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Biomedical subjects

T N Chase

Publications and source records attributed to T N Chase.

At least 181 records · Page 10Linked to original sources
PubMed1990

Subgroups in Alzheimer's disease: fact or fiction?

Alzheimer's disease, which accounts for the majority of all dementing disorders, presents with a wide spectrum of demographic, neuropsychological, pathological and biochemical characteristics. It has become increasingly clear that Alzheimer's disease is indeed heterogeneous and lack of success in symptomatic treatment may be in part related to this. In an attempt to evaluate the utility of possible subgrouping schemas, we reviewed current criteria used to subclassify patients with Alzheimer's disease. Results suggest that although treatment attempts may have to take a more individualized approach, most current subgrouping concepts will probably have limited therapeutic utility.

Aged↗
PubMed1989

Synergy between a selective D1 antagonist and a selective D2 antagonist in the induction of catalepsy.

The cataleptogenic effects of the selective D1 dopamine receptor antagonist, SCH 23390, and the selective D2 dopamine receptor antagonist, raclopride, when administered alone or in combination were studied in rats using the vertical grid and horizontal bar methods. In either model both agents, given alone, produced dose-dependent catalepsy. When administered together, there was a marked synergy between the two drugs. Thus, a low dose of SCH 23390 resulted in a 10-fold shift to the left of the raclopride dose-effect curve. When the same low dose of SCH 23390 was administered together with a subcataleptogenic dose of raclopride, marked catalepsy was produced. The finding of synergy between selective D1 and D2 dopamine antagonists in the induction of catalepsy suggests that mixed antagonists may possess greater antipsychotic activity than neuroleptics acting mainly on one receptor subtype.

Animals↗
PubMed1989

No changes in central quinolinic acid levels in Alzheimer's disease.

Levels of the endogenous excitotoxin quinolinic acid were measured in brain and lumbar spinal fluid from Alzheimer patients and age-matched controls. Values in post mortem brain tissue, unlike those in spinal fluid, showed considerable variability among subjects. In the control group, frontal cortex and caudate nucleus had higher concentrations of quinolinic acid compared to other regions studied. No significant differences were found between Alzheimer brains and controls in any of the regions analyzed. Studies in lumbar spinal fluid showed no gradient for quinolinic acid along the neuraxis, a trend for increasing levels with normal aging, and no difference between Alzheimer patients and age-matched control subjects. The lack of increased central quinolinic acid levels in Alzheimer's disease does not necessarily negate the possibility of excitotoxins contributing to cell death in this disorder.

Aged↗
PubMed1989

Behavioral evaluation of the anti-excitotoxic properties of MK-801: comparison with neurochemical measurements.

The ability of MK-801 to protect striatal neurons from the excitotoxic action of quinolinic acid was evaluated by means of apomorphine-induced rotational behavior and by measurement of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activity, neurochemical markers for cholinergic and GABAergic neurons, respectively. Animals with a unilateral quinolinic acid lesion of the striatum exhibited a vigorous rotational response when challenged with apomorphine (0.5 mg/kg, s.c.) 6 days later and were found to have an 88 90% depletion of striatal ChAT and GAD activity. Treatment with a high dose of MK-801 (10 mg/kg, i.p.) prior to intrastriatal injection of quinolinic acid eliminated the subsequent rotational response to apomorphine and resulted in complete protection of striatal ChAT and GAD activity. Lower doses of MK-801 (1, 3 and 5 mg/kg, i.p.) failed to significantly reduce the rotational response to apomorphine but provided partial, dose-dependent protection of both ChAT and GAD activity. The rotational response to apomorphine correlated with the percent reduction in both ChAT activity (r = 0.57, P less than 0.0005) and GAD activity (r = 0.49, P less than 0.0005). Rotational behavior may thus provide a means to evaluate the functional integrity of the striatum.

Animals↗
PubMed1989

Continuous and intermittent levodopa differentially affect rotation induced by D-1 and D-2 dopamine agonists.

The effects of continuous and intermittent levodopa treatment on rotational behavior induced by dopamine agonists were examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. Chronic administration of levodopa by continuous infusion (90-100 mg/kg per day i.p. by osmotic pump for 19 days with a 3 day washout) enhanced the rotational response to the D-2 dopamine receptor agonist quinpirole, but had no effect on rotation induced by the D-1 agonist SKF 38393 or that due to the non-selective dopamine agonist apomorphine. The rotational responses to the selective dopamine agonists differed dramatically in rats treated with levodopa by intermittent injection (45-50 mg/kg i.p., b.i.d. for 19 days with a 3 day washout): they showed a markedly increased response to quinpirole, a greatly diminished response to SKF 38393, and a modestly enhanced response to apomorphine. Continuous and intermittent treatment resulted in equivalent daily plasma levodopa levels. These findings suggest that the intermittence of central dopamine receptor stimulation may be an important factor in determining the subsequent responses of the dopamine system. The dissociation between the effects of both continuous and intermittent levodopa on D-1 and D-2 agonist-induced rotation indicates that D-1 and D-2 dopamine receptor-mediated mechanisms respond differently to chronic levodopa treatment.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Clonidine treatment of Alzheimer's disease.

A loss of cortical noradrenergic innervation may contribute to the intellectual deterioration in Alzheimer's disease. To test the hypothesis that noradrenergic replacement may confer symptomatic benefit, a double-blind, placebo-controlled therapeutic trial with clonidine hydrochloride (Catapres), a centrally active noradrenergic receptor agonist, was undertaken in eight patients with the clinical diagnosis of Alzheimer's disease. No statistically significant changes in cognitive function were found over a range of doses, including those that produced clinically observable side effects. These preliminary results indicate a need for alternative noradrenergic replacement strategies in Alzheimer's disease.

Aged↗
PubMed1989

Memory impairment in patients with progressive supranuclear palsy.

Verbal memory was compared in 12 patients with progressive supranuclear palsy and 12 healthy control subjects matched for age, sex, and education. Learning, consolidation, and retrieval were significantly impaired in patients with progressive supranuclear palsy. Information scanning, which requires the use of short-term memory processes, remained intact. Duration of symptoms and degree of motor dysfunction correlated with intrusions during learning. No relation between central dopamine metabolism and memory dysfunction could be established.

Aged↗
PubMed1989

Continuous and intermittent levodopa differentially affect basal ganglia function.

The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.

Animals↗
PubMed1989

Pathogenesis of dyskinesias in Parkinson's disease.

Abnormal involuntary movements complicate the management of a majority of patients with advanced Parkinson's disease. The ability of levodopa to induce dyskinesias and alleviate parkinsonism has generally been considered a continuous dose-dependent pharmacological spectrum. In this study, the acute dose-response profile of intravenously administered levodopa for both inducing dyskinesia and alleviating parkinsonism, and its duration of action on these motor manifestations were evaluated in 52 parkinsonian patients. The minimum dose of levodopa required to produce mild dyskinetic movements was significantly lower in patients with fluctuations in motor response compared with those who had a stable response to standard oral therapy; the minimum dose for antiparkinsonian benefit, however, failed to show significant differences. The rate of disappearance of dyskinetic movements was faster than the rate of reappearance of parkinsonian signs following withdrawal of a steady-state infusion of levodopa. The dissociation of the pharmacodynamic profile of the two major motor effects of levodopa suggests their mediation through two different central pharmacological mechanisms, perhaps involving the two classes of dopamine receptors or other transmitter systems, and could have important implications for the design of future antiparkinsonian agents.

Adult↗
PubMed1989

Physostigmine treatment of progressive supranuclear palsy.

Cognitive and extrapyramidal effects of cholinomimetic therapy were evaluated in 8 patients with progressive supranuclear palsy. Each was randomized to a 10-day double-blind crossover trial of physostigmine and placebo. Physostigmine treatment was associated with marginal and inconsistent changes in long-term memory, suggesting that cholinergic therapy alone is insufficient to restore cognitive function. Motor scores remained unchanged.

Aged↗
PubMed1989

Dopamine and memory function in Parkinson's disease.

Response fluctuations in motor function, complicating long-term dopaminomimetic therapy of Parkinson's disease, may extend to the cognitive realm. To evaluate the effect of levodopa treatment both on attention as well as acquisition and retrieval of memory tasks, parkinsonian patients were examined neuropsychologically both while medicated with levodopa/carbidopa ("on") and when the medication's antiparkinsonian effect had worn off ("off"). Significant cognitive differences emerged only on the delayed recall of complex verbal materials, where patients when "on" performed better compared with their "off" state. Comparison of change scores across states (administration or withholding of levodopa/carbidopa between acquisition and retrieval, "off" to "on" or "on" to "off"), revealed no substantial differences as a function of dopaminomimetic therapy. These results support the view that slight changes in cognition are associated with dopaminomimetic therapy of Parkinson's disease, but that these changes may be task-specific.

Aged↗
PubMed1989

Haloperidol- and SCH23390-induced dopaminergic supersensitivities are not additive in the rat.

The effect of chronic D-1 and/or D-2 dopamine receptor blockade on apomorphine-induced behaviors was studied in rats treated for 21 days with the selective D-1 antagonist SCH23390, the predominantly D-2 antagonist haloperidol, and the combination of the two drugs at the same daily doses (0.1 and 1 mg/kg respectively). Apomorphine (0.3 mg/kg) 4 days following the last injection of the drugs increased (49-70%) stereotypic behavior in all animals as compared to saline-treated controls. Although the SCH23390-induced increase was lower than haloperidol-induced supersensitivity, stereotypies after combined administration of both drugs did not differ significantly from either, suggesting that the effects of the two drugs are not additive. Underlying receptor changes and modified D-1/D-2 receptor interactions may account for the participation of both receptor subtypes to the development of neuroleptic-induced dopaminergic supersensitivity.

Animals↗
PubMed1989

Selective D-1 dopamine receptor agonist effects in hyperkinetic extrapyramidal disorders.

The motor and cognitive effects of a selective D-1 dopamine receptor agonist, SKF 39393, were assessed in patients with Huntington's disease, Gilles de la Tourette's syndrome, tardive dyskinesia, and torsion dystonia, using a double-blind placebo-controlled design. Over daily doses ranging from 3.2 to 32 mg/kg and treatment intervals extending from one to seven weeks, no consistent changes could be discerned. The contribution of D-1 receptor mediated mechanisms to the pathophysiology of hyperkinetic extrapyramidal disorders remains uncertain.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

D-1 dopamine agonist administration reduces the threshold for convulsions produced by pilocarpine.

Focal, limbic seizures were produced by systemically administered pilocarpine (200 mg/kg, i.p.); as previously described this dose produces limbic stereotypies but neither convulsions nor seizure-related brain damage. The pretreatment, 5 minutes prior pilocarpine, with the D-1 agonist SKF 38393 (-ED50 = 1 mg/kg; i.p.) induced convulsions similar to those produced by a higher, convulsant dose of pilocarpine. On the other hand, the pretreatment with the D-2 agonist LY 171555 failed to induce convulsions. The D-1 receptor antagonist SCH 23390 prevented the convulsions induced by SKF 38393 plus pilocarpine (200 mg/kg). This study indicates that D-1, but not D-2, receptor stimulation converts subconvulsant doses of pilocarpine into convulsant ones.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗