent pK(B) values best correlated with pK(B) or pKi values derived from the rat ileum peristaltic reflex preparation and other tissues known to have the alpha2D-subtype. The rank order of potencies at inhibiting carbachol-induced responses of both muscle layers was: phenylephrineor = oxymetazolineclonidineor = talipexoleazepexoleguanfacine. UK 14,304 was inactive up to 10 microM. The EC50 value of each agonist on the longitudinal muscle was not significantly different to the corresponding value on the circular muscle. Prazosin was more potent than yohimbine at inhibiting the relaxant effect of phenylephrine in both muscle layers of carbachol-contracted tissues. It is concluded that the recently identified alpha2D-adrenoceptors of the rat ileum are located on cholinergic neurons controlling circular muscle contraction. The study also demonstrated the presence of postsynaptic alpha1-adrenoceptors involved in mediating relaxation in both muscle layers.

Male squirrel monkeys (Saimiri sciureus) were surgically prepared with cranial guide cannulae for acute microdialysis sampling of the putamen nucleus, a dopamine (DA)-rich brain region. On the day of an experiment an animal was placed in a Plexiglas restraining chair and a microdialysis probe was inserted through the guide into the putamen. Perfusates of artificial cerebrospinal fluid were collected every 20 min over several hours and analyzed via HPLC with electrochemical detection. DA D2/ D3 agonist drugs were administered either orally (p.o.) or subcutaneously (s.c.), and changes in levels of DA in the dialysates were measured. All of the drugs tested, i.e., quinpirole (0.5 mg/kg p.o.), talipexole (0.75 mg/kg p.o. or s.c.), and PD 135222 (7 mg/kg p.o.), decreased spontaneous DA overflow by approximately 40-50% during the first 2 h following dosing. In animals that routinely underwent the microdialysis procedure up to 23 times over a 2-year period, there was neither an appreciable change in basal DA overflow nor a significant change in the magnitude of drug response. These data suggest that DA D2/D3 agonists attenuate DA neuronal overflow in the primate brain, similar to effects seen in rodents. Furthermore, these results also demonstrate the utility of repeated intracerebral microdialysis as a tool to monitor dynamic changes in neurochemical activity in monkeys over a prolonged period of time.

This study was aimed at in vivo characterisation of the possible role of dopamine receptors in the modulation of adrenaline release from the adrenal medulla in rats. Quinpirole (0.3, 1 and 3 mg/kg s.c., 30 min), an agonist at dopamine D2-like receptors induced a statistically significant increase not only in adrenal dopamine but also in plasma and heart adrenaline levels. The effects of the lowest dose of quinpirole were blocked by domperidone (5 mg/kg s.c., 150 min). Implantation of catheters followed by blood sampling appeared to be a stressful procedure, inducing itself an elevation of adrenal dopamine and of heart adrenaline by 100 and 250%, respectively. To explore the possibility of determining the plasma levels of adrenaline without blood sampling, regression modelling was performed by means of partial least squares regression (PLS) using treatment and levels of heart adrenaline and adrenal dopamine as predictor variables. The selected variables were found to be good predictors of plasma adrenaline levels. Accordingly, the increase in adrenal dopamine and heart adrenaline levels following administration of the dopamine autoreceptor agonist, talipexole, and the classical non-selective dopamine receptor agonist, apomorphine, were interpreted as indicators of the increased adrenomedullary adrenaline release. Neither of the dopamine D2 receptor antagonists used, i.e. domperidone, supposed to have only peripheral effects, nor raclopride, had significant effects on adrenal dopamine and heart adrenaline. Our results support the presence of peripherally located dopamine D2-like receptors, capable of acutely stimulating not only the synthesis of catecholamines, but also the release of adrenaline from adrenals in the conscious rat.

Mouse or rat brain cortex slices were preincubated with 3H-noradrenaline and superfused with physiological salt solution containing desipramine. We studied the effects of prostaglandin E2 (PGE2), prostaglandin D2 (PGD2) and related drugs on the electrically evoked (50 mA, 2 ms, 0.3 Hz) tritium overflow. PGE2 inhibited the electrically evoked tritium overflow from mouse brain cortex slices; the maximum effect of PGE2 (79010) was attenuated by the α2-adrenoceptor agonist talipexole (to 52010) and enhanced by the α2-adrenoceptor antagonist rauwolscine (to 92%). Rauwolscine was added to the superfusion medium in all subsequent experiments. The effect of PGE2 was readily reversible upon withdrawal from the medium and remained constant upon prolonged exposure of the tissue to the prostanoid. Studies with EP receptor agonists, mimicking the inhibitory effect of PGE2, showed the following potencies (pIC50): sulprostone (8.22); misoprostol (8.00); PGE2 (7.74); PGEZ (7.61); iloprost (5.86). The concentration-response curve of PGE2 was marginally shifted to the right by the EP1 receptor antagonist AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; apparent pA2 3.97) and by the TP receptor antagonist vapiprost (4.50). AH 6809, by itself, did not affect the evoked overflow whereas vapiprost increased it. PGD2 inhibited the evoked overflow at high concentrations (pIC50 4.90); this effect was not altered by the DP receptor antagonist BW A868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2hydroxyethylamino)hydantoin), which, by itself, did not affect the evoked overflow. Indometacin slightly increased the evoked overflow and tended to increase the inhibitory effect of PGE2. PGE2 inhibited the electrically evoked tritium overflow also in rat brain cortex slices. The maximum effect (obtained in the presence of rauwolscine) was 61%; the pIC30 value was 7.67. The present study suggests that PGE2 inhibits noradrenaline release from mouse brain cortex via EP3 receptors and that its maximum effect is more marked in the mouse than in the rat. The inhibitory effect of PGD2 (in the mouse brain) does not involve DP receptors and may also be related to EP3 receptors. The EP3 receptors interact with a2-adrenoceptors and may be activated by endogenous prostanoids.

We examined whether or not the antiparkinsonian activity of talipexole (B-HT 920, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) could be optimised by combination with L-3,4-dihydroxyphenylalanine (L-dopa). Additionally, the effects of chronic treatment with talipexole on motor behavior were investigated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated and normal common marmosets. Administration of MPTP (0.5 mg/animal i.v. once or twice) to marmosets induced persistent parkinsonian motor deficits. The antiparkinsonian activity of talipexole (40 micrograms/kg s.c.) was significantly enhanced by its combination with L-dopa (30 mg/kg i.p.). This may further support the postulated postsynaptic dopamine D2 receptor agonist properties of talipexole. Chronic treatment with talipexole (a daily dose of 40 micrograms/kg s.c. for 21 days) did not lead to tolerance to the antiparkinsonian activity in MPTP-treated animals. No obvious dyskinesia was seen throughout the chronic treatment. In contrast, in normal marmosets, talipexole at a dose of 80 micrograms/kg which is a dose sufficient to induce hyperactivity did not increase motor activity during the treatment repeated for 21 days. These results suggest that talipexole is a selective dopamine D2 receptor agonist drug of potential use in the treatment of Parkinson's disease.

The interactions of talipexole (B-HT 920) and clonidine with selective alpha-adrenoceptor antagonists, yohimbine (alpha 2) and prazosin (alpha 1), as well as with dopamine receptor antagonists, metoclopramide (D2), domperidone (D2) and SCH23,390 (D1) were investigated in anaesthetized rabbits after i.v. administration. Both talipexole (0.03-0.1 mg/kg) and clonidine (0.01-0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action. The hypotensive effect of the alpha 2-adrenoceptor and D2 agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3-3 mg/kg), but not with yohimbine (3 mg/kg), prazosin (0.1 mg/kg) or SCH23,390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3-3 mg/kg). These findings indicate that in anaesthetized rabbits after i.v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D2 agonism.

The effect of pretreatment with a high dose of the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (20 mg/kg, 24 h) on the intrinsic activity displayed by a series of full and partial dopamine D2 receptor agonists on prolactin regulating pituitary D2 receptors in male rats was studied. To increase baseline prolactin levels, gamma-butyrolactone in a dose inhibiting brain dopamine neurotransmission was given to all animals. In controls, i.e. rats not given EEDQ, supramaximal doses of all full and partial D2 receptor agonists tested decreased serum prolactin levels with greater than 80%. While the intrinsic activities of the dopamine precursor 1-DOPA and of the full agonists (+)-3-PPP, 5-OH-DPAT, B-HT 920 (talipexole), apomorphine, and NPA (R-(-)-N-n-propylnorapomorphine) were not affected by pretreatment with EEDQ, the effects of supramaximal doses of the partial agonists (-)-HW-165, TDHL (terguride), SDZ208-911, (-)-3-PP) (preclamol), and SDZ 208-912 were reduced to 66%, 74%, 59%, 100%, and 100%, respectively. The effect of EEDQ on the intrinsic activity displayed by the various agonists corresponds inversely to the intrinsic efficacy displayed by the drugs in other models of D2 receptor function with one exception only; thus, the prolactin suppressive effect of (-)-3-PPP was more effectively antagonized by EEDQ than would have been predicted from the intrinsic efficacy usually attributed to the drug. Since the dose of EEDQ used in the present study has previously been shown not to decrease D2 receptor density in the pituitary as measured using in vivo radioligand binding, it is suggested that alkylation of D2 receptors may change the conformation of the individual receptor complexes in a way that decreases the responsiveness to partial but not full agonists.

Previous studies using clonidine indicate that alpha 2-adrenoceptors are involved in suppressing opiate-withdrawal symptoms. However, clonidine may act as a partial agonist at alpha 2-adrenoceptors and it also possesses significant alpha 1-receptor agonist activity. The aim of this study was to determine the role of alpha 2-adrenoceptors in the expression of opiate withdrawal signs using morphine-dependent rats. A range of agonists were selected for study on the basis of their differential preferences for alpha-adrenoceptors. Hooded Wistar rats were made physically dependent on morphine (s.c. injection of an emulsion releasing a total of 250 mg/kg of morphine base over 48 h). Test drugs were injected s.c. followed by naloxone (10 mg/kg i.p.) 20 min later. The incidence of 5 selected withdrawal signs was recorded during the following 20 min. The alpha 2-adrenoceptor agonists displayed different profiles of activity. Azepexole (1-10 mg/kg) reduced all signs. Clonidine (80-800 micrograms/kg) reduced all signs except paw shakes while guanfacine (25-250 micrograms/kg) reduced all except jumping and diarrhoea. Talipexole (0.1-1 mg/kg) reduced all signs except diarrhoea which was not affected and jumping which was markedly enhanced. UK 14,304 (80-800 micrograms/kg) reduced jumps, potentiated paw shakes but did not affect body shakes, teeth chattering or diarrhoea. The results suggest that there are subpopulations of alpha 2-adrenoceptors that modulate the expression of opiate withdrawal signs and/or that some of the drugs used affect receptors other than alpha 2-adrenoceptors.

The effects of different dopamine (DA) D 2 receptor agonists and the DA D 2 receptor antagonists, emonapride, on body temperature were studied in male mice. The aim of the study was to test whether DA D 2 receptor agonists ranging from full agonists to agonists with low efficacy could be differentiated by means of their effect on body temperature. Talipexole induced a marked hypothermia (maximum decrease of 6.5°C). Apomorphine, quinelorane, (+)-4-propyl-9-hydroxy-naphtoxazine ((+)-PHNO), and (−)-N-n-propylnorapomorphine ((−)-NPA) induced a maximum hypothermia of 3.5–4.1°C. Quinpirole and (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP) induced a less pronounced hypothermia (1.7 and 1.5°C), and preclamol ((−)-3-PPP), terguride and 3-(4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-(1))-butyl)-indole (EMD 23448) had no or only a slight effect. Emonapride induced significant hyperthermia at high doses. Apomorphine-, quinelorane- and talipexole-induced hypothermia was reversed by terguride and preclamol, whereas EMD 23448 partially reversed the apomorphine-induced hypothermia. The α 2 -adrenoceptor antagonist, idazoxan, partly reversed the effect of talipexole. Quinpirole had no effect on the hypothermic effect of the above-mentioned agonists. Pretreatment with the catecholamine synthesis inhibitor, α-methyl-m-tyrosine, increased significantly the hypothermic response to quinpirole, whereas the effect of quinelorane was unchanged. It is suggested that the effect of DA D 2 agonists on body temperature in mice can be used to differentiate between agonists with different efficacies. Talipexole, apomorphine, quinelorane, (−)-NPA and (+)-PHNO are classified as agonists with high efficacies. (+)-3-PPP is suggested to possess an efficacy lower than of the above-mentioned drugs, but higher than that of preclamol. EMD 23448 is suggested to possess an efficacy slightly higher than that od preclamol and terguride, but lower than that of (+)-3-PPP. The hyperthermic effect of emonapride (D 2 receptor antagonist) and the weak hypothermic effect of quinpirole (considered as a full agonist) were unexpected. Hypotheses for the mechanisms involved are discussed.

The present experiments were performed in order to investigate the effects of dopamine(DA)ergic drugs on the concentrations of extracellular glutamate (GLU) in the striatum of non-anaesthetised, freely moving rats by using microdialysis and to get further information about the interactions between glutamatergic and dopaminergic pathways. GLU was determined after pre-column derivatisation with o-phthaldialdehyde by HPLC and fluorescence detection. For increasing the fraction of extracellular GLU which is of neuronal origin, an enhanced release of this neurotransmitter was evoked by 100 mM K+ administered via the dialysis probe. This stimulation was applied twice in each experiment, at the second time after administration of a subcutaneously (s.c.) given DAergic drug. For basal conditions, a perfusion fluid containing 148.2 mM Na+, 4mM K+, 1.2 mM Ca2+ was used, for conditions of stimulation with 100 mM K+ the Na+ concentration was reduced correspondingly. Activation of the D1 receptor with the selective D1 sector agonist SKF 38393 ((+/-) 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) 15 mg/kg) failed to influence the stimulated release of GLU, and neither a combination of the selective D2 antagonist (-)sulpiride (150 mg/kg) with the mixed D1/D2 agonist apomorphine (1 mg/kg), nor a combination of sulpiride (150 mg/kg) with SKF 38393 (15 mg/kg) were effective. Also the two selective D2 agonists quinpirole (0.5 mg/kg) or talipexole (50 micrograms/kg) had no significant influence on the release of GLU. The results suggest that DA receptor agonists have less effect on the K(+)-stimulated GLU-release than might be expected from in vitro studies or behavioral experiments (Kornhuber and Kornhuber, 1986).

Pramipexole (SND 919) is a dopamine D2 autoreceptor agonist which is structurally related to talipexole (B-HT 920), a potential antipsychotic agent. The aim of this study was to investigate the effects of pramipexole on the extracellular concentration of dopamine in vivo. Dopamine and its metabolites, 3,4-dihydrophenylacetic acid and homovanillic acid, were measured in the anterior striatum of freely moving rats by microdialysis and high-performance liquid chromatography with electrochemical detection. Pramipexole (30 and 100 micrograms/kg) caused long-lasting decreases in the extracellular concentrations of dopamine and its metabolites. Talipexole (30 micrograms/kg) produced similar effects. Sulpiride (5 mg/kg), a selective dopamine D2 antagonist, caused a transient increase in the concentration of dopamine and long-lasting increases in the concentrations of its metabolites; it also reversed the effects of pramipexole. SCH-23390 (100 micrograms/kg), a selective dopamine D1 receptor antagonist, caused a transient increase in the concentration of dopamine but did not affect the concentrations of the metabolites. SCH-23390 failed to reverse the effects of pramipexole. These results indicate that pramipexole reduces the extracellular concentrations of dopamine and its metabolites in vivo through a reversible interaction with the dopamine D2 receptor.

The present experiments were performed to investigate differences in the properties of the dopamine D-2 receptors related to yawning and stereotypy. Subcutaneous injection of talipexole (B-HT 920) (10-250 micrograms/kg) or SND 919 ((S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole) (25-500 micrograms/kg) evoked yawning behavior with bell-shaped responses. However, SK&F 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (0.5-10 mg/kg SC) did not elicit yawning and decreased yawning responses to low doses of talipexole (25 micrograms/kg SC) or SND 919 (100 micrograms/kg SC). These low but effective doses for inducing yawning of talipexole or SND 919 in combination with SK&F 38393 (0.5-10 mg/kg SC) did not elicit stereotypy. In contrast, yawning behavior was not produced after very high doses of talipexole (500 micrograms/kg SC) or SND 919 (1000 micrograms/kg SC) given alone or in combination with SK&F 38393 (0.5-10 mg/kg SC). These extremely high doses of talipexole or SND 919 evoked slight stereotypy, which was enhanced by the combined treatment with SK&F 38393. The present results suggest that the dopamine D-2 receptors related to yawning are more sensitive to dopamine receptor agonists than those related to stereotypy, and that concurrent stimulation of postsynaptic dopamine D-1 receptors with D-2 receptors reduces the incidence of yawning but enhances that of stereotypy.

B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]azepine), an agonist at alpha 2-adrenoceptors and at dopamine autoreceptors, was tested with respect to stimulation of postsynaptic brain dopamine receptors in mice, rats and rhesus monkeys. In mice B-HT 920 (0.2-20 mg/kg s.c.) injected 4 h after reserpine did not stimulate locomotor activity; this was in contrast to apomorphine (0.1-10 mg/kg s.c.) which elicited locomotor activity in a dose-dependent manner. However, B-HT 920 was effective in inducing locomotor activity when injected 12, 24 and 48 h after reserpine. This effect was dose-dependent and increased with the duration of reserpine pretreatment. In naive rats, B-HT 920 (0.02-2.0 mg/kg s.c.) only decreased exploratory activity and did not elicit stereotyped activity in doses up to 4 mg/kg s.c. This was in contrast to the stereotypy-inducing effect of apomorphine (2.0 and 4.0 mg/kg s.c.). In rats with unilateral striatal ibotenic acid lesion, B-HT 920 (0.2-2.0 mg/kg s.c.) was ineffective in producing significant ipsilateral rotation, whereas apomorphine (0.5-10.0 mg/kg s.c.) was very potent in this model. In rats with unilateral 6-OH-dopamine lesions of the medial forebrain bundle B-HT 920 elicited strong contralateral rotation in a dose-dependent manner (0.02-1.0 mg/kg s.c.). In this model B-HT 920 was equi-effective but long acting when compared with apomorphine. The contralateral rotation produced by B-HT 920 was antagonized by the D2-antagonist sulpiride but not by the D1-antagonist SCH 23390. In rhesus monkeys with severe parkinson-like symptoms induced by MPTP, B-HT 920 in doses of 10 micrograms/kg i.m. and higher restored normal behavior, resulting in complete relief of parkinson symptoms in all animals with 100 micrograms/kg i.m. It is concluded that the property of B-HT 920 to stimulate the 'denervated' supersensitive (reserpine, 6-OH-dopamine, MPTP) but not the normosensitive postsynaptic dopamine receptor in the striatum may represent a novel principle for a specific approach to dopamine substitution treatment of Parkinson's disease.

1. The azepine derivatives B-HT 920 and B-HT 933 did not increase the motor activity of mice pretreated with reserpine or reserpine plus apomorphine, indicating that they do not stimulate postsynaptic dopamine receptors or noradrenaline α1-receptors in the brain. 2. The motor activity of mice not pretreated with reserpine was reduced by a low dose of B-HT 920 and by B-HT 933. The α1-adrenoceptor antagonist yohimbine reversed the sedation induced by B-HT 933, but not that induced by B-HT 920. 3. B-HT 933 and a high dose of B-HT 920 retarded the α-methyltyrosine-induced disappearance of noradrenaline in the mouse brain by a yohimbine-sensitive mechanism. 4. The α-methyltyrosine-induced disappearance of dopamine in the mouse brain was decelerated by a low dose of B-HT 920 and to a smaller degree by B-HT 933. The effects were inhibited by the dopamine receptor antagonist haloperidol. The effect of B-HT 933, but not that of B-HT 920, was partly antagonized by yohimbine. 5. The enhanced synthesis of dopamine in the corpus striatum of mice following treatment with gammabutyrolactone was completely antagonized by B-HT 920, but not by B-HT 933, via a haloperidol-sensitive mechanism. The synthesis of noradrenaline in the brain stem and in the hemispheres was reduced by B-HT 933 via a yohimbine-sensitive mechanism. 6. The results indicate that B-HT 920 can selectively and potently stimulate dopamine autoreceptor and that B-HT 933 can preferentially stimulate noradrenaline autoreceptors (α2-adrenoreceptors). These actions might cause the decreases in motor activity observed in mice not pretreated with reserpine.