Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the density of dopamine receptor subtypes and behaviors mediated by the D1-selective agonist SKF-38393 were examined in rats treated chronically with reserpine, SKF-38393 or the combination of these drugs. Animals received either vehicle or reserpine (1 mg/kg s.c.) on days 1 to 28 and, in addition, half of each of these groups were treated with vehicle and half were treated with SKF-38393 (5-10 mg/kg s.c.) on days 15 to 29. Quantitative autoradiographic measurement of D1 receptors labeled with [3H]SCH-23390 and D2 receptors labeled with [3H]spiroperidol revealed that chronic administration of reserpine increased the density of both receptor subtypes in the nucleus accumbens and caudate-putamen, but not in the substantia nigra. Chronic administration of SKF-38393 alone did not alter D1 receptor density in any of these regions. However, chronic administration of the agonist in reserpinized animals decreased D1 receptor density in the nucleus accumbens, but not in the caudate-putamen or substantia nigra, demonstrating that this partial agonist can selectively down-regulate D1 receptors when endogenous dopaminergic tone is removed. The chronic drug treatments also altered behavioral responses. Chronic administration of SKF-38393 alone produced sensitization of the oral dyskinesia response elicited by a challenge injection of the agonist, but no significant change in the grooming response. Acute administration of SKF-38393 in rats treated with reserpine for 14 days produced stereotypy which was not altered after chronic administration of the agonist. Surprisingly, chronic administration of reserpine alone produced a spontaneous oral dyskinesia, which was blocked dose-dependently by the D2-selective antagonist spiroperidol. These findings are discussed in terms of their relevance to Parkinson's disease and tardive dyskinesia.
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PMID:Behavioral and neurochemical effects of chronic administration of reserpine and SKF-38393 in rats. 203 24

The morphochemical disposition of the adenylate cyclase-linked dopamine receptor (D1 type) in the rat striatum has been assessed at various time points after a neurotoxic lesion of the dopaminergic afferent pathway to the caudate nucleus. D1 receptor binding sites in the caudate nucleus were determined by in vitro autoradiography of the substituted benzazepine D1 antagonists, [3H]SCH 23390 or [125I]SCH 23982, and contrasted to the pattern of striatal immunohistochemical reactivity of the second messenger compound, cyclic 3',5'-adenosine monophosphate. The results demonstrate that the specific association of this dopamine receptor type with cyclic 3',5'-adenosine monophosphate-stained neurons is abolished at 7 days following chemical interruption of the nigrostriatal pathway, and the receptor disruption is persistent for durations as long as 20 weeks. This investigation suggests that once the postsynaptic receptor pathology is produced by deafferentation, it does not recover the selective morphochemical relationship normally established with the target cell containing the second messenger. This is in contrast to modest biochemical recuperation in D1 dopamine receptor binding seen using this experimental paradigm. This change in D1 dopamine receptor morphochemistry is discussed in relation to the neurochemical deficits produced by dopaminergic denervation and in Parkinson's disease.
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PMID:Long-term changes in striatal D1 dopamine receptor distribution after dopaminergic deafferentation. 253

The distribution and density of dopamine D1 and D2 receptors were examined by autoradiography in postmortem brain tissue from patients with pathological diagnosis of Parkinson's disease, status lacunaris, clinical parkinsonism without neuropathological lesions and in age-matched controls. The D1 antagonist [3H]SCH 23390 and the D2 agonist [3H]CV 205-502 were used as ligands. No significant differences in the distribution or density of D1 or D2 receptors were found in Parkinson's disease in the areas examined, including the nucleus caudatus, putamen, globus pallidus and substantia nigra. In contrast, cases presenting lacunar lesions in the striatum showed marked decreases in D1 and D2 receptor densities in this region. Patients clinically diagnosed as parkinsonians but without Parkinson's disease lesions or striatal lacunar softenings showed reduced densities of D2 receptors in the nucleus caudatus and putamen, while in the substantia nigra the densities were comparable to controls. In the basal ganglia of these cases D1 receptors were slightly decreased.
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PMID:Dopamine receptors in human brain: autoradiographic distribution of D1 and D2 sites in Parkinson syndrome of different etiology. 265 Aug 6

Parkinson's disease results from the death of the dopamine-containing neurons in the substantia nigra pars compacta (SNC). This is accompanied by a loss of dopamine in brain regions, such as the corpus striatum, which receives input from dopaminergic neurons in the substantia nigra (SN). Since the corpus striatum is the primary target for these dopaminergic neurons, it has long been thought that the corpus striatum is the principal region affected. It was, therefore, natural to assume that replenishing dopamine in the striatum might be an effective treatment for Parkinson's disease. In fact, the dopamine precursor L-dihydroxyphenylalanine (L-dopa), the current drug of choice for treatment of Parkinson's disease, is believed to exert its therapeutic effect by replenishing dopamine levels in the corpus striatum via enzymatic decarboxylation within the synaptic terminals of surviving nigrostriatal neurons (Hornykiewicz, 1974). However, dopamine is also synthesized, stored, and released from the dendrites of SNC neurons that arborize in the substantia nigra pars reticulata (SNR) (Cheramy et al., 1981). Using a classic animal model for Parkinson's disease (rats with a unilateral 6-hydroxydopamine lesion of the SN), we show that L-dopa is also converted to dopamine in significant amounts within the 6-OHDA-lesioned SN. Furthermore, in contrast to the situation in the striatum where dopamine levels are only elevated for a short time, dopamine levels in the SN remain elevated until the behavioral effects of L-dopa have subsided. This elevation of nigral dopamine levels produces rotation that can be blocked by injecting a selective D1 dopamine receptor antagonist (SCH 23390, 2 micrograms in 1 microliter) directly into the SN pars reticulata. Infusion of SCH 23390 into the ipsilateral striatum produced only a modest reduction in L-dopa-induced circling behavior. These results suggest that D1 dopamine receptors in the SN may be at least as important as D1 dopamine receptors in the striatum as a site for the effects of L-dopa. This may have important implications for the therapy of Parkinson's disease.
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PMID:Evidence that L-dopa-induced rotational behavior is dependent on both striatal and nigral mechanisms. 279 65

We have investigated the anatomic localization of dopamine D1 and D2 receptors in the human brain using selective high affinity ligands for both types of dopamine receptors and the technique of receptor autoradiography. Dopamine D1 receptors were labeled in postmortem human brain tissue sections using the antagonist [3H]SCH 23390. Dopamine D2 receptors were labeled in consecutive tissue sections using the agonist [3H]205-502 and the antagonist [3H]spiroperidol. D1 and D2 dopamine receptors presented a heterogeneous distribution in the human brain. The highest concentrations of both D1 and D2 receptors were found in parts of the basal ganglia, particularly the nucleus caudatus and putamen. Lower concentrations were seen in other areas for example, the lateral globus pallidus was enriched in D2 receptors and the medial globus pallidus in D1 receptors. The substantia nigra contained intermediate densities of both D1 and D2, D1 receptors being present in higher concentrations. Dopamine D1 receptors were also localized in areas outside of the basal ganglia, particularly in the neocortex, amygdala and hippocampal formation. Dopamine D2 receptors were also present in areas outside of the basal ganglia, the most significant densities being found in the hippocampal formation. We observed a marked age-dependent decline in the density of D1 receptors during the first decades of life. In contrast, D2 receptor concentrations appeared to be unaltered with age. The distribution and densities of dopamine receptors were examined in 12 cases of Parkinson's disease and compared to a control adult population. No significant differences in density and distribution were seen for either D1 nor D2 receptors.
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PMID:Mapping dopamine receptors in the human brain. 296 52

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.
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PMID:The dopamine autoreceptor agonist B-HT 920 stimulates denervated postsynaptic brain dopamine receptors in rodent and primate models of Parkinson's disease: a novel approach to treatment. 381 49

To explore the possible therapeutic use of electric convulsive treatment in Parkinson's disease (PD), the authors examined the biochemical effects of electroconvulsive shock (ECS) on dopaminergic systems in a rodent model of PD, induced with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP increased dopamine turnover, as indicated by an increase in the ratio of the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to dopamine. [3H]Spiperone binding to the D2 site increased after lesioning of striatal dopamine terminals. With ECS alone, no changes were found in monoamine levels, brain monoamine oxidase activity, or the D2-labeled sites measured 24 hours after the last treatment. [3H]SCH-23390 binding to the D1 site increased after ECS. In MPTP-treated mice, ECS also increased [3H]SCH-23390 binding to the D1 site, whereas [3H]spiperone binding to the D2 site was unchanged compared to control or to only ECS-treated animals, and decreased compared to the MPTP-treated group that did not receive ECS. ECS appears to selectively modify both the D1 and D2 sites when given after MPTP, increasing the binding of a D1 radioligand and decreasing the binding of a D2 radioligand.
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PMID:The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice. 758 Jan 73

To clarify the roles of dopamine D1 and D2 receptors in behavioral symptoms of Parkinson's disease, antiparkinsonian effects of various dopamine agonists in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian monkeys were investigated with regard to induction of hyperactivity such as excitability, irritability and aggressiveness. The non-selective dopamine agonist apomorphine ameliorated the parkinsonism, but induced marked hyperactivity dose-dependently. Pretreatment with either the dopamine D1 antagonist SCH 23390 or the dopamine D2 antagonist sulpiride markedly suppressed the apomorphine-induced hyperactivity with slight attenuation of the antiparkinsonian effects. Both the dopamine D2-receptor agonist quinpirole and the dopamine D1-receptor agonist SKF 82958 ameliorated the parkinsonism in a dose-dependent manner with a slight induction of hyperactivity. Combination treatment of a threshold dose of quinpirole with that of SKF 82958 augmented the antiparkinsonian effects without a marked induction of hyperactivity. However, the combination treatment at higher doses induced marked hyperactivity accompanied by augmented antiparkinsonian effects. These results suggest that stimulation of either central dopamine D1 or D2 receptors is requisite for the antiparkinsonian effects and concurrent strong stimulation of both central dopamine D1 and D2 receptors causes marked hyperactivity which may be predictive of dopaminergic psychiatric side effects.
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PMID:Behavioral involvement of central dopamine D1 and D2 receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys. 761 86

Animal models with partial lesions of the dopaminergic nigrostriatal pathway may be useful for developing neuroprotective and neurotrophic therapies for Parkinson's disease. To develop such a model, different doses of 6-hydroxydopamine (0.0, 0.625, 1.25, 2.5 and 5.0 micrograms/microliters in 3.5 microliters of saline) were unilaterally injected into the striatum of rats. Animals that received 1.25 to 5.0 micrograms/microliters 6-hydroxydopamine displayed dose-dependent amphetamine and apomorphine-induced circling. 6-Hydroxydopamine also caused dose-dependent reductions in [3H]mazindol-labeled dopamine uptake sites in the lesioned striatum and ipsilateral substantia nigra pars compacta (up to 93% versus contralateral binding), with smaller losses in the nucleus accumbens, olfactory tubercle and ventral tegmental area. In the substantia nigra pars compacta and the ventral tegmental area, the number of Nissl-stained neurons decreases in parallel with the reduction in [3H]mazindol binding. The reduction in [3H]mazindol binding in the striatum and the nucleus accumbens, and the reduction in [3H]mazindol binding and in the number of Nissl-stained neurons in the substantia nigra pars compacta and the ventral tegmental area is stable for up to 12 weeks after the lesion. Macroscopically, forebrain coronal sections showed normal morphology, except for rats receiving 5.0 micrograms/microliters 6-hydroxydopamine in which striatal cross-sectional area was reduced, suggesting that this high dose non-specifically damages intrinsic striatal neurons. Nissl-stained sections revealed an area of neuronal loss and intense gliosis centered around the needle track, which increased in size with the dose of neurotoxin. Striatal [3H]sulpiride binding was increased by 2.5 micrograms/microliters and 5.0 micrograms/microliters 6-hydroxydopamine, suggesting up-regulation of dopamine D2 receptors. Striatal binding of [3H]CGS 21680-labeled adenosine A2a receptors, but not of [3H]SCH 23390-labeled dopamine D1 receptors, was reduced at the highest dose, suggesting preservation of the striatal intrinsic neurons with the lower doses. This study indicates that intrastriatal injection of different doses of 6-hydroxydopamine can be used to cause increasing amounts of dopamine denervation, which could model Parkinson's disease of varying degrees of severity. Injecting 3.5 microliters of 2.5 micrograms/microliters 6-hydroxydopamine appears to be particularly useful as a general model of early Parkinson's disease, since it induces a lesion characterized by robust drug-induced rotation, changes in binding consistent with approximately 70% dopamine denervation, approximately 19% dopamine D22 receptor up-regulation, negligible intrinsic striatal damage and stability for at least 12 weeks. This study outlines a technique for inducing partial lesions of the nigrostriatal dopamine pathway in rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. 767 92

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.
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PMID:Dihydrexidine, a full D1 dopamine receptor agonist, induces rotational asymmetry in hemiparkinsonian monkeys. 767 33


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