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Biomedical subjects

T K Murray

Publications and source records attributed to T K Murray.

At least 37 records · Page 2Linked to original sources
PubMed1991

Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses.

1. The concentration of tacrine (tetrahydroaminoacridine or THA) in plasma, regions of brain and cerebral extracellular fluid has been studied in the rat at various times following injection of a dose of 5 mg kg-1, i.p. 2. The peak plasma THA concentration was 2.46 nmol ml-1, and occurred 30 min post injection and clearance was first order (t1/2 = 90 min). The concentration in the brain peaked between 30-60 min, and was around 30 times plasma concentration (striatum peak concentration = 65 +/- 3 nmol g-1). Extracellular cerebral concentration measured by in vivo microdialysis was similar to plasma concentration with the peak occurring 100 min post-injection. 3. No evidence was obtained by in vivo dialysis for THA inducing dopamine release from striatum or 5-hydroxytryptamine (5-HT) release from the frontal cortex. Enhanced release of dopamine did occur after (+)-amphetamine (5 mg kg-1, i.p.) injection, while KCl (100 mM) in the probe released both dopamine and 5-HT. 4. Since the minimum plasma THA concentration achieved in this study was at least twice that found in the plasma of patients given THA for the treatment of dementia, these results suggest that monoamine release in the brain does not occur during therapy.

Animals↗
PubMed1989

Cholinergic mechanisms in a simple test of olfactory learning in the rat.

Male rats were tested in a simple olfactory habituation and discrimination paradigm. Untreated rats habituated their responses over three trials to one odour but were capable of recognising a novel odour presented on the fourth trial. Administration (SC) of either scopolamine or N-methylscopolamine before trials commenced produced a decrease in overall responding. Scopolamine, but not N-methylscopolamine, also blocked habituation to the first odour and recognition to the second, novel odour. Administration of scopolamine after trial 3 did not block the ability of the animals to respond differentially to a novel odour, although again overall levels of responding were decreased. Electrolytic lesions of the medial septal area increased overall levels of responding but lesioned animals still habituated their response over trials and were capable of recognising a novel odour. Therefore although cholinergic mechanisms appear to be involved in this type of learning, these effects are unlikely to be mediated via the septohippocampal system.

Animals↗
PubMed1989

The cholinergic pharmacology of tetrahydroaminoacridine in vivo and in vitro.

1. The effect of tetrahydroaminoacridine (THA) on cholinergically mediated behaviour in the rat and mouse has been investigated. In addition the actions of this compound on cholinesterase activity and on muscarinic and nicotinic receptors has also been examined. 2. Administration of THA (5-20 mg kg-1, i.p.) produced a dose-dependent increase in tremor, hypothermia and salivation in both rats and mice. A similar profile of activity was seen following physostigmine (0.1-0.6 mg kg-1) administration. 3. THA was approximately fifty fold less potent than physostigmine in inducing behavioural change but its effects persisted for over twice as long as those of physostigmine. For example THA-induced hypothermia was still present at 4 h in the mouse and 8 h in the rat. 4. In vitro THA was a potent non-competitive inhibitor of rat brain cholinesterase (IC50: 57 +/- 6 nM) and bovine erythrocyte acetylcholinesterase (IC50: 50 +/- 10 nM) but was a more potent inhibitor of horse serum butyrylcholinesterase (IC50: 7.2 +/- 1.4 nM). 5. Radioligand binding studies indicated that THA binds non-selectively but with moderate potency to both M1 (Ki: 600 nM) and M2 (Ki: 880 nM) muscarinic receptors. THA also interacted with the allosteric site present on cardiac M2 receptors. 6. It is concluded that THA is a reversible non-competitive inhibitor of cholinesterase with a long half life (compared with physostigmine). It also may antagonize muscarinic receptors at high doses. The long half life may account for its reported efficacy in the treatment of Alzheimer's disease.

Aminoacridines↗
PubMed1989

A simple intravenous infusion method in rodents for determining the potency of anticonvulsants acting through GABAergic mechanisms.

A simple method of intravenous infusion of convulsant drugs (pentetrazol and bicuculline) into the tail vein of rats has been used to determine seizure threshold and construct log-dose seizure threshold response curves for several anticonvulsant drugs (diazepam, phenobarbitone, pentobarbitone, chlormethiazole and valproate). It has been shown that an index of the dose required to increase seizure threshold by 50% (TI50) can be obtained using small numbers of animals. The advantages of this method over that of the subcutaneous pentetrazol method are several: small numbers of animals required, speed and reproducibility. The data also demonstrate the concordance between TI50 values obtained using pentetrazol and bicuculline as the convulsant agent. It is suggested that this method can be used routinely in screens of anticonvulsant drugs thought to work through GABAergic mechanisms.

Animals↗
PubMed1986

Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs.

Five common marmosets (Callithrix jacchus) received unilateral ibotenic acid lesions of the basal nucleus of Meynert (nBM). Seven days later, choline acetyltransferase activity was significantly reduced by 50% in the frontal and temporal neocortex, 40% in the amygdala, and approximately 30% in the motor, parietal and occipital cortex in the ipsilateral hemisphere. Four marmosets receiving equivalent bilateral ibotenic acid lesions were severely impaired on new visual object discrimination learning and on relearning an object discrimination learnt prior to surgery when compared with operated controls. New learning in lesioned animals was substantially improved by i.m. administration of the cholinergic agonist arecoline. Lesioned animals' learning ability improved with time but these animals were then differentially sensitive to the disruptive effect of scopolamine on discrimination learning. These results show that lesions of the nBM which destroy the rising cholinergic pathways impair learning ability but that this ability can be substantially restored by administration of a cholinergic agonist.

Acetylcholine↗
PubMed1969

Vitamin A reserves of Canadians.

-A survey of vitamin A and carotene stores of Canadians at five major centres across Canada was completed. Vitamin A and carotene analyses were performed on approximately 100 human liver specimens obtained at necropsy from each location.Age influenced liver vitamin A stores. Children between 1 and 10 years of age had the highest vitamin A stores while a trend toward lower liver stores occurred between 20 and 40 years of age. Females had higher liver carotene stores than males but there was no such difference in vitamin A stores.SUBJECTS FROM ALL LOCATIONS WERE CLASSIFIED ACCORDING TO CAUSE OF DEATH: accidental, heart and coronary artery diseases, cancer, respiratory diseases and a miscellaneous disease group. The mean liver vitamin A and carotene stores of the accidental death group differed only from the cancer group. In contrast to the disease groups, no case with undetectable vitamin A was found in the accidental death group.The mean vitamin A and carotene stores of Vancouver subjects were generally higher than those for the other locations. Montreal showed more values in the 0-40 mug. per g. range than the other locations. Vancouver had the least number (15%), with Halifax, Ottawa and Winnipeg being intermediate (32%). These data suggest the need for improved nutrition, prophylactic treatment in disease states and the need for further research on the utilization and metabolism of vitamin A.

Accidents↗