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)

The effects of single doses of haloperidol (2, 4 and 6 mg) were compared with lorazepam 2.5 mg and placebo in 15 healthy subjects. Visual search strategy was measured, along with a range of psychomotor and eye movement tests. Patients with Parkinson's disease have been shown to exhibit a shift from parallel to serial processing in visual search, but we demonstrated that this does not occur following administration of either haloperidol or lorazepam. Haloperidol was detected by visual analogue rating scales and peak saccadic velocity, the latter being the more sensitive measure. Haloperidol had no statistically significant effect on smooth pursuit position error, velocity error or saccadic intrusions. Digit symbol substitution performance was clearly diminished by haloperidol, but there was no effect on the continuous attention test. Lorazepam decreased performance in all tests apart from saccadic latency.
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PMID:The effects of haloperidol on visual search, eye movements and psychomotor performance. 936 28

Antiparkinsonian-like activity of glutamate receptor antagonists (mostly of N-methyl-D-aspartate (NMDA) receptors) has been demonstrated in animals and for uncompetitive agents, also in humans. In the present study we investigated the potential antiparkinsonian-like activity of compounds acting at the glycine site of the NMDA receptor complex in three animal models of Parkinson's disease and compared them with the new uncompetitive NMDA receptor antagonist MRZ 2/579. Haloperidol-induced catalepsy was inhibited by the Merz glycine site antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 but not by another antagonist L-701,324 or the glycine site partial agonists ACPC and D-CS. None of the tested glycine site antagonists or partial agonists increased locomotor activity or potentiated L-DOPA responses in reserpine and alpha-MT treated rats. In rats with a unilateral 6-OHDA medial forebrain bundle lesion neither glycine site antagonists nor partial agonists affected rotations on their own or enhanced the contralateral rotations induced by L-DOPA. In contrast, the uncompetitive NMDA receptor antagonist MRZ 2/579 was active in all antiparkinsonian tests used in this study. Based on the present data the therapeutic potential of the glycine site antagonists and partial agonists tested for the treatment of Parkinson's disease is rather doubtful. Uncompetitive NMDA receptor antagonists seem to possess a better profile as antiparkinsonian agents.
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PMID:GlycineB antagonists and partial agonists in rodent models of Parkinson's disease--comparison with uncompetitive N-methyl-D-aspartate receptor antagonist. 1019 2

An interaction between brain serotonergic and dopaminergic systems involving 5-HT(1B) receptors may contribute to motor complications arising from the drug treatment of neurological and psychiatric disorders. This study assessed the effects of treatment with a non-selective 5-HT(1B/D) receptor agonist and a selective 5-HT(1B) receptor antagonist on akinesia induced in marmosets by long-term treatment with haloperidol and on motor disability and l-3, 4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. In marmosets treated chronically with haloperidol, the 5-HT(1B) agonist SKF-99101-H reduced locomotor activity and induced motor disability, whereas the 5-HT(1B) antagonist SB-224289-A had no effect on motor behaviour. Haloperidol administration induced a suppression of locomotor activity which was not reversed by co-administration of either SKF-99101-H or SB-224289-A. In MPTP-treated common marmosets, neither SKF-99101-H nor SB-224289-A induced any significant change in motor function. However, SKF-99101-H inhibited L-DOPA-induced dyskinesia and the reversal of motor deficits whereas SB-224289-A was without effect. The results of this study indicate that the 5-HT(1B) receptor appears not to be an appropriate target for the treatment of Parkinson's disease (PD) or for the control of drug-induced motor complications developed as a tong-term consequence of neuroleptic or L-DOPA treatment.
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PMID:Effect of 5-HT1B/D receptor agonist and antagonist administration on motor function in haloperidol and MPTP-treated common marmosets. 1558 11

The Dutch Association of Psychiatry, together with the Dutch Association of Clinical Geriatrics and with methodological support from the Dutch Institute for Healthcare Improvement (CBO) has developed a guideline for the optimal diagnosis, treatment and prevention of delirium. Delirium is caused by somatic illness or the use of medication, drugs or alcohol. Delirium is common among the somatically ill admitted to a general hospital and is associated with increased morbidity and mortality. Important predisposing factors for delirium are: age > or =70 years, cognitive disturbances, sensory impairments, problems in daily activities, and the use of alcohol and opiates. Precipitating factors that may provoke delirium are: infection, fever, dehydration, serum electrolyte imbalance, polypharmacy, and the use of psychotropic medication, particularly anticholinergic drugs. Detection, diagnosis, and assessment of the severity of delirium are based on clinical examination, case history, observation, mental status examination including tests of cognitive function, and diagnosis of underlying somatic diseases. For daily practice, measurement tools are not necessary, nor are laboratory or imaging tests, such as electroencephalography. Haloperidol is the treatment of first choice for delirium due to somatic illness, except in patients with delirium due to drug use or medication, Parkinson's disease or Lewy body dementia. In cases of concurrent alcohol withdrawal syndrome, delirium may be treated with haloperidol and a benzodiazepine and B-vitamins. Medical and environmental interventions have been shown to reduce the incidence and duration of delirium.
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PMID:[Guideline 'Delirium']. 1590 90

It is well established that nicotine activates brain dopaminergic systems and in addition has neuroprotective actions. Thus, nicotinic acetylcholine receptor (nAChR) agonists might be beneficial in the treatment of Parkinson's disease, and it is important to study the interactions of nicotine with drugs affecting the nigrostriatal dopaminergic pathway. We used brain microdialysis to study the effects of nicotine on extracellular levels of dopamine (DA) and its metabolites in the rat dorsal striatum in combination with drugs inhibiting either DA uptake (nomifensine), catechol-O-methyltransferase (COMT; tolcapone), monoamine oxidase B (MAO-B; selegiline) or DA receptors (haloperidol). Nicotine (0.5 mg/kg, s.c.) modestly increased DA output, and this effect was antagonised by mecamylamine but not by hexamethonium. Nomifensine (3 mg/kg, i.p.) substantially further enhanced the nicotine-induced increase in DA output and nomifensine+nicotine also evoked a strong mecamylamine-sensitive ipsilateral rotational behaviour in 6-hydroxydopamine lesioned rats. Tolcapone (10 mg/kg, i.p.) did not alter DA output, but markedly decreased homovanillic acid (HVA) and increased 3,4-dihydroxyphenylacetic acid (DOPAC). Selegiline pretreatment (5 x 1 mg/kg, i.p.) significantly increased extracellular DA and decreased DOPAC and HVA. Haloperidol (0.1 mg/kg, s.c.) slightly increased DA output and more clearly DOPAC and HVA. Tolcapone, selegiline or haloperidol did not enhance the nicotine-induced DA output. These results indicate that the activation of nigrostriatal nAChRs induces a significant DA release in the striatum, which is potentiated by DA uptake inhibition but not by COMT, MAO-B or presynaptic DA receptor inhibition. Our findings therefore agree with the notion that the termination of the effect of DA in the synapse mainly occurs via neuronal reuptake. Thus, selective nAChR agonists, possibly in combination with a DA uptake inhibitor, might improve dopaminergic transmission in Parkinson's disease.
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PMID:The effect of nicotine in combination with various dopaminergic drugs on nigrostriatal dopamine in rats. 1601 72

Apomorphine (Apo), a dopaminergic agonist used for treatment of Parkinson disease, is a potent antioxidant. In addition to its antioxidative effects, the dopaminergic and adrenergic effects of Apo were studied. Isolated perfused rat hearts were exposed to 25 min of no-flow global ischemia (37 degrees C) and 60 min of reperfusion (I/R, control). Drugs were introduced for the first 20 min of reperfusion. The LVDP of the control group recovered to 54.6 +/- 3.3%. Apo-treated hearts had significantly improved recovery (61.6 +/- 5%, p < 0.05). The recovery of the work index LVDP x HR was even bigger: 67.8 +/- 3.7% (Apo treatment) vs 41.7 +/- 4.6% (control, p < 0.001). Haloperidol, a dopaminergic antagonist, did not affect the recovery with Apo. Propranolol, a beta-adrenergic blocker, initially inhibited the effect of Apo. However, the recovery of the combined group (Apo + propranolol) increased and reached significance (LVDP, p < 0.05 vs control group) after cessation of propranolol perfusion. At 60 min of reperfusion this group was superior to Apo-treated hearts (LVDP, p < 0.05). Propranolol (without Apo) did not improve the hemodynamic recovery. The same pattern of recovery applies also to the recovery of the +dP/dt during the reperfusion. L-DOPA was less effective than Apo. I/R caused significant increase in carbonylation of proteins. Apomorphine inhibited the increase in carbonylation. Haloperidol did not affect this beneficial effect of Apo. L-DOPA significantly decreased the carbonylation of proteins. We conclude that the antioxidative effect of Apo is its main mechanism of cardioprotection.
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PMID:Apomorphine-induced myocardial protection is due to antioxidant and not adrenergic/dopaminergic effects. 1667 10

Investigation of the pathophysiology of psychosis in Parkinson's disease (PD), as well as the assessment of potential novel therapeutics, has been limited by the lack of a well-validated animal model. MPTP-lesioned primates exhibit abnormal behaviors that are distinct from dyskinesia and parkinsonism and may represent behavioral correlates of neural processes related to psychosis in PD. Here we assess four types of behavior--agitation, hallucinatory-like responses to nonapparent stimuli, obsessive grooming, and stereotypies that are termed "psychosis-like"--and define their pharmacology using a psychosis-like behavior rating scale. By assessing the actions of drugs known to enhance or attenuate psychosis in PD patients, we find that the pharmacology of these behaviors recapitulates, in several respects, the pharmacology of psychosis in PD. Thus, levodopa and apomorphine elicited psychosis-like behaviors. Amantadine significantly decreased levodopa-induced dyskinesia but exacerbated psychosis-like behaviors. Haloperidol reduced psychosis-like behaviors but at the expense of increased parkinsonian disability while the atypical neuroleptics clozapine and quetiapine reduced psychosis-like behaviors without significant effect on parkinsonian disability. The response of different components of the psychotomimetic behavior suggested the involvement of both dopaminergic and nondopaminergic mechanisms in their expression.
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PMID:Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease. 1696 Aug 62

Group III metabotropic glutamate receptors (mGluRs) are widely distributed in the basal ganglia, especially on the terminals of pathways which seem to be overactive in Parkinson's disease. The aim of the present study was to determine whether (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-1), an agonist of group III mGluRs, injected bilaterally into the globus pallidus (GP), striatum or substantia nigra pars reticulata (SNr), can attenuate the haloperidol-induced catalepsy in rats, and whether that effect was related to modulation of proenkephalin (PENK) or prodynorphin (PDYN) mRNA expression in the striatum. Administration of ACPT-1 (0.05-1.6 microg/0.5 microl/side) caused a dose-and-structure-dependent decrease in the haloperidol (0.5 mg/kg i.p. or 1.5 mg/kg s.c.)-induced catalepsy whose order was as follows: GP>striatum>SNr. ACPT-1, given alone to any of those structures, induced no catalepsy in rats. Haloperidol (3 x 1.5 mg/kg s.c.) significantly increased PENK mRNA expression in the striatum, while PDYN mRNA levels were not affected by that treatment. ACPT-1 (3 x 1.6 microg/0.5 microl/side) injected into the striatum significantly attenuated the haloperidol-increased PENK mRNA expression, whereas administration of that compound into the GP or SNr did not influence the haloperidol-increased striatal PENK mRNA levels. Our results demonstrate that stimulation of group III mGluRs in the striatum, GP or SNr exerts antiparkinsonian-like effects in rats. The anticataleptic effect of intrastriatally injected ACPT-1 seems to correlate with diminished striatal PENK mRNA expression. However, since the anticataleptic effect produced by intrapallidal and intranigral injection of ACPT-1 is not related to a simultaneous decrease in striatal PENK mRNA levels, it is likely that a decrease in enkephalin biosynthesis is not a necessary condition to obtain an antiparkinsonian effect.
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PMID:The influence of group III metabotropic glutamate receptor stimulation by (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid on the parkinsonian-like akinesia and striatal proenkephalin and prodynorphin mRNA expression in rats. 1722 39

Deep brain stimulation (DBS) of the subthalamic nucleus has been used extensively in the treatment of Parkinson's disease. However, the efficacy of such treatments on bradykinesia/akinesia remains low. DBS of the posterior hypothalamic nucleus (PH) elicits spontaneous, non-stereotypical motor behaviours. We tested the hypothesis that PH stimulation could restore movement in animals made cataleptic by the D(2) receptor antagonist haloperidol. We further hypothesized that hippocampal-striatal neural synchrony may be important in the organization of motor behaviours. Animals chronically implanted with hippocampal and striatal recording electrodes and PH stimulating electrode were tested in open field, catalepsy and active avoidance paradigms. The degree of hippocampal-striatal theta (5-10 Hz) field coherence was assessed during baseline avoidance testing and following the administration of haloperidol. Haloperidol abolished movement in open field and active avoidance tasks and increased the latency to respond in the catalepsy test. Stimulation of the PH under haloperidol reversed catalepsy. Hippocampal-striatal theta coherence was high throughout the active avoidance task in control experiments but was greatly reduced under haloperidol. PH stimulation was able to reinstate the hippocampal-striatal theta coherence while restoring task-related behaviours. These results support the hypothesis that DBS of the PH could restore motor behaviours in rats made cataleptic with haloperidol, thus providing strong support for the PH as a promising candidate for DBS in the treatment of Parkinson's disease. Furthermore, the results support the view that hippocampal-striatal theta coherence may be important for the planning and execution of goal-oriented behaviors.
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PMID:High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy. 1863 77

Increased oxidative stress has been implicated in the pathogenesis of dopaminergic neurodegeneration leading to the development of Parkinson's disease. In this study, we investigated whether naphtha[1,2-d]thiazol-2-amine (NTA) may ameliorate haloperidol-induced catalepsy and oxidative damage in mice brain. Haloperidol-induced catalepsy was measured with the standard bar test. The extent of oxidative stress has been evaluated by measuring levels of MDA, GSH and activities of antioxidant enzymes (SOD and GSH-Px) from brain homogenate. Haloperidol treatment significantly induced the catalepsy as observed from increased descent time measured in the bar test. Pretreatment with NTA significantly reduced the catalepsy induced by haloperidol in a dose-dependent manner. The elevated level of MDA in haloperidol-treated mice was significantly decreased by NTA pretreatment. The decreased level of GSH as well as SOD and GSH-Px activities in haloperidol-treated mice were significantly increased by NTA pretreatment. NTA reduces the oxidative stress allowing recovery of detoxifying enzyme activities and controlling free radical production, suggesting a potential role of the drug as an alternative/adjuvant drug in preventing and treating the neurodegenerative diseases, such as Parkinson's disease.
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PMID:Neuroprotective effect of naphtha[1,2-d]thiazol-2-amine in an animal model of Parkinson's disease. 1884 62


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