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Biomedical subjects

C R Gardner

Publications and source records attributed to C R Gardner.

At least 91 records · Page 5Linked to original sources
PubMed1984

Agonist and inverse agonist effects of CL 218872 on benzodiazepine receptors.

Extracellular action potentials were recorded from cerebellar Purkinje cells in urethane-anaesthetised rats. Synaptic inhibition was evoked by electrical stimulation of the nearby cortical surface and recorded using peristimulus-time histograms. A benzodiazepine agonist, RU 32007, decreased cell firing rate and increased the inhibitory response duration in parallel. beta-Carboline ethyl ester increased firing and decreased the inhibitory response. In some cases the inhibitory response was abolished, independent of the change in firing. CL 218872 decreased firing with the parallel increase in inhibitory response. However, in some cases the inhibitory response was abolished despite decreases in firing. All the effects of all three agents were blocked by Ro 15-1788.

Action Potentials↗
PubMed1984

Normotensive and spontaneously-hypertensive rats show differences in sensitivity to arginine-vasopressin as a modulator of noradrenaline release from brainstem slices.

The effect of arginine-vasopressin (AVP) on potassium ion-evoked release of [3H]noradrenaline (NA) from rat brainstem slices was investigated. In normotensive Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats, AVP inhibited release of [3H]NA in a dose-dependent fashion, the magnitude and time course of inhibition at 10(-12)M AVP being similar to that observed using the alpha 2-adrenoceptor agonist, clonidine at 10(-7) M. However, it is unlikely that AVP functions through alpha-receptors since its effect is not blocked by phentolamine (10(-6) M). When brainstems from spontaneously-hypertensive (SH) rats (stroke-prone strain) were used, AVP was found to be without effect on [3H]NA-release at concentrations up to 10(-8) M. The potassium ion-evoked release appeared to have two components. The early phase of release was tetrodoxotin (TTX)-sensitive and was probably due to action potential conduction within the slices. The later phase, which was unaffected by tetrodotoxin, was probably a result of potassium-induced depolarization of nerve endings. AVP appeared to affect principally the early, TTX-sensitive release. In the presence of TTX (0.3 microM) the inhibitory effects of AVP were no longer seen. Thus, AVP may affect generation or conduction of action potentials within this tissue. There is published evidence that central vasopressinergic neurons may play a role in controlling the baroreceptor reflex arc. The present study provides a possible biochemical basis for this effect and is consistent with a neuromodulatory role of AVP in the CNS.

Animals↗
PubMed1984

The behavioural effects of RU 24969, a suggested 5-HT1 receptor agonist in rodents and the effect on the behaviour of treatment with antidepressants.

Some behavioural and biochemical consequences of the administration of RU 24969 (5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole), a drug which has been shown to be a potent displacing agent at the 5-HT1 binding site, have been studied in mice and rats. In both species RU 24969 produced a dose-dependent increase in locomotor activity. No head-weaving, head-twitching or reciprocal forepaw treading (behaviour suggested to be 5-HT2 receptor mediated) were seen, nor did the body temperature increase p-Chlorophenylalanine did not alter either the behaviour or its intensity. Pretreatment with both methysergide (10 mg/kg) and metergoline (2.5 mg/kg) enhanced the behavioural response in rats, whilst haloperidol (100 micrograms/kg) inhibited the response. Propranolol caused a small and variable decrease in the increase in locomotion induced by RU 24969 in both mice and rats. The drug RU 24969 (10 mg/kg) inhibited the rate of synthesis of 5-HT in rat brain by about 50%. Pretreatment of rats with desmethylimipramine over a longer term or clenbuterol given acutely, treatments known to enhance the behavioural responses of rats to various other 5-HT agonists, did not alter the RU 24969-induced response. Repeated administration of electroconvulsive shock, however, did produce an enhanced locomotor response to RU 24969. The results obtained are consistent with the view that administration of 5-HT agonists, such as quipazine and 5-methoxy-N,N-dimethyltryptamine, produces behaviour that results from stimulation of both 5-HT1 and 5-HT2 receptor populations.

Animals↗
PubMed1984

The pull-up test in rats: a simple method for evaluating muscle relaxation.

A test for muscle relaxation in rats is described. The pull-up test is performed by holding an inverted rat by its hind legs. The time taken by the rat to pull itself up and grasp the hand of the experimenter is used as the test parameter. It is simple and quick and separates muscle relaxation from sedation, catalepsy, and catatonia.

Animals↗
PubMed1984

The action of gamma-aminobutyric acid (GABA) and ethylenediamine (EDA) on Limulus and Helix central neurones and rat cerebellar and sympathetic ganglion neurones.

Intracellular recordings were made from central Limulus and Helix neurones and extracellular recordings from rat cerebellar Purkinje cells and sympathetic ganglia. The actions of gamma-aminobutyric acid (GABA) and ethylenediamine (EDA) and related analogues on these preparations were investigated. On Limulus neurones inhibited by GABA, EDA and piperazine were 81 and 186 times respectively less potent than GABA. Both the GABA and EDA events were chloride mediated, having similar reversal potentials and were reversibly antagonised by picrotoxinin. The EDA response persisted in high magnesium Ringer. On Helix neurones inhibited by GABA, EDA was 92 times less potent while on neurones excited by GABA, EDA was 9.25 times less potent. The other analogues tested had little or no GABA-like effect on either preparation. On rat cerebellar Purkinje cells, EDA was equipotent with GABA and both compounds were antagonised by bicuculline. Flurazepam only potentiated the action of EDA on 3 out of 23 cells tested while the GABA response of all 23 cells was potentiated by the benzodiazepine. Diaminopropionic acid was a weak inhibitor of cerebellar Purkinje cell firing but flurazepam potentiated this response in 6 out of 10 cells tested. On rat cervical ganglion neurones, EDA was half the potency of GABA and likewise the other analogues were less potent than GABA as depolarising agents. Incubation with glutamic acid decarboxylase inhibitors had no effect on the EDA response. Cross desensitisation between GABA and EDA was demonstrated using the ganglion preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Chronic elevation of brain GABA by gamma-vinyl GABA treatment does not alter the sensitivity of GABAergic or dopaminergic receptors in rat CNS.

Rat brain GABA levels were elevated chronically by daily administration of gamma-vinyl GABA, an enzyme-activated, irreversible inhibitor of GABA:2-oxo-glutarate aminotransferase (GABA-T; EC2.6.1.19). Following various periods of drug treatment and withdrawal, the sensitivity of dopamine and GABA receptors in the CNS was determined by biochemical and behavioral evaluations. In contrast to chronic haloperidol treatment, none of the treatment schedules with gamma-vinyl GABA had any significant effect on parameters such as apomorphine induced locomotor activity, [3H] spiperone binding or dopamine-stimulated adenylate cyclase in the corpus striatum; nor did gamma-vinyl GABA treatment affect [3H] GABA binding or GABA-activated [3H] diazepam binding in the cerebral cortex. Moreover, co-administration of gamma-vinyl GABA and haloperidol did not alter the ability of the neuroleptic to induce supersensitivity in the striatal dopaminergic system. Thus, it appears that, in contrast to reported studies using chronic administration of other less specific GABA-T inhibitors such as gamma-acetylenic GABA, amino-oxyacetic acid and isonicotinic acid hydrazide or direct GABA agonists such as THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c-)-pyridin-3-ol) or kojic amine, gamma-vinyl GABA does not alter the sensitivity of the striatal dopaminergic system.

Adenylyl Cyclases↗
PubMed1982

Effects of agents which enhance GABA-mediated neurotransmission on licking conflict in rats and exploration in mice.

On the holeboard, exploration (dipping) and locomotion of mice were enhanced by non-sedative doses of anxiolytics; clobazam, diazepam, nitrazepam and flunitrazepam. After chronic dosing the sedative effects of flunitrazepam showed tolerance and the increases in exploration remained while locomotion was less increased. Sodium valproate and to a lesser extent GAG also increased both exploration and locomotion at non-sedative doses. Muscimol, AOAA and urethane increased locomotion at threshold sedative doses with little or no increase in exploration. Baclofen only decreased behaviour. In a drinking test benzodiazepines evoked large increases in punished drinking. After chronic dosing of flunitrazepam there was a greater increase. Sodium valproate evoked a response of similar magnitude to the benzodiazepines whilst GAG evoked a smaller increase. Muscimol did not increase punished drinking. It is suggested that anxiolytic drug actions result from a more selective enhancement of brain GABA transmission.

Animals↗
PubMed1982

Measurement of release of endogenous GABA and catabolites of [3H]GABA from synaptosomal preparations using ion-exchange chromatography.

Picomole quantities of endogenous GABA in acidified superfusates of synaptosomal preparations have been measured using micro-bore ion-exchange chromatography and post-column formation of the fluorescent iso-indole derivative. Using this technique superfusates have been analyzed directly, without further manipulations, to investigate the release of endogenous GABA. Spontaneous release of GABA was 2-5 pmol/200 microliters superfusate increasing to 20 pmol/200 microliters with potassium stimulation. When gamma-vinyl GABA (RMI 71754), an inhibitor of GABA-T was injected into rats (750 mg/kg) and synaptosomes prepared the potassium-evoked release of GABA was increased 3-fold compared to controls. Chromatographic separations and measurement of release of endogenous and radiolabeled GABA allowed the real specific activity of released GABA to be calculated. Only when 500 microM amino-oxyacetic acid was added during isolation of synaptosomes was the specific activity of released GABA the same as the initial specific activity.

4-Aminobutyrate Transaminase↗
PubMed1982

The activity of cis and trans -2- (aminomethyl) cyclopropane carboxylic acids on GABA - related mechanisms in the central nervous system of Limulus and Periplanata and of mammals.

Some pharmacological actions of (+/-) - cis - and (+/-) - trans -2-(aminomethyl) cyclopropane carboxylic acids, conformationally restricted analogues of GABA, are described. The trans isomer (TAMP) was 17 and 4.5 times less active than GABA in hyperpolarising central neurones of Limulus and Periplanata and 10.8 times less active in displacing [3H]-muscimol from rat brain membranes. The cis isomer (CAMP) was ineffective on Limulus neurones at 35 mumoles, 650 times less active on Periplanata neurones and only weakly displaced [3H]-muscimol at 100 microM. Neither isomer inhibited synaptosomal uptake of [3H]-GABA at 100 microM. These data suggest that the invertebrate receptors studied respond to GABA in an extended conformation.

Animals↗
PubMed1981

Endogenous GABA determines the characteristics of [3H]GABA-binding.

Since the identification of sodium-independent GABA-binding sites in membrane preparations from the mammalian central nervous system numerous publications have dealt with the effects of putative endogenous inhibitors of GABA-binding. However, controversy has arisen over the existence and identity of such inhibitors and the possible artifactural role of residual endogenous GABA in the interpretation of GABA-binding data. Using direct determination of GABA concentrations we have demonstrated that it is extremely difficult to remove endogenous GABA from rat brain membrane preparations and have shown that, even in well-washed preparations, there is a source of GABA production which compounds this problem. When care has been taken to ensure that GABA concentrations are minimal, analysis of binding data reveals the presence of two classes of GABA-binding sites with dissociation constants of the order of 9 nM and 318 nM and maximum binding capacities of 0.63 and 1.65 pmol/mg protein respectively (i.e., 63 and 165 pmol/g original wet tissue). A theoretical analysis of the effects of endogenous GABA demonstrates how failure to take into account even very low concentrations of GABA leads to misinterpretation of the results.

Animals↗
PubMed1981

Use of D,L-alpha-monofluoromethyldopa to distinguish subcellular pools of aromatic amino acid decarboxylase in mouse brain.

Mice treated with D,L-alpha-monofluoromethyl-dopa (MFMD, RMI 71963), an irreversible inhibitor of aromatic L-amino acid decarboxylase (AADC), showed marked decrease in whole-brain concentrations of norepinephrine, dopamine and serotonin. The recovery of these concentrations to control values was slower than would be predicted on the basis of the activity of AADC measured in whole-brain homogenates. Subcellular fractionation of brain homogenates prepared from mice treated with MFMD showed that at least two pools of AADC activity could be distinguished by differences in their recovery rates. In the synaptosomal pool, which represents the nerve terminal AADC, the recovery of enzyme activity was significantly delayed with respect to the non-synaptosomal pool. These findings can be explained on the basis of enzyme synthesis within the nerve cell bodies and subsequent axonal transport to the nerve terminals which are the major sites of neurotransmitter synthesis.

Animals↗
PubMed1981

Presence of radiolabelled metabolites in release studies using [3H]gamma-aminobutyric acid.

Most studies on gamma-aminobutyric acid (GABA) release from nervous tissue have been conducted using radiolabelled GABA in the presence of aminooxyacetic acid (AOAA) to inhibit GABA: 2-oxoglutarate aminotransferase (GABA-T) to prevent conversion of labelled GABA to labelled catabolites. Here we present data showing that even in the presence of 10 microM-AOAA the spontaneous release of tritium from rat cortical synaptosomes prelabelled with 2,3-[3H]GABA is mainly in the form of tritiated water but that the increase in tritium release in the presence of unlabelled GABA or high potassium-ion concentrations is in the form of authentic [3H]GABA. Interpretation of results should take these facts into account.

4-Aminobutyrate Transaminase↗