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Biomedical subjects

C L Davies

Publications and source records attributed to C L Davies.

At least 37 records · Page 2Linked to original sources
PubMed1986

The influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice: possible implications for the actions of antidepressant drugs.

This study has investigated the influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice. Central injection of low doses of the alpha 1-adrenoceptor agonists phenylephrine or methoxamine, or peripheral administration of the antagonist prazosin had no effect on the head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). High doses of both alpha 1-adrenoceptor agonists and antagonists markedly inhibited this response. Head-twitches induced by 5-MeODMT were potently inhibited by low doses of the alpha 2-adrenoceptor agonist clonidine, and potentiated by the antagonists idazoxan and yohimbine. Clonidine also potently inhibited this response when produced by 5-hydroxytryptophan (5-HTP) and carbidopa. The action of the beta-adrenoceptor agonist clenbuterol on head-twitches was paradoxical, this drug enhancing the responses to precursor loading (5-HTP/carbidopa) but inhibiting those induced by direct agonists (5-MeODMT, quipazine). Lesioning noradrenergic neurons by central injection of 6-hydroxydopamine (6-OHDA) or peripheral administration of DSP-4 resulted in enhanced head-twitch behaviour. 6-Hydroxydopamine lesioning did not alter the inhibition of head-twitch responses by clonidine but prevented their enhancement following withdrawal from repeated desmethylimipramine (DMI) administration. It is therefore suggested that head-twitch behaviour may be under tonic control by a population of alpha 2-adrenoceptors which are not on presynaptic noradrenergic terminals, but are postsynaptic and located "down-stream" of the 5-HT2 receptor. In addition, the enhancement of this behaviour produced by withdrawal from repeated DMI administration probably also resulted from alterations in central noradrenergic function.

Animals↗
PubMed1986

Determination of 3-methoxytyramine in rat brain by HPLC with electrochemical detection and its correlation with dopamine function after administration of a monoamine oxidase inhibitor and L-3,4-dihydroxyphenylalanine.

3-Methoxytyramine (3-MT), normally a minor metabolite of 3,4-dihydroxyphenylethylamine (dopamine) in brain, becomes the sole product of metabolism following the administration of a monoamine oxidase (MAO) inhibitor. A simplified reverse-phase HPLC method for 3-MT employing electrochemical detection is fully described. This method has a detection limit of 0.1 microgram/g brain wet weight and is sensitive enough to detect 3-MT in individual brain regions after rats have been pretreated with an MAO inhibitor. Administration of tranylcypromine (TCP, 10 mg/kg) and L-3,4-dihydroxyphenylalanine (L-DOPA) (10-50 mg/kg) produced a dose-dependent linear increase in 3-MT concentrations in the dopaminergic brain regions n. caudatus (r = 0.95; p less than 0.01) and n. accumbens (r = 0.96; p less than 0.01). This treatment also produced a dose-dependent increase in behavioural activity in rats (r = 0.88; p less than 0.01). Furthermore, a good correlation was found between the activity responses of individual rats and the accumulation of 3-MT after TCP/L-DOPA in both n. caudatus (r = 0.76; p less than 0.01) and n. accumbens (r = 0.84; p less than 0.01). These data describe a simple and sensitive HPLC analysis technique for 3-MT and demonstrate that following administration of an MAO inhibitor this metabolite may provide a useful monitor of central dopamine function.

Animals↗
PubMed1985

DSP-4 lesioning prevents the enhancement of dopamine and 5-hydroxytryptamine mediated behavioural changes by repeated electroconvulsive shock.

DSP-4 (N-(2-chloroethyl)-ethyl-2-bromobenzylamine) a novel neurotoxin which destroys central noradrenaline neurones after peripheral injection was administered to rats (50 mg/kg X 2). This procedure did not alter activity responses to quipazine (7.5 mg/kg) or apomorphine (0.2 mg/kg) but prevented their enhancement by repeated electroconvulsive shocks (ECS X 10). This confirms that intact noradrenergic function is required for ECS-induced enhancement of 5-HT and dopamine mediated responses. Furthermore, DSP-4 is shown to provide a simple, effective alternative to centrally injected 6-hydroxydopamine for noradrenergic lesioning.

Amines↗
PubMed1985

Down-regulation of beta-adrenoceptors in rat cortex by repeated administration of desipramine, electroconvulsive shock and clenbuterol requires 5-HT neurones but not 5-HT.

Repeated administration to rats of desipramine (5 mg kg-1, twice daily for 14 days), clenbuterol (5 mg kg-1, twice daily for 14 days) or electroconvulsive shocks (5 ECS over 10 days) decreased the number of beta-adrenoceptors in the cortex. Injection of 5,7-dihydroxytryptamine into the lateral ventricle produced a selective depletion of cerebral 5-HT, particularly in the cortex. In confirmation of earlier studies, this lesion prevented the decrease in the number of beta-adrenoceptors produced by desipramine. However, it was found that this lesion also prevented the down-regulation of beta-adrenoceptors produced by repeated electroconvulsive shock and administration of clenbuterol. Treatment of rats with p-chlorophenylalanine (PCPA) produced a similar depletion of cerebral content of 5-HT. However, this depletion did not prevent the decrease in density of beta-adrenoceptors induced by desipramine or electroconvulsive shock. It is concluded that the modulation of the decrease in the number of beta-adrenoceptors by diverse antidepressant treatments is not by the action of 5-HT itself, but by the action of some other factor present at 5-HT terminals, which is removed by a neurotoxic lesion.

5,7-Dihydroxytryptamine↗
PubMed1984

The relationship between plasma catecholamines and severity of injury in man.

The relationship between plasma catecholamines and injury severity was investigated in order to determine: a) whether a correlation existed between the severity of injury as assessed by the Injury Severity Score (ISS), and circulating noradrenaline and adrenaline; and b) whether such measurements were of prognostic value. It was found that in the immediate postinjury period, both noradrenaline and adrenaline correlated positively with ISS over the range of injury studied (ISS = 0-54; r = 0.67, p less than 0.01). It appeared that part of the response might be attributed to psychological rather than physical factors; at lower levels of injury (ISS less than 9) these psychological factors were possibly responsible for the whole of the observed effect. In the subsequent recovery period (greater than 24 hr postinjury) no clear relationship between plasma catecholamines and injury severity was maintained. Studies on patients who died as a consequence of their injuries failed to confirm the previously suggested prognostic value of plasma catecholamine determinations in this later postinjury period. However, plasma noradrenaline levels in this group were significantly higher on admission than in the casualties who survived serious injury (p less than 0.05). It is concluded that plasma catecholamine concentrations, in combination with other indices of injury severity, may provide useful information on the response to injury in man, and aid in the assessment of its overall severity in physiologic terms.

Accidents, Traffic↗
PubMed1984

Domperidone and levodopa in Parkinson's disease.

To study the absorption of levodopa and interaction with the extracerebral dopamine antagonist domperidone, 15 patients with idiopathic Parkinson's disease were given levodopa 500 mg p.o., alone, and with domperidone pre-treatment. Domperidone pretreatment (10, 20, 40 mg, p.o., i.v. or i.m.) caused a mean 12% increase in peak plasma levodopa concentration, which occurred a mean of 10 min earlier than when levodopa was given alone. Parkinsonian disability scores were improved and peak clinical response occurred 16 min earlier with domperidone than without. Domperidone slightly increases the immediate bioavailability (over 4 h) and anti-parkinsonian response to a given dose of levodopa.

Aged↗
PubMed1984

Simplified determination of serotonin in plasma by liquid chromatography with electrochemical detection.

This simplified determination of serotonin in human plasma involves "high-performance" liquid chromatography with electrochemical detection. Deproteinated samples of platelet-poor plasma are injected directly into the chromatograph without preliminary chromatographic purification. The limit of quantitative detection of serotonin in plasma is 5 nmol/L (equivalent to 250 fmol injected). Intra- and inter-assay CVs ranged from 5.6% to 7.7% and 3.5% to 14.9%, respectively, for concentrations of serotonin from 0.02 to 10.0 mumol/L. Results agreed well with those by spectrofluorometry, both for plasma standards (r = 0.985, range 100 nmol/L to 100 mumol/L) and for pathological samples obtained from four carcinoid syndrome patients (r = 0.964). The method is also applicable to the concurrent measurement of 5-hydroxytryptophan and 5-hydroxyindoleacetic acid.

5-Hydroxytryptophan↗
PubMed1983

The effects of acute and repeated administration of various antidepressant drugs on clonidine-induced hypoactivity in mice and rats.

Small doses of clonidine produce hypoactivity in mice and rats, probably by stimulating pre-synaptic alpha 2-adrenoceptors in the brain. When mice were injected with desmethylimipramine (DMI, 5 mg/kg) before clonidine it attenuated the hypoactivity, while pretreatment with amitriptyline (5 mg/kg) or mianserin (5 mg/kg) potentiated this behaviour. In rats, desmethylimipramine (20 mg/kg) inhibited and mianserin (5 mg/kg) potentiated the clonidine-induced hypoactivity. Amitriptyline (20 mg/kg), however, had no effect on this behaviour in rats. Mice were also given repeated injections of these 3 antidepressant drugs (5 mg/kg twice daily for 14 days) and were tested with clonidine 12 and 60 hr after the final treatment. At 12 hr desmethylimipramine and amitriptyline both attenuated the hypoactivity responses while the reduction by mianserin was marginal (potency DMI greater than amitriptyline greater than mianserin). At 60 hr, however, amitriptyline and mianserin both decreased the clonidine-induced responses while the attenuation by desmethylimipramine was slight (potency amitriptyline congruent to mianserin greater than DMI). In rats, repeated injections of desmethylimipramine (20 mg/kg), administered twice daily for 14 days, attenuated the clonidine-induced hypoactivity 12 hr after the final treatment and this effect persisted for at least 72 hr. Furthermore, the degree of inhibition of the behavioural responses did not correlate with plasma concentrations of desmethylimipramine and persisted after disappearance of the drug from plasma. In conclusion, these data suggest that after repeated injection, desmethylimipramine, amitriptyline and mianserin all produce an adaptive decrease in the function of central alpha 2-adrenoceptors but the time course of this change differs with the individual antidepressant drug administered.

Amitriptyline↗
PubMed1983

Pharmacokinetic investigation of the interaction of azapropazone with phenytoin.

We have investigated the interaction of azapropazone with phenytoin in five healthy volunteers. From steady-state plasma phenytoin concentrations of about 17 mumol/l there was at least a two-fold increase following the introduction of azapropazone. The main mechanism of the interaction was a decrease in phenytoin clearance, attributable to competitive inhibition by azapropazone of phenytoin p-hydroxylation. Protein-binding of phenytoin in the plasma (as assessed by salivary phenytoin concentrations) was significantly reduced from 92 to 90% by azapropazone and similar changes occurred in in vitro studies of [3H]-phenytoin protein binding.

Adult↗
PubMed1982

Routine determination of plasma catecholamines using reversed-phase, ion-pair high-performance liquid chromatography with electrochemical detection.

A procedure is described for the determination of plasma catecholamines using reversed-phase, ion-pair high-performance liquid chromatography coupled with electrochemical detection. Optimisation of chromatographic conditions with respect to detector performance and adherence to procedures and precautions described, render the method applicable to both neurochemical research and routine clinical analysis. The limit of quantitative detection of the method was found to be approximately 30 pg per injection for individual catecholamines. A single chromatographic run, providing adequate resolution of each component, could be completed in approximately 12 min.

Catecholamines↗