ergoline and Parkinson-Disease--Secondary

The ability of MPTP to induce persistent parkinsonism in man may provide a vital clue to the cause of the idiopathic disease. However, the peripheral administration of MPTP to rodent species only produces losses in brain dopamine content and damage to the nigrostriatal system in high doses and no persistent motor deficits have been observed. In contrast, in primates, the administration of MPTP rapidly induces a persistent parkinsonian syndrome accompanied by evidence for selective damage to the nigro-striatal dopamine containing system. Other neurotransmitter systems appear unaffected by MPTP treatment. The MPTP-treated primate responds to the administration of L-DOPA and other antiparkinsonian drugs and may provide a useful test-bed for the development of novel antiparkinsonian medication. Administration of MPTP to primates causes an accumulation of MPP+ in a variety of brain areas. The accumulation of MPP+ and the neurotoxic actions of MPTP in primates can be prevented by the prior administration of monoamine oxidase inhibitors. The ability of monoamine oxidase inhibitors to prevent MPTP toxicity is related to the metabolism of MPTP by monoamine oxidase B, probably extraneuronally in glia, to produce MPDP+ and subsequently MPP+. In rodent synaptosomal preparations MPP+ is a substrate for the dopamine uptake mechanism and so would be selectively accumulated in brain dopamine neurones. Administration of MPTP to animals results in the production of a partial model of idiopathic Parkinson's disease as it occurs in man. MPTP treatment produces the major symptoms of Parkinson's disease in primates but the pathology is limited to the nigro-striatal system, whereas in Parkinson's disease pathology is more widespread. Biochemical changes induced by MPTP again seem primarily limited to those induced by damage to the nigro-striatal dopamine containing system. MPP+ (or another metabolite of MPTP) may be responsible for the neurotoxicity of MPTP but not all neurones which accumulate products of MPTP metabolism are damaged. The nigro-striatal system may be peculiarly sensitive to the effects of MPTP.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Callithrix; Corpus Striatum; Disease Models, Animal; Dopamine; Ergolines; Humans; Levodopa; Macaca mulatta; Neural Pathways; Pargyline; Parkinson Disease; Parkinson Disease, Secondary; Pyridines; Quinpirole; Rats; Saimiri; Selegiline; Species Specificity; Substantia Nigra

Topics: Adult; Aged; Apomorphine; Clinical Trials as Topic; Ergolines; Humans; Infusion Pumps; Lisuride; Middle Aged; Parkinson Disease, Secondary

Topics: Acetonitriles; Adult; Antiparkinson Agents; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Ergolines; Female; Fluphenazine; Humans; Middle Aged; Parkinson Disease, Secondary; Prolactin; Schizophrenia

Nine patients suffering from Parkinson's disease and 2 cases of Parkinsonian syndrome were treated with bromocriptine, for 41 to 117 days, with a daily dose of 20 to 40 mg. The results were very good in 4 cases, satisfactory in 6 and nil in one case. Improvement concerned akinesias, rigidity and tremor, and was more marked in patients with more advanced signs. In 2 patients, amantadine was stopped. The dose of L-dopa was decreased by 2/3 without any change in clinical condition and L-dopa could be withdrawn in 5 cases out of 8. Bromocriptine appears to be an interesting development in the treatment of Parkinson's disease.

Topics: Aged; Amantadine; Bromocriptine; Clinical Trials as Topic; Drug Evaluation; Ergolines; Female; Humans; Hypotension; Levodopa; Male; Movement Disorders; Nausea; Parkinson Disease, Secondary

Topics: Adult; Aged; Clinical Trials as Topic; Drug Evaluation; Ergolines; Humans; Middle Aged; Parkinson Disease, Secondary

Topics: Animals; Antiparkinson Agents; Cabergoline; Caspase 12; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Ergolines; Male; Mice; Mice, Inbred ICR; Oligopeptides; Oxidopamine; Parkinson Disease, Secondary; Substantia Nigra; Transcription Factor CHOP

Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects (EPS). Role of 5-HT-2A/2C receptors in the attenuation of acute Parkinsonian-like effects of typical antipsychotics is investigated by prior administration of mianserin and mesulergine to rats injected with haloperidol. In the first part of study effects of various doses of haloperidol (0.5, 1.0, 2.5 and 5.0 mg/kg) were determined on motor activity and a selected dose (1 mg/kg) was used to monitor attenuation of parkinsonian effects by two different doses of 5-HT-2A/2C receptor antagonists mianserin (2.5 & 5.0 mg/kg) and mesulergine (1.0 & 3.0 mg/kg). Rats treated with haloperidol at doses of 0.5-5.0 mg/kg exhibited impaired motor coordination and a decrease in exploratory activity in an open field. The dose response curve showed that at a dose of 1 mg/kg significant and submaximal effects are produced on motor coordination and exploratory activity. Coadministration of mianserin and mesulergine attenuated and reversed haloperidol-induced motor deficits in a dose dependent manner. The mechanism involved in the attenuation / reversal of haloperidol-induced parkinsonian like symptoms by mianserin and mesulergine is discussed. Prior administration of mianserin or mesulergine may be of use in the alleviation of EPS induced by conventional antipsychotic drugs.The findings have potential implication in the treatment of schizophrenia and motor disorders.

Topics: Animals; Antipsychotic Agents; Catalepsy; Dopamine Agonists; Dyskinesia, Drug-Induced; Ergolines; Haloperidol; Male; Mianserin; Motor Activity; Parkinson Disease, Secondary; Psychomotor Performance; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors

Much evidence indicates that abnormal GABA neurotransmission may be implicated in the pathophysiology of Parkinson's disease (PD) and dopaminomimetic-induced dyskinesias (DID). In this study, autoradiography using (125)I-CGP 64213 was performed to investigate GABA(B) receptor density in the brain of control monkeys as well as monkeys with MPTP-induced nigrostriatal depletion. Three MPTP monkeys received pulsatile administrations of the D1 dopamine (DA) receptor agonist (SKF 82958) whereas a long-acting D2 DA receptor agonist (cabergoline) was given to another three animals. SKF 82958 treatment relieved parkinsonian symptoms but two of three animals developed DID. Cabergoline induced a comparable motor benefit effect without persistent DID. (125)I-CGP 64213 binding to GABA(B) receptors was heterogeneous throughout the brain with the highest levels in the medial habenula of the thalamus. MPTP induced a decrease (-40%) of (125)I-CGP 64213 binding to GABA(B) receptors in the substantia nigra pars compacta (SNpc) and an increase (+29%) in the internal segment of the globus pallidus (GPi). This increase in the GPi was not affected by SKF 82958 but partly reversed by cabergoline. No change was seen in the striatum, the thalamus, the external segment of the globus pallidus, and the substantia nigra pars reticulata following MPTP and dopaminomimetic treatments. The changes of GABA(B) receptors observed in the SNpc and in the GPi suggest that alteration of GABA(B) receptors may play a role in the pathophysiology of PD and DID.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Autoradiography; Basal Ganglia; Benzazepines; Benzoates; Binding Sites; Brain; Cabergoline; Corpus Striatum; Dopamine Agonists; Drug Administration Schedule; Dyskinesia, Drug-Induced; Ergolines; Female; GABA Antagonists; GABA-B Receptor Antagonists; Injections, Subcutaneous; Iodine Radioisotopes; Macaca fascicularis; Organophosphorus Compounds; Parkinson Disease, Secondary; Receptors, GABA-B; Substantia Nigra; Thalamus

Cabergoline is one of several ergoline dopamine agonist medications used in the treatment of Parkinson's disease (PD). We diagnosed constrictive pericarditis (CP) in a patient with PD receiving cabergoline therapy (10 mg daily), who had symptoms and signs of congestive heart failure (CHF). In the absence of previous reported cases of this condition linked to ergoline drugs, cabergoline was not initially identified as the cause. Shortly thereafter, however, the patient developed of a severe pleuropulmonary inflammatory-fibrotic syndrome, a recognized complication of ergoline medications, thus suggesting a common pathogenesis due to cabergoline therapy. To our knowledge, this is the first case in the English literature, although we speculate that CP may be more common than reported among patients with PD who are treated with an ergoline drug (cabergoline, bromocriptine, pergolide, or lisuride). The diagnosis of CP is difficult and requires a high level of suspicion; symptoms may masquerade as CHF due to common mechanisms such as coronary artery disease. In patients with PD who are taking not only cabergoline but also one of the other ergoline drugs, CP should be suspected if symptoms of CHF develop.

Topics: Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Humans; Lung Diseases; Male; Parkinson Disease, Secondary; Pericarditis, Constrictive; Pleural Diseases; Tomography, X-Ray Computed

The effects of a single treatment or chronic administration of cabergoline (1-[(6-allylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino)p ropyl]-3-ethyl-urea), a potent, long-lasting dopamine receptor agonist, on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in common marmosets were studied. The administration of 0.2 mg/kg or a higer dose of cabergoline began to reverse parkinsonism-like symptoms 60 min after a subcutaneous injection, and showed steady and constant effects throughout the observation period. For prolonged administration, 0.2 mg/kg cabergoline was injected daily for 22 consecutive days. Locomotor activity in MPTP-treated animals increased until it reached its peak on the third day, then it gradually decreased. Akinesia scores, rating the quality of movements, were also improved, and the improvement was sustained up to the last day of chronic administration. None of the animals developed abnormal behaviors after either acute or chronic administration. These results suggest that cabergoline has long-acting effects in the marmoset model of parkinsonism, and that it will be a useful agent for the treatment of Parkinson's disease, particularly in cases with fluctuating motor disabilities.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Cabergoline; Callithrix; Dopamine Agents; Dopamine Agonists; Ergolines; Female; Male; Motor Activity; Parkinson Disease, Secondary

The effects of dopamine receptor agonists on urinary bladder function were evaluated in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys to investigate the therapeutic efficacy in the treatment of urinary symptoms in Parkinson's disease. Under ketamine anesthesia, cystometrograms exhibited significant reduction in the volume threshold for the micturition reflex in MPTP-lesioned parkinsonian monkeys when compared with those of normal monkeys. The selective dopamine D2 receptor agonist bromocriptine significantly reduced the bladder volume threshold for the micturition reflex by 25 to 30% in both normal and MPTP-lesioned animals. The nonselective D1/D2 receptor agonist pergolide significantly reduced the bladder volume threshold by 22% in normal monkeys, but increased the volume threshold by 50% in MPTP-lesioned parkinsonian monkeys. Another D1/D2 agonist (5R,8R,10R)-6-methyl-8-(1,2,4-triazol-1-ylmethyl) ergoline maleate (BAM-1110) also increased the bladder volume threshold (by 80%) in parkinsonian monkeys without significant effects on the micturition reflex in normal monkeys. The reduction in the volume threshold by bromocriptine in both normal and MPTP-treated groups and by pergolide in normal monkeys was suppressed by pretreatment with the selective D2 antagonist sulpiride, whereas the increment in the volume threshold by pergolide and BAM-1110 in parkinsonian monkeys was antagonized by pretreatment with the selective D1 antagonist SCH 23390, but not by sulpiride. These findings suggest that concurrent activation of D1/D2 receptors, rather than selective stimulation of D2 receptors, might be beneficial for treating urinary symptoms caused by detrusor hyperreflexia in Parkinson's disease.

Topics: Animals; Bromocriptine; Dopamine Agonists; Ergolines; Macaca fascicularis; Male; MPTP Poisoning; Parkinson Disease, Secondary; Pergolide; Receptors, Dopamine D1; Receptors, Dopamine D2; Reflex; Triazoles; Urinary Bladder; Urination

Using an antibody that recognizes the products of all known members of the fos family of immediate early genes, it was demonstrated that destruction of the nigrostriatal pathway by 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle produces a prolonged (>3 months) elevation of Fos-like immunoreactivity in the striatum. Using retrograde tract tracing techniques, we have previously shown that this increase in Fos-like immunoreactivity is located predominantly in striatal neurons that project to the globus pallidus. In the present study, Western blots were performed on nuclear extracts from the intact and denervated striatum of 6-OHDA-lesioned rats to determine the nature of Fos-immunoreactive protein(s) responsible for this increase. Approximately 6 weeks after the 6-OHDA lesion, expression of two Fos-related antigens with apparent molecular masses of 43 and 45 kDa was enhanced in the denervated striatum. Chronic haloperidol administration also selectively elevated expression of these Fos-related antigens, suggesting that their induction after dopaminergic denervation is mediated by reduced activation of D2-like dopamine receptors. Western blot immunostaining using an antibody which recognizes the N-terminus of FosB indicated that the 43 and 45 kDa Fos-related antigens induced by dopaminergic denervation and chronic haloperidol administration may be related to a truncated form of FosB known as deltaFosB. Consistent with this proposal, retrograde tracing experiments confirmed that deltaFosB-like immunoreactivity in the deafferented striatum was located predominantly in striatopallidal neurons. Gel shift experiments demonstrated that elevated AP-1 binding activity in denervated striata contained FosB-like protein(s), suggesting that enhanced deltaFosB levels may mediate some of the effects of prolonged dopamine depletion on AP-1-regulated genes in striatopallidal neurons. In contrast, chronic administration of the D1-like receptor agonist CY 208243 to 6-OHDA-lesioned rats dramatically enhanced deltaFosB-like immunoreactivity in striatal neurons projecting to the substantia nigra. Western blot immunostaining revealed that deltaFosB and, to a lesser extent, FosB are elevated by chronic D1-like agonist administration. Both the quantitative reverse transcriptase-polymerase chain reaction and the ribonuclease protection assay demonstrated that deltafosB mRNA levels were substantially enhanced in the denervated striatum by chronic D1-like agonist adm

Topics: Animals; Bacterial Proteins; Base Sequence; Benzazepines; Blotting, Western; Cabergoline; Corpus Striatum; Denervation; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ergolines; Female; Gene Expression Regulation; Genes, fos; Haloperidol; Indoles; Macaca fascicularis; Male; Molecular Weight; MPTP Poisoning; Nerve Tissue Proteins; Oxidopamine; Parkinson Disease, Secondary; Phenanthridines; Polymerase Chain Reaction; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Receptors, Dopamine D1; RNA, Messenger; Species Specificity; Time Factors; Transcription Factors

The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2 mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038 mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Cabergoline; Drug Interactions; Dyskinesia, Drug-Induced; Ergolines; Hyperkinesis; Levodopa; Macaca fascicularis; Movement; Parkinson Disease, Secondary

Dihydrexidine (trans-10,11-dihydroxy5,6,6a,7,8,12b hexanhyydrobenso- [alpha]phenanthridine) is a full dopamine D1 agonist. In rhesus macaque monkeys rendered hemiparkinsonian by unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dihydrexidine (0.15-0.9 mg/kg) elicited dose-dependent contralateral rotation. The effects of dihydrexidine were blocked by pretreatment with the D1 antagonist SCH 23390 (0.03 mg/kg), but not by the D2 antagonist raclopride (0.025 mg/kg). These results suggest a functional role for D1 receptors in stimulating motor behavior in a primate model of Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Benzazepines; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Ergolines; Functional Laterality; Macaca mulatta; Male; Parkinson Disease, Secondary; Phenanthridines; Quinpirole; Raclopride; Receptors, Dopamine D1; Rotation; Salicylamides

The effects of co-administration of quinpirole with benzazepine D1 dopamine (DA) agonists possessing full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393 and SKF 75670) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) were investigated in rodent and primate models of Parkinson's disease (PD). In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle, co-administration of SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine), SKF 75670 (3-CH3 analogue), SKF 80723 (6-Br analogue), SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) strongly potentiated the contralateral circling induced by quinpirole. In MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) treated common marmosets, administration of quinpirole alone increased locomotor activity and reversed motor deficits. Grooming and oral activity were unaltered. Co-administration of SKF 38393 and SKF 75670 inhibited the quinpirole-induced changes in locomotor activity and motor disability. The combined treatment of SKF 80723 or SKF 82958 with quinpirole had no overall effect on locomotor activity or motor disability. In contrast, SKF 83959 extended the duration of the quinpirole-induced increase in locomotor activity with corresponding decreases in motor disability. Co-administration of high doses of SKF 82958 and more especially SKF 83959 and SKF 80723, with quinpirole induced hyperexcitability and seizures. Oral activity and grooming were unaltered following the co-administration of benzazepine derivatives with quinpirole. The ability of some benzazepine D1 DA agonists to prolong the antiparkinsonian effects of quinpirole in the MPTP-treated marmoset may indicate a role for certain D1 DA agonists in the clinical treatment of PD. In general, the behavioural responses to the combined administration of benzazepines with quinpirole in the 6-OHDA lesioned rat and more especially the MPTP-treated marmoset failed to correlate with their ability to stimulate AC. These observations further implicate a behavioural role for D1 DA receptors not linked to AC.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adenylyl Cyclases; Animals; Behavior, Animal; Callithrix; Dopamine Agonists; Ergolines; Female; In Vitro Techniques; Male; Parkinson Disease, Secondary; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine D1; Species Specificity

In common marmosets systemically treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the behavioural effects of benzazepine D1 dopamine (DA) agonists with full/supramaximal (SKF 80723 and SKF 82958), partial (SKF 38393, SKF 75670 and SKF 83565) and no efficacies (SKF 83959) in stimulating adenylate cyclase (AC) activity were investigated. The benzazepine derivatives, with the exception of SKF 82958 (8 fold D1 DA receptor selectivity), demonstrated high D1 DA receptor affinity and selectivity (approximately 100 fold or more) in rat striatal homogenates. Administration of MPTP in marmosets induced locomotor hypoactivity, rigidity and motor disability. SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) and SKF 75670 (3-CH3 analogue) further reduced locomotor activity (by -70 to -80%) and increased motor disability (by +22 to +67%) in these animals. SKF 83565 (6-Cl, 3-CH3, 3'-Cl analogue) and SKF 82958 (6-Cl, 3-C3H5 analogue) had only a slight effect on locomotor activity but decreased motor disability at high doses (-46 to -60%). In contrast, SKF 83959 (6-Cl, 3-CH3, 3'-CH3 analogue) and SKF 80723 (6-Br analogue) produced pronounced increases in locomotion (6-10 fold) and a reversal in motor disability (by -64 to -77%). Oral activity, consisting largely of abnormal, 'dyskinetic' tongue protrusions and vacuous chews, was increased in animals treated with SKF 38393, SKF 83565, SKF 82958 and more especially with SKF 80723 and SKF 83959. Grooming was increased with SKF 82958 and more especially with SKF 80723 and SKF 83959. In contrast, quinpirole (D2 DA agonist), reversed the MPTP-induced motor deficits in the marmoset, with no effect on grooming and oral activity. The present findings further demonstrate the antiparkinsonian actions of some D1 DA agonists in MPTP-treated primates. However, in general the behavioural effects of benzazepines failed to correlate with either their D1 DA receptor affinity/selectivity or their efficacy in stimulating adenylate cyclase (AC) activity. These observations further implicate a behavioural role for D1 DA receptors uncoupled to AC and/or a role for extrastriatal D1 DA receptors in mediating the behavioural response to D1 DA agonists.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Benzazepines; Binding, Competitive; Callithrix; Dopamine Agonists; Ergolines; In Vitro Techniques; Male; Parkinson Disease, Secondary; Quinpirole; Radioligand Assay; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Spiperone

Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM L-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The L-DOPA-induced decrease was not affected by (-)-sulpiride which completely blocked D2- and D3-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM D-DOPA nor 100 nM dopamine caused by any change in ACh release. These findings suggest that L-DOPA-sensitive mechanisms are supersensitized in Parkinson's disease model rats.

Topics: Acetylcholine; Analysis of Variance; Animals; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Drug Synergism; Ergolines; Levodopa; Male; Oxidopamine; Parkinson Disease, Secondary; Quinpirole; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes

The behavioral effects of cabergoline, pergolide and bromocriptine were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity, as evidenced by irritability, excitability and aggressiveness. All three drugs improved the parkinsonism in a dose-dependent fashion following a single injection. Among the three dopamine (DA) receptor agonists used, the antiparkinsonian effect of pergolide was the strongest and had an immediate effect, while cabergoline showed the longest duration of the antiparkinsonian effect and was least potent in inducing hyperactivity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Bromocriptine; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Macaca fascicularis; Parkinson Disease, Secondary; Pergolide

At present, the pharmacotherapy of Parkinson's disease (PD) consists mainly of L-dihydroxyphenylalanine (L-DOPA) and/or dopamine D2 receptor agonists. However, in general the clinical efficacy of D2 agonists is less than that of L-DOPA. Therefore, attention is being focussed on the role of the D1 receptor as a target for therapeutic intervention in PD. Recently, we reported that SKF 81297 is a selective D1 agonist that stimulates motor behavior of unilaterally MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned rhesus monkeys. Presently, we studied the effect of coadministration of SKF 81297 and the D2 agonist LY 171555 using the same model of PD. Coadministration of behaviorally active doses of SKF 81297 (0.3 mg/kg) and LY 171555 (0.01 mg/kg) resulted in a prolongation of the motor stimulation induced by either of the drugs alone. Neither administration of SKF 81297, in a dose of 0.03 mg/kg, nor of LY 171555, in a dose of 0.003 mg/kg, were behaviorally active, whereas the combined administration of these compounds induced a significant stimulation of motor behavior. These data suggest that (a) D1 receptor stimulation will prove to be useful in the treatment of PD and (b) better therapeutic results will be obtained by simultaneous stimulation of D1 and D2 receptors as compared with stimulation of both receptors alone.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzazepines; Corpus Striatum; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Macaca mulatta; Male; Motor Activity; Motor Skills; Parkinson Disease, Secondary; Psychomotor Performance; Quinpirole; Receptors, Dopamine D1; Receptors, Dopamine D2; Stereotyped Behavior; Substantia Nigra

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

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

Using striatal microdialysis, we studied effects of SKF 38393, a D1 agonist, and quinpirole, a D2 agonist, on the acetylcholine (ACh) release from the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats by local infusion into the striatum. The present experiments clearly demonstrated evidence for the existence of intrastriatal D1 and D2 receptors regulating ACh release and for supersensitization of the striatal stimulatory D1 and inhibitory D2 receptor mechanisms in 6-OHDA lesioned rats.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acetylcholine; Animals; Benzazepines; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ergolines; Male; Microdialysis; Neostriatum; Neurons; Oxidopamine; Parkinson Disease, Secondary; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulpiride; Sympathectomy, Chemical

Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson's disease. Although the biochemical and the behavioural effects of striatal denervation have been widely characterized, the physiological and pharmacological changes caused by dopamine depletion at the cellular level are still unknown. We studied the electrical activity of single rat striatal neurons recorded intracellularly in vitro from a brain slice preparation. Recordings were obtained at different periods after the denervation (4, 6, 8 months). In dopamine-denervated slices, unlike naive slices, most of the neurons showed spontaneous depolarizing postsynaptic potentials. The percentage of cells showing spontaneous depolarizing postsynaptic potentials was maximal 4 months after the denervation. In most of the dopamine-denervated neurons (60%) spontaneous depolarizing postsynaptic potentials were reversibly blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an antagonist of non-N-methyl-D-aspartate glutamate receptors. In some neurons, however, the amplitude of spontaneous depolarizing postsynaptic potentials was reduced by bicuculline (30 microM) suggesting that they were mediated by the release of endogenous gamma-aminobutyric acid (GABA). Intrinsic membrane properties (membrane potential, input resistance and firing pattern) and postsynaptic responses to different agonists of excitatory amino acid receptors were not altered in neurons recorded from dopamine-depleted slices. In dopamine-depleted slices, unlike in naive slices, LY 171555 (0.1-10 microM), a D2 dopamine receptor agonist, reduced the frequency and the amplitude of CNQX-sensitive spontaneous depolarizing postsynaptic potentials and reduced the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. LY 171555 did not affect the membrane responses to exogenous glutamate. SKF 38393 (3 microM), a D1 dopamine receptor agonist, decreased postsynaptic excitability of striatal neurons recorded from naive animals. On the contrary, this agonist was ineffective in most of the cells obtained from dopamine-depleted slices. These results suggest that dopamine-denervation augments neuronal excitability in the striatum. Abnormal excitability of striatal neurons is not caused by changes of the intrinsic membrane properties of these cells, but is the result of increased glutamatergic cortical inputs to the striatum. Dopamine-denervation also

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Corpus Striatum; Denervation; Dopamine; Dopamine Agents; Ergolines; Male; Oxidopamine; Parkinson Disease, Secondary; Quinoxalines; Quinpirole; Rats; Rats, Wistar; Substantia Nigra; Synaptic Membranes; Tetrodotoxin

A pharmacological study using monkeys, in which parkinsonism was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was undertaken to elucidate the mechanism underlying urinary bladder dysfunctions in Parkinson's disease. Under ketamine anesthesia, cystometrograms showed that, in MPTP-treated monkeys, a contraction of the urinary bladder was induced with smaller bladder volume than that in normal monkeys. In MPTP-treated monkeys, subcutaneously injected SKF 38393, a dopamine D1 receptor agonist, significantly increased the bladder volume and pressure thresholds for inducing the micturition reflex without affecting those in normal monkeys. In contrast, subcutaneous injections of quinpirole, a dopamine D2 receptor agonist, and apomorphine, a dopamine D1 and D2 receptor agonist, slightly, but significantly reduced the volume threshold of the bladder for the micturition reflex in both normal and MPTP-treated groups. These results indicate that, in parkinsonism, the degeneration of dopaminergic neurons in the substantia nigra leads to the detrusor hyperreflexia, probably due to a failure of activation of dopamine D1 receptors.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Dopamine Agents; Ergolines; Macaca fascicularis; Male; Parkinson Disease, Secondary; Quinpirole; Reflex; Urinary Bladder; Urination

While intrastriatal transplants of dopamine-rich ventral mesencephalic tissue are effective in reversing a variety of drug-induced behaviors in the rat Parkinson model, previous studies have failed to obtain significant graft-induced effects on deficits in certain aspects of complex sensorimotor behaviors. In the present study we have applied a modified cell suspension transplantation procedure, which allows more reproducible and consistent ventral mesencephalic transplants of large size, as well as more wide-spread distribution of the ventral mesencephalic tissue over multiple graft sites within the denervated caudate-putamen. Using this approach it has for the first time been possible to obtain significant amelioration of the lesion-induced deficits in skilled forelimb use and in the rats ability to switch from one behavior (eating) to another (orientation towards tactile stimuli), so-called disengage behavior. Rats with unilateral 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received a total of 450,000 fetal ventral mesencephalic cells, implanted either as two large deposits along a single injection tract ("Macro" grafts), or as 18 small deposits along six injection tracts in the head of the denervated caudate-putamen ("Micro" grafts) and the behavioral changes were studied up to three months after transplantation. On the drug-induced tests, both types of transplants reversed amphetamine- and D1-receptor agonist-induced turning, and produced a partial (50-75%) reduction in apomorphine-induced and D2-receptor agonist-induced turning. On the spontaneous sensorimotor tests, both types of grafts reversed the deficit in simple sensorimotor orientation. In addition, the Micro-grafted animals (which produced the most extensive reinnervation of the denervated striatum) showed a significant improvement in skilled forelimb use and in response latency in the disengage behavior test. Although the large sized Macro-grafted animals showed a similar trend, it did not reach significance. Moreover, the Micro grafts had a more pronounced effect on spontaneous turning behavior in a conditioned response test. The improvement in response latency in the disengage test was significantly correlated with the dopamine level in the nucleus accumbens, whereas the magnitude of the conditioned turning response was significantly correlated with the dopamine levels in the head of the caudate-putamen. The results show that intrastriatal nigral transplants, despite th

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Behavior, Animal; Brain Tissue Transplantation; Caudate Nucleus; Corpus Striatum; Denervation; Dextroamphetamine; Dopamine; Ergolines; Feeding Behavior; Female; Fetal Tissue Transplantation; Forelimb; Motor Activity; Orientation; Oxidopamine; Parkinson Disease, Secondary; Putamen; Quinpirole; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Regression Analysis; Rotation; Substantia Nigra

The antitremor effect of the D2 agonist LY 171555 and of the D1 agonist CY 208-243 alone and in combination was tested in a monkey previously rendered parkinsonian by MPTP and displaying exceptionally a rest tremor in the limbs. The D2 agonist suppressed rest tremor in a dose-dependent fashion. The D1 agonist by itself had no effect but it potentiated the effect of a small dose of LY 171555.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Dopamine Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electromyography; Ergolines; Female; Indoles; Injections, Subcutaneous; Macaca fascicularis; Parkinson Disease, Secondary; Phenanthridines; Quinpirole; Tremor

Based on the hypothesis that low-threshold calcium conductance in the thalamus might be involved in the pathophysiology of parkinsonian tremor, ethosuximide was given chronically to a monkey previously treated with MPTP and displaying exceptionally a typical rest tremor. After 5 days of daily treatment, the tremor was reduced by 60%. Diltiazem and verapamil which act on different calcium channels had no such effect. Ethosuximide also potentiated the anti-tremor effect of the dopamine D2 agonist LY-171555.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Diltiazem; Dopamine Agents; Dose-Response Relationship, Drug; Electromyography; Ergolines; Ethosuximide; Female; Macaca fascicularis; Neurologic Examination; Parkinson Disease, Secondary; Quinpirole; Tremor; Verapamil

In a modified MPTP model of Parkinson's disease in the marmoset, both L-DOPA and the dopamine D2 agonist quinpirole were found to exhibit anti-bradykinetic activity. Both the dopamine D1 agonist SKF38393 and the D1 antagonist SCH23390 reduced the anti-bradykinetic action of L-DOPA and quinpirole. These results are discussed with respect to partial agonist activity of SKF38393 and the possibility that other dopamine receptors may be required for anti-Parkinsonian drug activity.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Callithrix; Dopamine Agents; Ergolines; Female; Levodopa; Male; Movement; Parkinson Disease, Secondary; Quinpirole; Receptors, Dopamine D1; Receptors, Dopamine D2

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benserazide; Dizocilpine Maleate; Dopamine Agents; Ergolines; Hydroxydopamines; Levodopa; Male; Medial Forebrain Bundle; Oxidopamine; Parkinson Disease, Secondary; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism; Stereotyped Behavior

The effect of a selective agonist of the dopamine D1 receptor (SKF 38393) and of the D2 receptor (LY-171555) was tested acutely in normal and in monkeys with a parkinsonian syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D2 agonist induced a strong locomotor response and lingual dyskinesia in both normal and parkinsonian monkeys. The D1 agonist however had no locomotor effect by itself but induced tongue protrusions in normal monkeys only. It appeared to potentiate the dyskinetic effect of LY 171555 in MPTP monkeys but it antagonized the locomotor action of the D2 agonist in both normal and MPTP monkeys. The selective D1 and D2 antagonists SCH 23390 and sulpiride were also tested. Both compounds were able to suppress the dyskinetic action of the combined agonists in normal animals but only the D2 antagonist was effective in the same conditions in MPTP monkeys. These findings emphasize the importance of the D2 receptor in mediating the locomotor response as well as dyskinesia in monkeys.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Dopamine Agents; Dopamine Antagonists; Dyskinesia, Drug-Induced; Ergolines; Female; Macaca fascicularis; Motor Activity; Parkinson Disease, Secondary; Quinpirole; Receptors, Dopamine; Receptors, Dopamine D1; Sulpiride

The relationship between severity of dopa-induced parkinsonian symptoms and the latency and severity of dopa-induced dyskinesias was studied in monkeys exposed to the toxin MPTP. Levodopa and D-2 receptor agonist-induced dyskinesias appeared early, between 2 and 12 days after initiation of dopa therapy in severely parkinsonian animals. In these animals, it was difficult to find a dose of L-dopa which had beneficial effects clinically and no dyskinesia-producing effects. These animals were all found to have massive (greater than or equal to 95%) striatal dopamine loss. A monkey with mild parkinsonian symptoms never developed dyskinesias similar to those produced in the severely affected animals. Stereotypies could be induced in this animal with excessively high doses of L-dopa or the dopamine D-2 receptor agonist, LY-171555. These movements were controlled by reducing the drug dose. This animal had less severe striatal dopamine loss (less than 80%) than the former group of monkeys. These results suggest that dopa dyskinesias in parkinsonian monkeys may be related to the extent of damage sustained by the nigrostriatal system.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Ergolines; Levodopa; Macaca fascicularis; Parkinson Disease, Secondary; Quinpirole

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5-2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. These drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apomorphine; Dose-Response Relationship, Drug; Ergolines; Injections, Intravenous; Levodopa; Macaca fascicularis; Movement Disorders; Parkinson Disease, Secondary; Pyridines; Quinpirole; Stereotyped Behavior

The partial dopamine agonist terguride (transdihydrolisuride) administered to four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian monkeys (at a dose of 4 mg/kg orally) induced marked contralateral turning that lasted 3.5 h. The 6-n-propyl derivative of terguride (proterguride) given to two monkeys (at a dose of 0.4 mg/kg orally) caused contralateral turning which lasted for more than 24 h but produced side effects such as dyskinesia and stereotype. After terguride treatment, cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG) were increased, whereas concentrations of the metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were not significantly altered.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Ergolines; Female; Lisuride; Macaca fascicularis; Parkinson Disease, Secondary; Pyridines; Receptors, Dopamine

Marmosets treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p. daily for up to 8 days) develop profound parkinsonian akinesia. Administration of the D1 agonist SKF 38393 (1-20 mg/kg i.p.) 4-6 weeks later had no effect on the motor activity of animals pretreated with MPTP. In contrast, the administration of the D2 agonist LY 141865 (0.1 or 0.5 mg/kg i.p.) caused a marked increase in motor activity lasting for up to 2 h. We conclude that stimulation of D2 dopamine receptors is essential for motor activation of parkinsonian marmosets and that D1 stimulation alone is not sufficient to overcome the akinesia induced by MPTP treatment.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antiparkinson Agents; Benzazepines; Callitrichinae; Ergolines; Female; Male; Parkinson Disease, Secondary; Pyridines; Quinpirole; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2

Lisuride is a soluble ergolene derivative with endocrine effects similar to but more potent than those of bromocriptine. In nine subjects with idiopathic, postencephalitic, or drug-induced parkinsonism, lisuride at a dosage of 0.05 to 0.15 mg intravenously caused an immediate improvement in tremor, rigidity, akinesia, and postural deformity, but also caused chorea and orofacial dyskinesia. Improvement lasted 2 to 3 hours. Lisuride had little or no effect in a single patient with progressively supranuclear palsy. Oral lisuride therapy, 0.8 to 4.8 mg daily, had similar effects but occasionally caused reduced awareness and hallucinations.

Topics: Administration, Oral; Aged; Benzimidazoles; Chorea; Domperidone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Growth Hormone; Humans; Injections, Intravenous; Lisuride; Male; Middle Aged; Paralysis; Parkinson Disease; Parkinson Disease, Postencephalitic; Parkinson Disease, Secondary; Piperidines; Prolactin

Topics: Aged; Bromocriptine; Ergolines; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Pituitary Hormones