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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 235 records · Page 13Linked to original sources
PubMed1987

A single dose of FG 7142 causes long-term increases in mouse cortical beta-adrenoceptors.

There is evidence that central monoamines are involved in the actions of benzodiazepines. We have investigated the effects of a single dose of the benzodiazepine partial inverse agonist, FG 7142, on radioligand binding to alpha 2- and beta-adrenoceptors in mouse cerebral cortex. We found that seven days after a single injection of FG 7142 there was a large increase in the density of beta-adrenoceptors. This rise was not detectable either 15-30 min, or 24 h after the injection and no statistically significant changes in alpha 2-adrenoceptor binding were found at any of these times. Administration of the benzodiazepine antagonist Ro 15-1788 at the same time as FG 7142 prevented the rise in beta-adrenoceptor density. We discuss the possibility that the beta-adrenoceptor upregulation is related to the behavioural effects of FG 7142.

Animals↗
PubMed1987

Selective effect of lithium on cognitive performance in man.

The effects of lithium on psychomotor performance were examined in six healthy male volunteers (aged 26-31 years) and compared with those of a similar control population. Three computerised psychomotor tests (serial reaction time, semantic reasoning and syntatic reasoning) were administered before lithium, after 5 and 22 days of lithium carbonate (800 mg/d) and 4 days and 1 month after stopping the lithium. The only significant effect was an impairment of semantic reasoning during the chronic (22 day) test. This suggests a selective effect of lithium on associative mental tasks and may explain the subjects' experience of slowing in recall of object names whilst taking lithium.

Adult↗
PubMed1987

Selective changes in the in vivo effects of benzodiazepine receptor ligands after chemical kindling with FG 7142.

It has recently been demonstrated that kindling occurs with repeated administration of the benzodiazepine "inverse agonist" FG 7142. The present study was an investigation of the effects of other ligands for the benzodiazepine receptor in mice kindled with FG 7142. It was shown that over a range of doses the lowering effects of FG 7142 on the seizure threshold were greater in kindled animals than in control. In contrast, the hypothermic effect of FG 7142 was unaltered. The effects of the partial inverse agonist CGS 8216 were unaltered. The effects of the full inverse agonist DMCM were unchanged except for an enhancement of its convulsant effect when infused at a concentration of 100 mu gm 1-1. Studies with the full agonist benzodiazepine, flurazepam and the full agonist beta-carboline, ZK 93423, showed small but significant reductions in their hypothermic effects. The sedative and anticonvulsant effects of flurazepam were unaltered, whereas the anticonvulsant effects of ZK 93423 were decreased in animals kindled with FG 7142. There was a pronounced reduction in the anticonvulsant and hypothermic effects of the partial agonist beta-carboline, ZK 91296. These data do not fit any simple explanation of kindling being due to a change in the function of benzodiazepine receptors, although they may offer some support for the idea that kindling with FG 7142 produces a change in the effects of all beta-carboline compounds which act at the benzodiazepine receptor.

Animals↗
PubMed1987

Bidirectional effects of chronic treatment with agonists and inverse agonists at the benzodiazepine receptor.

We have studied in rodents the effects of beta-carboline inverse agonists on chronic treatment and after repeated administration of benzodiazepine agonists. Chronically, the inverse agonist FG 7142 caused chemical kindling, i.e., a decrease in the threshold to the convulsive effects of the drug. This change was accompanied by decreases in the effects of beta-carboline but not benzodiazepine agonists. In addition the effects of GABA receptor agonists were decreased and the effects of GABA antagonists marginally increased. The GABA stimulated benzodiazepine binding was lower after FG 7142 kindling. Some evidence was found in mice to suggest that these changes were accompanied by behavioural alterations, but studies in rats did not show any changes. Repeated administration of benzodiazepine agonists, sufficient to cause tolerance to their pharmacological actions and to those of beta-carboline agonists, increased all of the effects of the partial inverse agonists and some of the actions of the full inverse agonists. We suggest that this is due not to precipitation of withdrawal but to a "withdrawal shift" in the coupling at the receptor inophore. This would increase the intrinsic properties of inverse agonists and decrease those of agonists. Evidence for this hypothesis is summarised.

Animals↗
PubMed1987

Diazepam alters brain 5-HT function in man: implications for the acute and chronic effects of benzodiazepines.

The effect of diazepam on brain 5-HT-mediated neuroendocrine responses was studied in healthy male volunteers. An acute dose of diazepam (15 mg) significantly attenuated the prolactin and growth hormone responses to intravenous L-tryptophan. After 3 weeks administration of diazepam (25 mg/d) these responses had returned to normal despite much higher plasma diazepam concentrations, suggesting that tolerance had occurred. A reduction in brain 5-HT function may underlie some of the acute therapeutic actions of benzodiazepines. It is possible that excessive 'rebound' 5-HT activity may contribute to the abstinence syndrome seen on benzodiazepine withdrawal.

Adult↗
PubMed1987

Effect of pregnancy on panic attacks.

Three women with panic disorder showed marked improvement in their panic symptoms during pregnancy. Such effects might be due to pregnancy's blunting of the sympathoadrenal response to simple physiologic stimuli, effects on barbiturate receptors, or improvement in psychological functioning.

Adult↗
PubMed1986

Effects of chronic treatment with benzodiazepine receptor ligands on cortical adrenoceptors.

We report the effects of kindling with the benzodiazepine partial inverse agonist, FG 7142 on adrenoceptor binding in mouse cerebral cortex. Twelve once-daily injections of FG 7142 caused a statistically significant increase in the density of both alpha 2- and beta-adrenoceptor binding sites, seven days after the last injection. Despite the marked effects of FG 7142 on adrenoceptors, there were no changes in either alpha 2- or beta-adrenoceptor binding after prolonged treatment with the benzodiazepine, flurazepam.

Animals↗
PubMed1986

Mice and rats are sensitized to the proconvulsant action of a benzodiazepine-receptor inverse agonist (FG 7142) following a single dose of lorazepam.

Rats and mice were treated with lorazepam (1.0 mg/kg) or its vehicle. Six h later seizure threshold to i.v. pentylenetetrazole was determined following treatment with the benzodiazepine-receptor inverse agonist FG 7142, the antagonist Ro 15-1788 or a second dose of lorazepam. Although lorazepam alone was anticonvulsant 6 h after its administration, animals pretreated with lorazepam were more sensitive to the proconvulsant action of FG 7142 and less sensitive to the effects of a second treatment with lorazepam.

Animals↗
PubMed1986

The effect of clonidine on plasma MHPG: evidence against tonic alpha 2-adrenoceptor control of noradrenergic function.

The effect of the alpha 2-adrenoceptor agonist clonidine on plasma free MHPG levels was assessed in 12 normal volunteers. A significant fall in MHPG was produced by 1.5 microgram X kg-1 clonidine IV whereas saline had no effect. The peak fall in MHPG correlated strongly with the area under the curve (AUC). In addition, a strong correlation was seen between basal MHPG and the extent of the clonidine-induced fall. This suggests that plasma MHPG levels are not simply a reflection of central alpha 2-adrenoceptor function and argues against tonic alpha 2-adrenoceptor-mediated inhibitory control of noradrenergic output.

Adult↗
PubMed1986

The effect of lithium on 5-HT-mediated neuroendocrine responses and platelet 5-HT receptors.

The effect of lithium on serotonin (5-HT)-mediated responses in the brain was assessed by measuring changes in the prolactin (PRL) and growth hormone (GH) responses to L-tryptophan (LTP) in eight normal subjects. On the 4th day of lithium treatment the PRL responses were significantly enhanced, and this enhancement was still apparent after 20 days' treatment. In contrast, GH responses to LTP were not altered. Lithium had no effect on platelet 5-HT content, platelet imipramine binding and platelet 5-HT receptor binding. The ability of lithium to enhance some aspects of brain 5-HT function may be important in its mode of action in manic-depressive illness and may be particularly relevant to its potentiation of the antidepressant effect of tricyclic antidepressants.

Adult↗
PubMed1986

Increased central alpha 2-adrenoceptor sensitivity in panic disorder.

Cardiovascular responses to an intravenous challenge dose of clonidine (1.5 micrograms/kg) were measured in eight patients with DSM III panic disorder. In comparison with an age- and sex-matched control population panic patients showed significantly greater falls in systolic and diastolic blood pressure, with similar falls in heart rate. These observations support the view of a biological abnormality in panic disorder.

Adult↗
PubMed1986

The effect of diazepam on indices of 5-HT function in man.

The effects of acute and chronic diazepam administration on L-tryptophan induced prolactin release was studied in seven male volunteers. Acute diazepam diminished the prolactin neuroendocrine response to L-tryptophan. On chronic administration this effect was lost, suggesting tolerance had developed. The sedative effects of L-tryptophan were unaltered by either acute or chronic diazepam administration. A possible explanation for the tolerance development to the neuroendocrine effects may be the observed reduction in platelet 3H-imipramine binding that was observed.

Adult↗
PubMed1986

Benzodiazepine-receptor mediated convulsions in infant rats: effects of beta-carbolines.

The effects of anticonvulsant and proconvulsant benzodiazepine-receptor ligands were studied in infant rats. The agonist flurazepam increased myoclonic twitching of the limbs as has previously been reported. In contrast, the convulsant beta-carbolines DMCM and beta-CCM did not produce twitching, but did produce marked increases in locomotor activity and whole body shakes. The standard convulsants pentylenetetrazol and bicuculline similarly increased locomotor activity and shaking. These findings suggest that the effects of agonist benzodiazepines cannot be interpreted as convulsant-type behaviour. In addition, the finding that DMCM and beta-CCM have equivalent effects despite showing preferential affinities for benzodiazepine-receptor subtypes argues against one particular subtype having proconvulsant effects.

Animals↗
PubMed1986

The effects of drugs acting at the GABAA-receptor/ionophore after chemical kindling with the benzodiazepine receptor ligand FG 7142.

Repeated administration of the beta-carboline benzodiazepine receptor ligand FG 7142 produces sensitization to its effects so that full seizures develop (chemical kindling); initially it is only pro-convulsant. The present study investigated alterations in the function of drugs which act at the different sites at the gamma-aminobutyric acid (GABA) benzodiazepine receptor complex, after repeated administration of FG 7142. In FG 7142 kindled mice decreased anticonvulsant and hypothermic effects of the GABA agonist muscimol were observed. The hypothermic effects of the GABA agonist progabide were reduced. In contrast a small increase in the hypothermic effect of pentobarbitone was seen. The convulsant effects of bicuculline and picrotoxin were unaltered when they were given intravenously but marginally increased when they were given by the intraperitoneal route. No changes were seen in the hypothermic effects of these drugs. No significant changes were seen in the convulsant or hypothermic effects of pentylenetetrazol. These results suggest that kindling with FG 7142 may alter GABA receptor function.

Animals↗
PubMed1986

Optimizing the pentetrazol infusion test for seizure threshold measurement.

Seizure thresholds in mice were determined using the pentetrazol infusion method. Concentration of infusate and rate of infusion were varied to assess the optimal parameters for seizure threshold detection. Seizure threshold elevations were produced by flurazepam and threshold decreases by FG 7142. An infusion rate of 1.1 ml min-1 was best for detecting both increases and decreases in threshold. However a concentration of 2.5 mg ml-1 gave optimal measurement of elevations in threshold whereas decreased thresholds were best detected with a concentration of 10 mg ml-1.

Animals↗
PubMed1985

The benzodiazepine antagonist, Ro 15-1788 does not decrease ethanol withdrawal convulsions in rats.

The effects of the benzodiazepine antagonist, Ro 15-1788 on ethanol withdrawal convulsions were investigated in rats. The study originated from recent reports of benzodiazepine binding activity in urine of alcoholics during withdrawal. No alleviation of convulsions was found with Ro 15-1788. This suggested that this component of the withdrawal syndrome is not due to endogenous production of a benzodiazepine inverse agonist (contragonist), as Ro 15-1788 prevents the action of this type of compound.

Animals↗