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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 253 records · Page 14Linked to original sources
PubMed1985

A benzodiazepine agonist and contragonist have hypothermic effects in rodents.

The effects on body temperature of the benzodiazepine contragonists FG 7142 (N-methyl-beta-carboline-3-carboxamide) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), the benzodiazepine antagonist Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-7-oxo-4H-imidazo-(1,5-a)(1,4)benzod iazepin e -3-carboxylate) and the benzodiazepine agonist, flurazepam, were investigated in mice. Both of the contragonists and flurazepam reduced the body temperature. The antagonist Ro 15-1788 did not alter body temperature alone but significantly antagonised the effects of FG 7142 and of flurazepam. The effects of the latter two drugs on locomotor activity in animals in a familiar environment were also investigated. Flurazepam reduced the activity counts in these circumstances but FG 7142 did not cause a significant change, at doses which considerably reduced body temperature. The drug FG 7142 also reduced the body temperature in rats. The effects on body temperature of the benzodiazepine contragonists and flurazepam were unusual in that they were changes in the same direction, both antagonised by Ro 15-1788. However, they differed in that while the effects of flurazepam on locomotor activity might contribute to its hypothermic effect this did not appear to be the case for FG 7142.

Animals↗
PubMed1984

Investigating benzodiazepine receptor function in vivo using an intravenous infusion of DMCM.

A method for measuring seizure thresholds using an intravenous infusion of a convulsant beta-carboline benzodiazepine receptor ligand (DMCM) is reported. Seizure thresholds to DMCM are elevated by the benzodiazepine receptor agonist, flurazepam and antagonist, Ro 15-1788, and the proconvulsant beta-carboline, FG 7142. Various other anticonvulsant also antagonise DMCM seizures. Selectivity for the benzodiazepine/GABA receptor complex is demonstrated since bicuculline and pentylenetetrazol lowered thresholds whereas strychnine and N-methyl DL-aspartate did not.

Animals↗
PubMed1984

On the convulsant action of Ro 5-4864 and the existence of a micromolar benzodiazepine binding site in rat brain.

The benzodiazepine Ro 5-4864 (60 mg/kg) produced convulsions in mice that could be antagonised either by diazepam (2-4 mg/kg) or by Ro 15-1788 (10-20 mg/kg). In mice and rats subconvulsant doses of Ro 5-4864 were proconvulsant when combined with subconvulsant doses of picrotoxin or pentylenetetrazole. Ro 15-1788 antagonised the tonic convulsions triggered by the drug combinations when it was given at the same time as Ro 5-4864; this antagonism was not observed when the drugs were injected at different times. In contrast to a previous report, we could find no evidence that Ro 5-4864 antagonised seizures induced by electroshock. Using two different ligand-binding techniques, no evidence was seen for the existence in rat brain of the previously reported "micromolar" benzodiazepine receptor, a suggested site of action of Ro 5-4864.

Animals↗
PubMed1984

Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling.

The effects of the acute and chronic administration of the beta-carboline benzodiazepine receptor ligand, FG 7142 were studied in mice. On acute administration FG 7142 (at doses between 10 and 40 mg kg-1) lowered seizure thresholds to infused pentylenetetrazol (PTZ) but showed an unusual dose-response curve in that higher doses had less effect. The duration of action was considerably longer than that of other beta-carbolines, such as ethyl-beta-carboline-3-carboxylate (beta CCE). During repeated administration, doses of FG 7142 which were initially proconvulsant subsequently produced generalized seizures on average in 60% of animals after 12 once daily treatments. This seemed to be a form of chemical kindling. The effects of different drug administration regimes were studied. Once daily dosage was shown to be the optimum for kindling production, and was therefore used for subsequent experiments. Kindling lasted for at least one month after 12 single once daily doses of 40 mg kg-1 (FG 7142). The administration of the benzodiazepine antagonist Ro 15-1788 concurrent with FG 7142 prevented kindling. When Ro 15-1788 was given to kindled animals along with a challenge dose of FG 7142, it prevented the expression of kindled seizures. These data show that kindling is mediated via the benzodiazepine receptor.

Animals↗
PubMed1983

Hypophysectomy alters both 5-hydroxytryptamine- and alpha 2-adrenoceptor-mediated behavioural changes in the rat.

Hypophysectomy, but not sham-hypophysectomy, reduced tranylcypromine/L-tryptophan hyperactivity when compared with unoperated controls although brain 5-hydroxytryptamine concentrations were not different. Hypophysectomy also reduced quipazine locomotor activity but did not alter spontaneous locomotion. Hypophysectomy potentiated clonidine hypoactivity but did not itself produce sedation. Furthermore, noradrenaline concentrations were not altered in either hypothalamus or nucleus accumbens. This suggests that pituitary function is necessary for the normal manifestation of behaviours mediated by postsynaptic 5-hydroxytryptamine receptors and presynaptic alpha 2-adrenoceptors.

Animals↗
PubMed1983

Regional GABA concentration and [3H]-diazepam binding in rat brain following repeated electroconvulsive shock.

It has been confirmed that 24 hours following a series of electroconvulsive shocks (ECS) given once daily for 10 days (ECS X 10) to rats there is an increase in GABA concentration in the corpus striatum. A similar change was seen after the ECS had been given to rats anaesthetised with halothane, or when 5 ECS were given spread out over 10 days, the rats being anaesthetised during the ECS. A daily convulsion for 10 days elicited by flurothyl exposure resulted in an increased striatal GABA concentration, but also increased the GABA concentration in the hypothalamus, hippocampus and cortex. The increase in striatal GABA concentration was present 24 hours after ECS daily for 5 days or 3 days after ECS daily for 10 days. No change in [3H]-diazepam binding was seen in hippocampus, cortex or corpus striatum 24 hours after the last of 10 once daily ECS. The increase in striatal GABA concentration was therefore seen at all times when enhanced monoamine-mediated behaviours have been demonstrated following seizures.

Animals↗
PubMed1983

Comparison of the effects of chronic desmethylimipramine administration on alpha 2- and beta-adrenoceptors in different regions of rat brain.

The effects of ten once-daily injections of desmethylimipramine (10 mg/kg i.p.) on alpha 2- and beta-adrenoceptor binding were investigated in the rat cortex, hippocampus and hypothalamus. [3H]clonidine and [3H]dihydroalprenolol were used as ligands for alpha 2- and beta-adrenoceptors, respectively. Twenty-four hours after the last injection, the density of beta-adrenoceptors was reduced in all regions studied. In contrast, there was no change in alpha 2-adrenoceptor binding in the cortex, while increased binding was found in the hypothalamus. The effects of desmethylimipramine are discussed in relation to those of other antidepressant treatments.

Animals↗
PubMed1983

Studies on [3H]diazepam and [3H]ethyl-beta-carboline carboxylate binding to rat brain in vivo. I. Regional variations in displacement.

The binding of [3H]diazepam and [3H]ethyl-beta-carboline carboxylate (beta-CCE) to rat brain membranes has been studied following injection of the ligand via a tail vein. "Ex vivo" binding was avoided by homogenising the tissue in an excess of unlabelled ligand. The dissociation rate constant for [3H]diazepam and [3H]beta-CCE was approximately 0.46 min-1 at 0 degree C. Displacement of [3H]diazepam by beta-CCE in vivo showed regional variation: the dose of beta-CCE required to inhibit 50% of [3H]diazepam binding in the cerebellum was one quarter of that required in the cortex, hippocampus, or striatum. However, when diazepam was used to displace [3H]beta-CCE in vivo the converse occurred: the dose needed for 50% inhibition in the cerebellum was more than four times that required in the other three regions. These findings support suggestions from in vitro experiments that two receptors exist with different affinities for benzodiazepines and beta-carbolines. The benzodiazepine receptor antagonist Ro 15-1788 did not differentiate between the two receptor subtypes.

Animals↗
PubMed1983

Studies on [3H]diazepam and [3H]ethyl-beta-carboline carboxylate binding to rat brain in vivo. II. Effects of electroconvulsive shock.

In vivo specific binding of [3H]diazepam was not altered by a single electroconvulsive shock given 5, 30, or 60 min, or 24 h previously, nor 24 h after the last of 10 daily shocks. Similarly, in vivo [3H]ethyl-beta-carboline carboxylate binding was not changed in the brains of animals that had been given a single electroconvulsive shock 30 min previously or a series of 10 daily shocks. Brain areas examined included cerebral cortex, hippocampus, cerebellum, and striatum. However, cortical binding of [3H]diazepam was increased by 32% in animals which were present in the same room while another was being injected and killed. This may represent a response to stress and/or anxiety.

Animals↗
PubMed1982

Intrinsic actions of benzodiazepine antagonists.

RO 15-1788 (4-20 mg/kg), both alone and in combination with chlordiazepoxide (5 mg/kg), increased exploratory head-dipping in an holeboard above control levels. This intrinsic action of a benzodiazepine antagonist is not reversed, and is even augmented, by chlordiazepoxide. RO 15-1788 alone had no effect on locomotor activity, but antagonized the sedative effects of chlordiazepoxide. beta-CCE (1 and 2 mg/kg) was without effect on locomotor activity, but the higher dose reduced head-dipping.

Animals↗
PubMed1982

Abstinence symptoms after withdrawal of tranquillising drugs: is there a common neurochemical mechanism?

Withdrawal of anxiolytic agents such as ethanol, barbiturates, and benzodiazepines may result in a syndrome characterised in its most severe form by delirium and seizures. There is increasing evidence that anxiolytic drugs produce their pharmacological effects by enhancing brain gamma-aminobutyric acid (GABA) transmission. During long-term exposure to anxiolytics, brain GABA synapses show evidence of adaptive changes which would tend to reduce the effect of the anxiolytic and restore normal GABA function. Abrupt cessation of anxiolytic treatment might therefore lead to an acute reduction in GABA function; this change could underlie the severe symptoms associated with tranquilliser withdrawal.

Anti-Anxiety Agents↗
PubMed1982

Using Ro 15-1788 to investigate the benzodiazepine receptor in vivo: studies on the anticonvulsant and sedative effect of melatonin and the convulsant effect of the benzodiazepine Ro 05-3663.

Both the anticonvulsant and sedative effects of diazepam (5 mg/kg) were reversed by subsequent administration of the suggested specific benzodiazepine antagonist Ro 15-1788. In contrast neither the seizure threshold raising or sedative effect of melatonin (200 mg/kg) was reversed by Ro 15-1788. Ro 15-1788 had no effect on the convulsant action of the benzodiazepine Ro 05-3663. These data therefore argue against the suggestion that melatonin produces its sedative and anticonvulsant effects in vivo by interacting with the benzodiazepine receptor, and also strengthens the suggestion that Ro 05-3663 does not act at this site. The use of Ro 15-1788 in demonstrating whether a drug acts in vivo at the benzodiazepine site to produce a pharmacological response is discussed.

Animals↗
PubMed1982

Repeated administration of subconvulsant doses of GABA antagonist drugs. I. Effect on seizure threshold (kindling).

Repeated subconvulsant doses of the GABA antagonist drugs picrotoxin (5 mg/kg), pentylenetetrazol (PTZ) (30 mg/kg), and bicuculline (3.5 mg/kg), were given IP once daily to rats. Picrotoxin produced rapid kindling to full seizures in about 5 days, PTZ produced sporadic myoclonic seizures after 17 days, PTZ produced sporadic myoclonic seizures after 17 days whereas bicuculline only produced occasional mild jerking. Following these treatments, seizure thresholds to these drugs were measured by an IV infusion method to minimise problems of systemic uptake and metabolism of the drugs. Picrotoxin- and PTZ-treated animals showed no alteration in seizure threshold. However, following bicuculline pretreatment, seizure threshold was raised. Methodological problems in the interpretation of pharmacological kindling are discussed.

Animals↗
PubMed1982

Repeated administration of subconvulsant doses of GABA antagonist drugs. II. Effect on monoamine-mediated behaviour.

The effect on monoamine-medical behaviour of repeated daily subconvulsive doses of the GABA antagonist drugs pentylenetetrazol (PTZ) (30 mg/kg for 8 days), picrotoxin (5 mg/kg for 4 days) and bicuculline (3.5 mg/kg for 16 days) was investigated. None of the drugs, administered chronically, increased behavioural responses to the 5-hydroxytryptamine agonist quipazine (25 mg/kg), and neither picrotoxin nor bicuculline altered the locomotor response to the dopamine agonist apomorphine (AP) (0.1 mg/kg). By contrast, repeated doses of PTZ increased the locomotor response to AP, and also increased circling responses to both AP (0.5 mg/kg) and methamphetamine (2.0 mg/kg) in unilateral nigrostriatal-lesioned rats.

Animals↗
PubMed1982

Hypophysectomy does not prevent the enhanced monoamine-mediated behavioural responses following repeated electroconvulsive shocks.

Groups of hypophysectomised rats were given either an electroconvulsive shock (ECS; 125V, 1 sec) once daily for 10 days or a sham-shock. Twenty-four hours after the final treatment both groups were tested for their responses to the dopamine agonist, apomorphine, the 5-hydroxytryptamine agonist, quipazine, and the alpha 2-adrenoceptor agonist, clonidine. Repeated electroconvulsive shock enhanced the locomotor activity produced by either quipazine (25 mg/kg i.p.) or apomorphine (0.2 mg/kg s.c.) compared to sham-shocked controls. This treatment also attenuated the hypoactivity produced by clonidine (0.5 mg/kg i.p.). These changes are identical to those produced in normal rats by repeated electroconvulsive shock. Hypophysectomy, therefore, did not abolish the increased 5-hydroxytryptaminergic and dopaminergic behavioural responses neither did it prevent the decreased functional activity of central alpha 2-adrenoceptors, which may be presynaptic. These data suggest that although electroconvulsive shock has been reported to stimulate the secretion of various pituitary hormones, this process is not essential for the development of the enhanced monoamine-mediated behavioural responses studied.

Animals↗