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T N Chase

Publications and source records attributed to T N Chase.

At least 109 records · Page 6Linked to original sources
PubMed1994

D-cycloserine treatment of Alzheimer disease.

Degeneration of cortical glutamatergic projections may contribute to the cognitive decline in Alzheimer disease (AD). To evaluate whether 1glutamate system stimulation might confer symptomatic benefit, we administered D-cycloserine, a putative partial indirect agonist at certain N-methyl-D-aspartate (NMDA) glutamate receptors, to 12 patients with probable AD. The patients (seven men, five women) had a mean age of 65 +/- 8.4 years; Mini Mental State Examination scores ranged from 15 to 25. A dose escalation phase, in which cycloserine was given in daily oral doses from 25 to 500 mg (total of six dose levels, 1 week per dose), was followed by a "best dose" crossover comparison with placebo under double-blind conditions. The crossover phase consisted of 2 weeks of cycloserine and 2 weeks of placebo, separated by a 1-week washout period. We observed no significant or consistent effect on neuropsychological outcome measures. The results suggest that short-term potentiation of NMDA-mediated glutamatergic transmission may not prove useful in the symptomatic treatment of Alzheimer dementia.

Aged↗
PubMed1994

Levodopa peak response time reflects severity of dopamine neuron loss in Parkinson's disease.

We measured the time to peak antiparkinson response following injection of levodopa or apomorphine in 57 patients with Parkinson's disease. The peak response time for levodopa fell from 53 +/- 6.5 minutes in patients at Hoehn and Yahr stage I-II, and 28 +/- 4.8 minutes in those at stage IV (p < 0.0005). There was a significant correlation between levodopa peak response time and symptom duration (r = 0.65; p < 0.0001), but there was no relation between apomorphine peak response time and measures of disease severity. Peak response time to levodopa appears to reflect predominantly the status of compensatory presynaptic dopaminergic mechanisms and thus may provide an index to the degree of dopamine neuron degeneration in parkinsonian patients.

Apomorphine↗
PubMed1994

Palliative and prophylactic benefits of continuously administered dopaminomimetics in Parkinson's disease.

Motor response complications that ultimately affect most parkinsonian patients appear related to altered dopaminergic mechanisms at both the presynaptic and postsynaptic levels. "Wearing-off" phenomena reflect a shortened duration of the antiparkinsonian action of levodopa, caused initially by the reduced capacity of the degenerating nigrostriatal system to store dopamine. Later, secondary changes in postsynaptic structures contribute substantially to these complications as well as to the changes in levodopa dose-antiparkinsonian response relation and the threshold for levodopa-induced dyskinesias that underlie "on-off" fluctuations and "peak-dose" dyskinesias. In parkinsonian rats, levodopa treatment not only fails to normalize striatal systems modified by the loss of dopaminergic afferents, but actually tends to exacerbate these alterations. Moreover, the vulnerability of these downstream systems to levodopa-induced change appears closely related to the severity of dopamine terminal loss and the intermittence of levodopa administration. In parkinsonian patients, switching from a standard intermittent levodopa regimen to a continuously infused dopaminomimetic alleviates motor fluctuations and widens the therapeutic window for levodopa. Taken together, currently available data support the view that continuous dopaminomimetic therapy has both immediate and delayed palliative value for advanced parkinsonian patients and potentially could confer prophylactic benefit to those at earlier stages of their disorder.

Animals↗
PubMed1994

Topographic investigation of brain atrophy in parkinsonism-dementia complex of Guam: a comparison with Alzheimer's disease and progressive supranuclear palsy.

The topographic distribution of brain atrophy in nine patients with parkinsonism-dementia complex of Guam (Guam PDC) was evaluated quantitatively, and compared with that in six Japanese patients with Alzheimer's disease or senile dementia of Alzheimer type (AD), five Japanese patients with progressive supranuclear palsy (PSP), and nine Japanese control subjects. Characteristic features of Guam PDC were as follows: (1) severe atrophy of the frontal and temporal cortex with relative preservation of the white matter; (2) atrophy of the tectum, tegmentum and cerebral peduncle of the midbrain, and (3) atrophy of the tegmentum and base of the upper pons. In contrast, sectional areas of the tectum and cerebral peduncle of the midbrain were relatively well preserved in PSP, while in AD there was no significant atrophy in the brain stem.

Aged↗
PubMed1994

Dopamine D1 receptor-stimulated release of acetylcholine in rat striatum is mediated indirectly by activation of striatal neurokinin1 receptors.

Activation of dopamine D1 receptors is thought to stimulate release of striatal acetylcholine (ACh) indirectly, possibly through local release of substance P which, in turn, may enhance release of ACh. To test this hypothesis, in vivo microdialysis was used to assess the effect of neurokinin1 (NK1) receptor blockade on D1 agonist-induced increases in ACh release in the striatum of awake, freely moving rats with and without a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway. Local perfusion with the D1 agonist (+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3- benzazepine-7,8-diol hydrochloride (SKF 38393; 1-25 microM for 20 min) increased striatal ACh release in both intact rats and rats with a 6-hydroxydopamine-induced lesion, although the increase was greater in magnitude in rats with a lesion. Local application of the NK1 antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N- [(methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine (CP-96,345; 10 and 25 microM), but not its less active enantiomer (2R,3R)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine (CP-96,344; 10 and 25 microM), decreased the elevation in ACh induced by SKF 38393 in both intact rats and rats treated with 6-hydroxydopamine. Systemic administration of the NK1 antagonist 17-beta-hydroxy-17-a-androstanol[3.2- b]pyrimidol[1,2-a]benzimidazole hydrochloride (WIN 51,708; 20 mg/kg i.p.) also reduced the increase in ACh release induced by local perfusion of SKF 38393.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Substance P increases release of acetylcholine in the dorsal striatum of freely moving rats.

Little is known about the role that neuropeptides such as substance P play in cell-to-cell interactions in the striatum. The effect of locally perfused substance P on extracellular acetylcholine (ACh) in the dorsal striatum of awake, freely moving rats was examined using microdialysis. Neostigmine (1 microM) was included in the perfusate to improve recovery of ACh. Basal extracellular ACh was sensitive to Na(+)-channel blockade with tetrodotoxin (0.3 microM) and Ca(2+)-channel blockade with MgCl2 (10 mM) and therefore largely neuronal in origin. Local perfusion with 10 and 25 microM substance P for 20 min elevated extracellular ACh by 30% and 51%, respectively. The NK1 receptor antagonist, CP 96,345 (10 microM), which by itself had no effect on extracellular ACh, prevented the substance P-induced increase in extracellular ACh. These results suggest that stimulation of NK1 receptors by substance P enhances ACh release in the dorsal striatum and is consistent with anatomical evidence of a substance P-cholinergic circuit in this region.

Acetylcholine↗
PubMed1993

GABAA and GABAB receptors differentially regulate striatal acetylcholine release in vivo.

Microdialysis was used to study the effects of selective GABAergic agents on striatal acetylcholine (ACh) release in awake, freely moving rats. Local perfusion with the GABAA agonist muscimol dramatically reduced striatal ACh release, while the GABAB agonist baclofen caused only minor decreases in ACh release. Co-perfusion with the GABAA antagonist bicuculline diminished the muscimol-induced decrease in ACh release. Likewise, co-perfusion with the GABAB antagonist 2-hydroxysaclofen attenuated the baclofen-induced reduction in ACh release. Bicuculline alone markedly increased striatal ACh release, but 2-hydroxysaclofen by itself had no effect. These results suggest that GABA tonically regulates striatal ACh release primarily through stimulation of inhibitory GABAA receptors.

Acetylcholine↗
PubMed1993

Differential effects of chronic dopamine D1 and D2 receptor agonists on rotational behavior and dopamine receptor binding.

The effects of chronic continuous and intermittent administration of the dopamine D1 receptor agonist SKF 38393 or the D2 receptor agonist quinpirole on rotational behavior and dopamine receptor binding were examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. Continuous and intermittent SKF 38393 both decreased the rotational response to subsequent challenge with SKF 38393. Intermittent SKF 38393 increased quinpirole rotation, while continuous SKF 38393 had no effect. Continuous administration of quinpirole did not affect rotation elicited by either SKF 38393 or quinpirole. Intermittent quinpirole, however, increased both SKF 38393- and quinpirole-induced rotation. Autoradiographic techniques were used to measure D1 receptor binding in striatum and substantia nigra pars reticulata and D2 receptor binding in striatum and nucleus accumbens. Intermittent SKF 38393 reduced D1 receptor Bmax and increased D1 Kd in the striatum, while both continuous and intermittent treatment with the D1 agonist decreased D1 binding in the substantia nigra pars reticulata. Intermittent quinpirole decreased D1 receptor Kd in striatum, and continuous quinpirole reduced D1 binding slightly in substantia nigra pars reticulata. Striatal D2 receptor binding was unaffected by treatment with either SKF 38393 or quinpirole. Intermittent SKF 38393 and continuous quinpirole both reversed the lesioned-induced elevation in D2 binding in the nucleus accumbens, while intermittent quinpirole decreased D2 binding in the accumbens on both the intact and denervated sides. Thus, the effects of chronic treatment with D1 and D2 agonists on behavioral responses to D1 and D2 receptor stimulation differed considerably and were dependent on the treatment regimen employed.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists.

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D1 or D2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.025, 0.05 or 0.1 mg/kg i.p.), 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX 12.5 mg/kg i.p.) or saline prior to administration of either raclopride (2.5 mg/kg i.p.) or SCH 23390 (0.5 mg/kg i.p.). Catalepsy was evaluated with both grid and bar tests every 20 min for 2.7 h. MK-801 (0.1 mg/kg) reversed the catalepsy produced by either raclopride or SCH 23390 but did not stimulate locomotion when given alone at this dose. At 0.05 mg/kg, MK-801 markedly decreased SCH 23390-induced catalepsy, but did not affect the catalepsy produced by raclopride. In contrast, NBQX increased raclopride-induced catalepsy, but had no effect on catalepsy elicited by SCH 23390. These findings suggest that blockade of NMDA receptors, but not non-NMDA receptors, may reverse the catalepsy produced by dopamine receptor antagonists.

Animals↗
PubMed1993

Dopamine D1 receptor stimulation but not dopamine D2 receptor stimulation attenuates haloperidol-induced behavioral supersensitivity and receptor up-regulation.

The effect of selective dopamine D1 and D2 receptor agonists on chronic haloperidol-treated rats was studied. Haloperidol treatment produced a 77% increase in apomorphine-induced sterotypy. The administration of the selective dopamine D1 receptor agonist SKF38393 alone or in combination with the selective dopamine D2 receptor agonist quinpirole attenuated the effect of haloperidol. Treatment with quinpirole alone did not have a significant effect on the response to haloperidol. Haloperidol did not modify the number of dopamine D1 receptors but increased that of dopamine D2 receptors. SKF38393 reversed the effect of haloperidol on dopamine D2 receptor binding. Co-administration of SKF38393 and quinpirole did not modify the increase in the number of dopamine D2 receptors induced by chronic treatment haloperidol. The results confirm a dissociation between behavioral supersensitivity and dopamine receptor up-regulation, suggesting that other mechanisms may be involved in the expression of behavioral supersensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

NBQX inhibits AMPA-induced locomotion after injection into the nucleus accumbens.

The role of glutamate receptors in locomotor activity was investigated by examining the ability of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX), a non-NMDA antagonist, to inhibit the stimulation of locomotion produced by the activation of various excitatory amino acid receptors in the nucleus accumbens. NBQX inhibited the stimulation of locomotor activity produced by intra-accumbens alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) at doses which had no effect on the locomotion produced by kainate or NMDA. Furthermore, this dose of NBQX had no effect on locomotion when injected alone into this brain region. These data suggest that AMPA receptors in the nucleus accumbens may play a very different role in the control of locomotion than NMDA receptors.

Animals↗
PubMed1993

Milacemide therapy for Parkinson's disease.

The clinical effects of central glutamatergic stimulation by the glycine prodrug milacemide were studied in six patients with Parkinson's disease under double-blind, placebo-controlled conditions. When administered as monotherapy at a single oral dose of 1,200 mg, the drug increased overall parkinsonian severity transiently, mostly due to an effect on rigidity. Milacemide did not, however, alter levodopa-induced dyskinesias. These results support the view that drugs acting on the glutamatergic system can influence motor function in patients with extrapyramidal movement disorders and that pharmaceutical agents that selectively block certain subtypes of glutamate receptors may ameliorate parkinsonian symptoms.

Acetamides↗
PubMed1993

Treatment of Parkinson's disease with the partial dopamine agonist EMD 49980.

The motor effects of the partial dopamine agonist EMD 49980 were evaluated in parkinsonian patients under controlled conditions. EMD 49980 monotherapy resulted in a mild improvement in parkinsonian symptoms, but when co-administered with levodopa, had no significant effect on dyskinesias or on the antiparkinsonian effect of the dopamine precursor. These results suggest that EMD 49980 exerts a net weak dopamine agonist effect but fails to ameliorate levodopa-induced dyskinesias.

Adult↗
PubMed1993

Intravenous administration of L-kynurenine to rhesus monkeys: effect on quinolinate and kynurenate levels in serum and cerebrospinal fluid.

L-Kynurenine was administered intravenously at doses of 25, 75 and 200 mg/kg to 4 rhesus monkeys to examine the acute metabolism of kynurenine to its neuroactive products quinolinate (QUIN) and kynurenate (KYNA). Eleven serum and 6 cerebrospinal fluid (CSF) samples, the latter obtained through indwelling cisternal catheters, were collected periodically for 4 hr after the kynurenine infusion. In both serum and CSF, basal concentration of QUIN exceeded KYNA concentrations several-fold (2715 +/- 356 vs 122 +/- 16 nM in serum and 84 +/- 34 vs 6 +/- 1 nM in CSF). Following kynurenine infusion, QUIN and KYNA levels were elevated in both serum and CSF in proportion to the dose of the bioprecursor. Serum QUIN concentrations increased slowly, reaching a steady-state level of 29 microM 90 min after 200 mg/kg kynurenine. Serum KYNA levels rose more rapidly, peaking within 10 min and gradually declining thereafter (2.8 microM after 4 hr using 200 mg/kg kynurenine). In CSF, both QUIN and KYNA increased steadily, attaining plateau levels of 2.8 and 0.3 microM, respectively, 4 hr after a kynurenine dose of 200 mg/kg. Under all experimental conditions, CSF KYNA levels were substantially lower than CSF QUIN levels. These data show that in non-human primates systematically administered kynurenine can serve as a bioprecursor of QUIN and KYNA in both serum and CSF. Moreover, the results demonstrate qualitative differences in the distribution of de novo synthesized QUIN and KYNA between peripheral and central compartments. The present study also indicates that pharmacological doses of systemically administered kynurenine are not capable of selectively increasing levels of the neuroprotectant KYNA.

Animals↗
PubMed1993

D1 and D2 dopamine receptor-mediated mechanisms and behavioral supersensitivity.

The contribution of D1 and D2 dopamine (DA) receptor mechanisms to the behavioral supersensitivity and receptor upregulation induced by chronic DA antagonist administration were compared. Rats received either the selective D1 DA receptor antagonist SCH23390, the selective D2 DA receptor antagonist raclopride, their combination, or haloperidol, a predominantly D2 antagonist, for 21 days. Equivalent cataleptogenic doses of all drugs and drug combinations were employed. Tolerance to the cataleptic response was observed only in the haloperidol-treated group. Apomorphine-induced stereotypies were significantly enhanced in SCH23390-, raclopride-, and haloperidol-treated rats. In contrast, coadministration of both SCH23390 and raclopride had no effect on apomorphine-induced stereotypy. These findings suggest that neuroleptics blocking in equal proportion D1 and D2 receptor sites might be less likely to induce tardive dyskinesia and drug tolerance than those acting selectively on one or the other of these receptor subtypes.

Animals↗
PubMed1993

N-methyl-D-aspartate receptor blockade differentially modifies regional cerebral metabolic responses to D1 and D2 dopamine agonists in rats with a unilateral 6-hydroxydopamine lesion.

Dopamine and the excitatory amino acids play important roles in the control of motor behavior by the basal ganglia; elucidating the manner in which these transmitter systems interact may provide new therapeutic approaches to the treatment of movement disorders such as Parkinson's disease. The 2-deoxyglucose autoradiographic technique was used to examine the effect of N-methyl-D-aspartate receptor blockade on regional cerebral metabolic responses to D1 and D2 dopamine receptor stimulation in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The D1 agonist SKF 38393 (5 mg/kg, i.v.) increased glucose utilization markedly in entopeduncular nucleus and substantia nigra pars reticulata ipsilateral to the lesion, while the D2 agonist quinpirole (1 mg/kg, i.v.) had no effect in these striatal output regions. SKF 38393 and quinpirole reduced 2-deoxyglucose uptake to a similar extent in the lateral habenula, a region which receives afferent input from entopeduncular nucleus; quinpirole also decreased glucose utilization bilaterally in nucleus accumbens. Pretreatment with the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (0.1 mg/kg, i.v.), which had little effect on cerebral metabolism by itself, reduced the effect of SKF 38393 in entopeduncular nucleus and substantia nigra pars reticulata and prevented the effect of quinpirole in nucleus accumbens. MK-801 did not alter the SKF 38393-induced reduction in glucose utilization in lateral habenula, but did reduce the effect of quinpirole in this structure. When these drugs were administered in the same manner to a separate group of lesioned animals, MK-801 did not affect rotational behavior elicited by SKF 38393, but completely eliminated contralateral rotation and actually caused some ipsilateral rotation in response to quinpirole. These findings indicate that D1 and D2 receptor-associated brain mechanisms are differentially influenced by N-methyl-D-aspartate receptor stimulation. D2-mediated behavioral and cerebral metabolic responses appear to require concurrent N-methyl-D-aspartate receptor stimulation. On the other hand, the preservation of D1-mediated rotational behavior and reduced lateral habenula glucose metabolism in the presence of MK-801 despite attenuation of the effects of the D1 agonist in entopeduncular nucleus and substantia nigra pars reticulata suggests that D1 receptor-regulated neuronal pathways exhibit varying degrees of sensitivity to N-methyl-D-aspartate receptor blockade.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

The functional neuroanatomy of Tourette's syndrome: an FDG-PET study. I. Regional changes in cerebral glucose metabolism differentiating patients and controls.

Regional metabolic rates for glucose estimated using [18F]fluorodeoxyglucose positron-emission tomography were compared in 16 drug-free patients with Tourette's syndrome (TS) and 16 age- and sex-matched normal volunteers. Tourette's syndrome patients were characterized by decreased normalized metabolic rates in paralimbic and ventral prefrontal cortices, particularly in orbitofrontal, inferior insular, and parahippocampal regions. Similar decreases were observed in subcortical regions, including the ventral striatum (nucleus accumbens/ventromedial caudate) and in the midbrain. These changes were more robust and occurred with greater frequency in the left hemisphere. They were associated with concomitant bilateral increases in metabolic activity the supplementary motor, lateral premotor, and Rolandic cortices. Effects of prior exposure to neuroactive drugs did not account for these findings. These results suggest that an altered relationship between limbic-related regions of the cortex and striatum and cortical regions involved in the initiation of movement may play a role in the pathogenesis of this illness.

Adult↗