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T Sharp

Publications and source records attributed to T Sharp.

At least 163 records · Page 9Linked to original sources
PubMed1986

Effect of dopamine D-1 and D-2 receptor selective drugs on dopamine release and metabolism in rat striatum in vivo.

The effect of the dopamine (DA) D-1 agonist SKF 38393, the D-2 agonist LY 171555 and the mixed D-1/D-2 agonist apomorphine on striatal DA release and metabolism was tested in vivo using an intracerebral dialysis method in halothane-anaesthetized rats. The specificity of responses to these agonists was tested using the selective DA antagonists SCH 23390 (D-1) and sulpiride (D-2). Both LY 171555, 0.01 mg/kg, and SKF 38393, 10 mg/kg, reduced levels of DA in striatal perfusates. Neither SCH 23390, 0.5 and 5 mg/kg, nor sulpiride, 10 mg/kg, affected levels of DA in striatal perfusates, but 250 mg/kg sulpiride caused a DA increase. The decrease of DA levels induced by LY 171555 (0.01 mg/kg) was prevented by pretreatment with sulpiride (10 mg/kg) but not SCH 23390 (0.5 mg/kg). In comparison, pretreatment with SCH 23390 (0.5 mg/kg) completely inhibited the reduction of DA induced by SKF 38393 (10 mg/kg) while sulpiride (10 mg/kg) was without effect. Apomorphine (0.05 mg/kg) also decreased DA in striatal perfusates and this action was partially inhibited by both SCH 23390 (0.5 mg/kg) and sulpiride (10 mg/kg). Levels of the DA metabolite DOPAC in striatal perfusates also significantly decreased following LY 171555 (0.01 mg/kg) and apomorphine (0.05 mg/kg) but not SKF 38393 (10 mg/kg). The antagonist SCH 23390, in a dose, 0.5 mg/kg, that alone did not increase levels of DOPAC, inhibited the reduction of DOPAC induced by both LY 171555 and apomorphine. Sulpiride, 10 mg/kg, caused a marked increase in striatal DOPAC and this was not affected by a subsequent injection of LY 171555, SKF 38393 or apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Intracerebral dialysis coupled to a novel activity box--a method to monitor dopamine release during behaviour.

This paper describes a method for monitoring drug-induced changes in brain dopamine (DA) release and metabolism in the awake rat simultaneous to measurements of behavioural activation. Intracerebral dialysis was combined with a novel activity box based on a circular running track and a simple method for perfusate collection. "Locomotor" and "general" activity were automatically monitored using a system of photobeams lining the track, and stereotyped behaviours were scored by direct observation. Striatal perfusates were analysed for endogenous DA and its main metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. This methodology was tested by comparing the behavioural effects of systemically administered amphetamine (2 mg/kg SC) and its central DA releasing action. Amphetamine caused a marked increase in striatal DA release (16-fold) which was followed over the time course by increased locomotion and stereotyped sniffing and head and forepaw movements. The limitations and wider applications of the methodology are discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

An in vivo study of dopamine release and metabolism in rat brain regions using intracerebral dialysis.

Intracerebral dialysis was used with a specifically designed HPLC with electrochemical detection assay to monitor extracellular levels of endogenous 3,4-dihydroxyphenylethylamine (dopamine, DA) and its major metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in brain regions of the halothane-anesthetized rat. Significant amounts of DA, DOPAC, and HVA were detected in control perfusates collected from striatum and n. accumbens whereas the medial prefrontal cortex showed lower monoamine levels. The ratio of DA in perfusate to DA in whole tissue suggests that in f. cortex, compared to n. accumbens and striatum, there is a greater amount of DA in the extracellular space relative to the intraneuronal DA content. The DOPAC/HVA ratio in control perfusates varied between regions in accordance with whole tissue measurements. This ratio was highest in n. accumbens and lowest in f. cortex. The monoamine oxidase inhibitor pargyline (100 mg/kg i.p.) caused an exponential decline in DOPAC, but not of HVA, in regional perfusates, an effect that was associated with an increase in DA. The data indicated a higher turnover of extracellular DOPAC in n. accumbens than in striatum and the lowest DOPAC turnover in f. cortex. The rate of decline in extracellular DA metabolite levels was slow compared to whole tissue measurements. In the perfusates there was no statistical correlation between basal amounts of DA in the perfusates and DOPAC and HVA levels or DOPAC turnover for any of the areas, indicating that measurement of DA metabolism in the brain under basal conditions does not provide a good index of DA release. In summary, this study shows clear regional differences in basal DA release and metabolite levels, metabolite patterns, and DOPAC turnover rates in rat brain in vivo.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Endoscopic evaluation of slow-release potassium chloride preparations.

In a double-blind, randomized, placebo-controlled clinical trial, 30 healthy subjects took one of two potassium chloride preparations or placebo three times a day for 1 week with concomitant oral glycopyrrolate dosing. The upper digestive tract was endoscopically examined immediately before and after the treatment period. One subject in both of the KCl treatment groups and six subjects in the placebo group developed submucosal lesions. All lesions were minor and of limited clinical significance. There may be reason to believe that glycopyrrolate plays a role in the production of such lesions. If so, the concomitant use of glycopyrrolate in clinical trials of KCl preparations may cloud the results of such studies.

Adult↗
PubMed1984

Differential pulse voltammetry: simultaneous in vivo measurement of ascorbic acid, catechols and 5-hydroxyindoles in the rat striatum.

This paper describes carbon fibre electrodes that can simultaneously monitor changes in ascorbic acid, dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in vivo in the rat striatum using differential pulse voltammetry. The separation between DOPAC and 5HIAA oxidation is improved and the size of the 5HIAA peak decreased by the removal of uric acid using the enzyme uricase indicating that uric acid oxidation may contribute to the oxidation peak at + 300 mV. Haloperidol (0.5 mg/kg) decreased ascorbic acid and 5HIAA but increased DOPAC and HVA while D-amphetamine (3 mg/kg) increased ascorbic acid, decreased DOPAC and HVA but had no effect on 5HIAA. These electrodes should be a useful means of investigating interactions between dopamine and serotoninergic systems in vivo.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Effect of neuroleptic drugs on striatal dopamine release and metabolism in the awake rat studied by intracerebral dialysis.

This study investigated the effect of three neuroleptic drugs, (+/-)-sulpiride, haloperidol and cis-flupenthixol, on dopamine release and metabolism in the striatum of the awake rat. Endogenous extracellular dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as the 5-hydroxytryptamine (5HT) metabolite 5-hydroxyindoleacetic acid (5HIAA), were determined in striatal perfusates in awake rats by using intracerebral dialysis together with high performance liquid chromatography with electrochemical detection. Sulpiride (10, 50 and 250 mg/kg), cis-flupenthixol (0.5 and 2 mg/kg) and haloperidol (2 mg/kg) all increased the levels of dopamine in striatal perfusates. However, the time course and magnitude of these effects differed markedly depending upon the neuroleptic used. Sulpiride (10, 50 and 250 mg/kg), cis-flupenthixol (0.05, 0.5 and 2 mg/kg) and haloperidol (0.05, 0.5 and 2 mg/kg) increased extracellular levels of DOPAC and HVA while having little effect on 5HIAA. In contrast to the effect on dopamine levels the changes in DOPAC and HVA followed similar time courses and were of similar magnitude independent of the neuroleptic used. The response of the dopamine metabolites seemed to occur at lower doses of the neuroleptics than the response of dopamine release itself. Furthermore, there was no close relationship between changes in dopamine as compared to changes in DOPAC and HVA. Finally, there was no correlation between any of the neurochemical changes measured and the occurrence of catalepsy. These data suggest that neuroleptic drugs have two separate actions on the dopamine neuron in vivo, one causing an increase in dopamine release and another producing an increase in dopamine metabolism, which is probably a consequence of increased dopamine synthesis. Furthermore neither of these effects are related to catalepsy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

The TRH analogue CG3509 increases in vivo catechol/ascorbate oxidation in the N. accumbens but not in the striatum of the rat.

The effects of injection of the thyrotrophin-releasing hormone (TRH) analogue, orotyl-histidyl-proline amide (CG3509) into the accumbens and striatum, was studied on dopamine metabolism by means of in vivo voltammetry. Forty minutes after infusion of CG3509 (1-5 micrograms) into the n. accumbens there was a significant dose-related increase in the oxidation peak, corresponding to the oxidation of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC) and ascorbic acid. The size of this peak returned to normal by 80 min after the infusion. There was no change in the indole oxidation peak. Infusion of CG3509 (5 micrograms) had no effect on the size of either the catechol or the indole oxidation peaks recorded in the striatum. Intraventricular injection of CG3509 (10 micrograms) also increased DOPAC/ascorbic acid oxidation peak recorded in the n. accumbens, without altering the indole peak. While the voltammetric technique used in the present experiments is not able fully to separate ascorbic acid and DOPAC in vivo, the results support the view that TRH and its analogues selectively increase dopaminergic activity in the mesolimbic region.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Analeptic effects of centrally injected TRH and analogues of TRH in the pentobarbitone-anaesthetized rat.

The effect of intracerebral injection of TRH and several biologically stable TRH analogues in the pentobarbitone anaesthetized rat was examined. Bilateral injection of TRH (5.0 micrograms total dose) and the analogues RX 77368 (0.01-1.0 microgram), CG 3509 (0.1-1.0 microgram), DN-1417 (1.0 microgram) and MK-771 (1.0 microgram) into the nucleus accumbens reduced the pentobarbitone-induced sleeping time. The TRH metabolite DKP (5 micrograms) had no effect on the sleeping time following intra-accumbens injection. Intra-septal injection of TRH (1.0-5.0 micrograms), RX 77368 (0.1-1.0 microgram) and CG 3509 (0.1-1.0 microgram) also reversed the pentobarbitone-induced sleeping time. In contrast, TRH (5 micrograms) injected into the striatum had no effect on the pentobarbitone-induced sleeping time, and CG 3509 (0.1 microgram) and RX 77368 (0.1 microgram) had weaker effects following intrastriatal injection compared to injection of these analogues into the nucleus accumbens and septum. Measurements of core temperature and respiration rate in rats following intra-accumbens or septal injection of TRH, CG 3509 and RX 77368 showed these peptides to reverse pentobarbitone-induced hypothermia and stimulate respiration rate. However, while intrastriatal injections of CG 3509 and RX 77368 caused an increase in respiration rate they had no effect on core temperature. These results suggest a close association between peptide-induced respiratory stimulation and reversal of pentobarbitone-induced anaesthesia. Since intra-accumbens and septal injection of dopamine (20-100 micrograms) failed to reverse anaesthesia, it is unlikely that the peptide-induced responses are mediated via dopamine release.

Anesthesia↗
PubMed1984

A comparison of the locomotor effects induced by centrally injected TRH and TRH analogues.

Thyrotrophin-releasing hormone (TRH) and its stable analogues CG3509 and RX77368 were injected directly into the nucleus accumbens, septum and striatum of the rat and locomotor activity was recorded. TRH (5-20 micrograms) caused a dose-dependent increase in locomotor activity when injected into the nucleus accumbens. TRH (20 micrograms) also increased locomotor activity after administration into the septum but not when put into the striatum. Both the TRH analogues (0.1 and 1.0 microgram) produced closely related increases in activity when injected into either the nucleus accumbens or septum but CG3509 was more potent with a longer lasting effect. Also, in contrast with TRH (20 micrograms), both TRH analogues stimulated locomotor activity when injected into the striatum at a dose of 1 microgram but the effect was less marked and delayed in onset compared to the nucleus accumbens and septum response. Dopamine (100 micrograms) injected into the accumbens or septum also produced significant increases in locomotor activity. The locomotor effects of the peptides are discussed in relation to a possible dopamine-mediated mechanism which contrasts with the actions of TRH and the analogues on barbiturate anaesthesia.

Animals↗
PubMed1984

Changes in monoamine metabolites measured by simultaneous in vivo differential pulse voltammetry and intracerebral dialysis.

A direct comparison has been made of the drug-induced changes in extracellular levels of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid measured using intracerebral dialysis and differential pulse voltammetry with carbon fibre electrodes. The comparison was carried out in chloral hydrate anaesthetized rats with a pretreated carbon fibre electrode implanted in one striatum and an intracerebral dialysis loop in the contralateral striatum. 3,4-Dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in the dialysis perfusates were assayed by high pressure liquid chromatography with electrochemical detection. d-Amphetamine (2 mg/kg) decreased extracellular 3,4-dihydroxyphenylacetic acid and the height of the 3,4-dihydroxyphenylacetic acid oxidation peak, while haloperidol (0.5 mg/kg) increased 3,4-dihydroxyphenylacetic acid levels measured in the perfusates and the height of the 3,4-dihydroxyphenylacetic acid oxidation peak. In these experiments there were parallel changes in 3,4-dihydroxyphenylacetic acid levels and peak height and a close correlation between these changes. Tranylcypromine (10 mg/kg) produced an almost parallel decrease in extracellular 5-hydroxyindoleacetic acid (dialysis) and the height of the 5-hydroxyindoleacetic acid oxidation peak, with similar percentage changes and good correlation values being obtained. However, while 5-hydroxy-L-tryptophan (25 mg/kg) increased both the 5-hydroxyindoleacetic acid levels and the height of the 5-hydroxyindoleacetic acid oxidation peak, 5-hydroxyindoleacetic acid in the dialysis perfusates showed a greater increase than the oxidation peak. The results show a close correlation between changes in extracellular 3,4-dihydroxyphenylacetic acid and its respective voltammetric peak and strongly support the use of in vivo differential pulse voltammetry for monitoring dopamine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Differential pulse voltammetry in vivo--evidence that uric acid contributes to the indole oxidation peak.

Previous studies using differential pulse voltammetry have shown that indoleamines contribute to the oxidation peak at +280-300 mV (peak 3) measured in the rat striatum in vivo using carbon fibre electrodes. In this study, using similar techniques, it is shown that 5-hydroxyindoleacetic acid and uric acid oxidize at a similar potential (+270-290 mV) in vitro. Additionally, by microinfusing uric acid or its metabolizing enzyme uricase, it is shown that uric acid oxidation contributes to about 30% of the height of peak 3 measured in the rat striatum in vivo. These results indicate that care needs to be taken in interpreting changes in the height of the in vivo peak 3 since it is not solely due to the oxidation of brain indoleamines.

Animals↗
PubMed1983

A manually-operated brain tissue slicer suitable for neurotransmitter release studies.

A simple, inexpensive device has been designed to prepare slices or prisms of brain tumor for metabolic and release experiments by means of a hand-operated method. It is particularly suitable for very rapid slicing of small, irregular pieces of brain tissue dissected from animals or specimens available at biopsy. This simple apparatus was produced as an alternative to the more widely used motor-driven tissue choppers. A comparison of the morphological and metabolic integrity of tissue produced by the new slicer and a conventional tissue chopper is presented. The hand tissue slicer has been used to measure the release of monoamine neurotransmitters and specific neuropeptides in vitro.

Animals↗
PubMed1983

In vivo measurement of dopamine and its metabolites by intracerebral dialysis: changes after d-amphetamine.

By using a new technique, intracerebral dialysis, in combination with high performance liquid chromatography and electrochemical detection, it was possible to recover and measure endogenous extracellular dopamine, together with its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) from the striatum and nucleus accumbens of anaesthetized or freely moving rats. In addition, measurements of extracellular 5-hydroxyindoleacetic acid, ascorbic acid, and uric acid were made. Basal extracellular concentrations of dopamine and DOPAC in the striatum were estimated to be 5 X 10(-8) M and 5 X 10(-6) M, respectively. d-Amphetamine (2 mg/kg s.c.) increased dopamine levels in the striatum perfusates by 14-fold, whereas levels of DOPAC and HVA decreased by 77% and 66%, respectively.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Thyrotrophin-releasing hormone analogues increase dopamine release from slices of rat brain.

Rat brain slices were incubated with a high concentration of K+, thyrotrophin-releasing hormone (TRH), or one of two biologically stable TRH analogues (CG 3509 or RX 77368). Basal release of endogenous dopamine, measured by electrochemical detection, was increased by K+ (30 mM) from slices of hypothalamus, septum, nucleus accumbens, and striatum. CG 3509 (10-(5) -10-(3) M) increased the release of dopamine from slices of nucleus accumbens, septum, and hypothalamus in a dose-dependent fashion, whereas RX 77368 (10-(4) M) increased the release of dopamine from the septum only. Neither analogue increased the release of striatal dopamine. The results provide further evidence for specific regional interactions between TRH and dopamine in rat brain.

Animals↗
PubMed1981

Electrochemical monitoring of 5-hydroxytryptamine release in vitro and related in vivo measurements of indoleamines.

1. Electrochemical techniques have been used to measure release of endogenous 5HT from brain regions in vitro and to record electrochemical changes induced by drugs acting on 5HT neurones in the anaesthetised and unanaesthetised rat in vivo. 2. 5HT release in vitro was observed in all regions studied. The highest level of basal release was observed in the nucleus accumbens/septal region and hypothalamus and the lowest in the striatum. 3. High potassium (55 mM) increased release of 5HT in all regions, where their basal release was observed. 5HT release was also increased by p-chloroamphetamine (1-10 microM). 4. In rats anaesthetised with pentobarbitone, three electrochemical peaks were observed in the striatum, nucleus accumbens and frontal cortex at + 0.12 V, +0.2 V and + 0.35 V using a micro-graphite paste electrode and differential pulse voltammetry. 5. The peak at + 0.12 V was increased by micro-infusion of ascorbic acid (5 X 10(-6) M) and that at + 0.35 V by micro-infusion of 5HT (5 X 10(-6) M) and 5-hydroxyindole acetic acid (5HIAA) (5 X 10(-6) M). 6. p-Chlorophenylalanine (2 X 150 mg/kg) caused the loss of the peak at + 0.35 V. Fenfluramine (10 mg/kg) also decreased the peak at + 0.35 V. 7. The results indicate the validity of the in vitro technique and demonstrate the future potential of the in vivo method, though further studies are needed to determine the precise chemical nature of the changes in oxidation following administration of drugs acting on 5HT neurones.

Action Potentials↗
PubMed1980

Infusional 5-fluorouracil and X-ray therapy for non-resectable esophageal cancer.

Six patients with unresectable carcinoma of the esophagus received a combined course of external radiation therapy (1000 rads in four fractions in four days commencing on day 2) combined with constant infusional 5-fluorouracil (20 mg/kg every 24 hours for five days beginning on day 1). This program was repeated every other week to give a total x-ray dose of 6000 rads. This regimen has been well-tolerated by the majority of the patients and resulted in a complete response rate within the x-ray treatment field of 83% (5/6). All patients who showed a demonstrable systemic response to 5-fluorouracil reached complete response. The median survival has not yet been reached at six months with post-treatment survivors alive and without disease (four patients) at one, six, nine, and 22 months. Our previous median survival by x-ray therapy alone was 4 1/2 months. Toxicity consists primarily of hematologic suppression at a subclinical level. Although the length of therapy is substantial (11 weeks), the program appears tolerable and is capable of inducing long-term remissions. The program is currently being studied for dose escalation because neither local nor systemic side effects of a dose-limiting nature have been observed at 20 mg/kg 5-FU.

Bone Marrow↗