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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 217 records · Page 12Linked to original sources
PubMed1988

Changes in benzodiazepine/GABA receptor complex function in benzodiazepine-tolerant mice.

Mice were given flurazepam, 40 mg k-1, IP, once daily for 7 consecutive days. Twenty-four and forty-eight hours after the last injection measurements were made of the effects on convulsion threshold, body temperature and locomotor activity, of drugs acting on the GABA receptor complex. Significant decreases were seen in the hypothermic and hypomobility effects of progabide at 48 h, but no significant changes were seen in the effects of pentylenetetrazol or pentobarbitone. The actions of picrotoxin in all three types of test and the convulsant action of bicuculline (IP) were significantly decreased at 24 h but not at 48 h. The convulsive, but not the hypothermic, effects of picrotoxin were increased at the 48 h interval. These results may suggest that the chronic benzodiazepine treatment decreased some aspects of GABA receptor function at 48 h after the last dose; however, such an effect probably does not explain the previously reported increases in the effects of inverse agonists following chronic agonist treatment.

Animals↗
PubMed1988

Repeated electroconvulsive shock does not change [3H]-paroxetine binding to the 5-HT uptake site in rat cortical membranes.

The effects of repeated electroconvulsive shock on the 5-HT uptake site were studied in rat cortex using [3H]-paroxetine binding. This ligand was used because it is thought to directly label the 5-HT uptake site, whereas [3H]-imipramine may bind to a presynaptic recognition site different from the uptake site. No changes were found in the maximum number of [3H]-paroxetine binding sites and equilibrium dissociation constant after repeated electroconvulsive shock, whereas a parallel investigation of beta-adrenoceptor binding showed the expected decrease in receptor number.

Animals↗
PubMed1988

The effect of acute and chronic electroconvulsive shock on [3H]phorbol-dibutyrate binding to rat brain membranes.

The present study investigated the effect of single and repeated electroconvulsive shock (ECS) on proteinkinase C in rat cerebral cortex, cerebellum, hippocampus and striatum using [3H]Phorbol-12,13-butyrate binding. In the postictal period and 24 hr after a single ECS there was no alteration in any brain region. Twenty four hr after 10 once-daily ECS there was a significant decrease the number of binding sites in cerebral cortex (30%) and in cerebellum (20%) without a change in the affinity constant. These findings are discussed with regard to earlier reports on phosphoinositide turnover following chemically and electrically induced seizures.

Animals↗
PubMed1988

Rapid induction of lorazepam dependence and reversal with flumazenil.

Benzodiazepine tolerance, dependence and withdrawal are well established clinical entities although the pharmacological basis for these are still unclear. Recent data suggest that the primary event may be a change in efficacy at the benzodiazepine receptor. The present study demonstrates the rapid development of tolerance and dependence to lorazepam, defines its pharmacology in more detail, and shows that it may be rapidly reversed by treatment with the benzodiazepine antagonist flumazenil. These observations argue in favour of a receptor efficacy change underlying benzodiazepine tolerance and withdrawal and suggest a potential pharmacological treatment for this common and disabling clinical problem.

Animals↗
PubMed1988

Chronic benzodiazepine treatment increases the effects of the inverse agonist FG7142.

A schedule of treatment with the benzodiazepine, flurazepam, in mice for 7 days caused a significant enhancement of the convulsive effects of the partial inverse agonist FG7142. Full convulsions were seen with FG7142 after the chronic administration of flurazepam, although this compound does not cause convulsions in normal mice of the strain used. The change appeared to be maximal at 24 hr after the last dose of flurazepam and lasted for up to a week. The chronic treatment with flurazepam caused tolerance to the effects of flurazepam, but the tolerance was of shorter duration than the increase in the effects of FG7142. When the benzodiazepine antagonist, Ro 15-1788, was given with the flurazepam, the incidence of convulsions induced by FG7142 was no longer significant. Repeated administration of midazolam also slightly increased the effects of FG7142. Single doses of flurazepam or midazolam did not significantly alter the effects of FG7142, although some convulsions were seen.

Animals↗
PubMed1988

Antagonizing the anticonvulsant effect of ethanol using drugs acting at the benzodiazepine/GABA receptor complex.

The ability of various benzodiazepine receptor ligands to antagonize the anticonvulsant action of ethanol was investigated using intravenous infusion of the GABA antagonist bicuculline. The partial inverse agonists FG 7142, RO 15-4513 and RO 15-3505 produced dose-related reductions in seizure threshold. These compounds also partially reversed the anticonvulsant action of ethanol. However, the magnitude of the effects in each case was only equivalent to the reduction in seizure threshold caused by each compound when administered alone. This is the proconvulsant effect of each compound merely subtracted from the anticonvulsant effect of ethanol. ZK 93426, a benzodiazepine receptor antagonist which alone failed to alter seizure threshold, did not affect the anticonvulsant action of ethanol. Both RO 15-4513 and RO 15-3505 also lowered the seizure threshold of barbiturate-treated mice, again in a subtractive fashion. The ability of RO 15-4513 and other inverse agonists to antagonize the anticonvulsant effect of ethanol appears to result from their intrinsic proconvulsant properties.

Animals↗
PubMed1988

Interactions of the imidazodiazepine Ro 15-4513 with chemical convulsants.

1. The proconvulsant effects of the imidazodiazepine Ro 15-4513, were investigated in mice by use of intravenous infusion of a variety of convulsant drugs. 2. Dose-response and time course studies of Ro 15-4513 against gamma-aminobutyric acid (GABA) antagonists were performed. On the basis of these studies a maximally effective dose of 5 mg kg-1 was administered 5 min before the determination of seizure thresholds in subsequent experiments. 3. Ro 15-4513 (5 mg kg-1) significantly lowered seizure thresholds to pentylenetetrazole, bicuculline and the convulsant benzodiazepine Ro 5-3663, but failed to alter seizure thresholds to picrotoxin, strychnine, caffeine and quipazine. 4. Ro 15-4513 significantly raised seizure threshold to the benzodiazepine receptor inverse agonist methyl 6,7-dimethoxy-4 ethyl-beta-carboline-3-carboxylate (DMCM). 5. These results are discussed in relation to other studies investigating the proconvulsant and alcohol-antagonizing effects of Ro 15-4513.

Animals↗
PubMed1988

Alpha-2-adrenoceptor function in alcoholics.

Alpha-2-adrenoceptor function has been assessed using the iv clonidine challenge test. During withdrawal clonidine effects on blood pressure, sedation and body temperature were blunted compared with the abstinent state and healthy controls. In contrast the growth hormone response was blunted in both the withdrawing and abstinent alcoholics. These findings suggest that a deficit of alpha-2-inhibitory control is a feature of withdrawal and, in the case of the endocrine response, may persist for some time.

Blood Pressure↗
PubMed1988

Measuring the serotonin uptake site using [3H]paroxetine--a new serotonin uptake inhibitor.

Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand.

Animals↗
PubMed1988

RO 15-4513 and its interaction with ethanol.

It has recently been claimed that RO 15-4513 selectively opposes some of the behavioral actions of ethanol. Our studies on the intrinsic effects of this compound have shown it to be proconvulsant and to reduce exploratory behavior in mice. In these respects RO 15-4513 resembles a benzodiazepine receptor partial inverse agonist. Such intrinsic actions may well explain its alcohol-antagonizing properties, and argue against its potential in humans. In addition to partially reversing the effects of ethanol, RO 15-4513 also partially reverses the behavioral effect of a barbiturate and completely reverses the effects of a benzodiazepine.

Animals↗
PubMed1987

The effect of the imidazodiazepine Ro 15-4513 on the anticonvulsant effects of diazepam, sodium pentobarbital and ethanol.

The ability of the imidazodiazepine Ro 15-4513 to antagonize the anticonvulsant effects of diazepam, sodium pentobarbital and ethanol was investigated. Ro 15-4513 alone significantly lowered seizure threshold to bicuculline and this effect subtracted from the anticonvulsant effects of sodium pentobarbital and ethanol. In contrast, Ro 15-4513 completely reversed the anticonvulsant effects of diazepam, consistent with suggestions that it is a competitive ligand for benzodiazepine receptors.

Animals↗