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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 181 records · Page 10Linked to original sources
PubMed1991

The effect of intravenous flumazenil on interictal electroencephalographic epileptic activity: results of a placebo-controlled study.

The effect on interictal electroencephalographic epileptic activity of intravenous flumazenil (Ro 15-1788), a benzodiazepine antagonist and potential antiepileptic drug, was studied in 10 patients. Comparison was made with intravenous diazepam (10 mg) and placebo using a single-blind, single-dose, cross-over design. A dose of 3 mg flumazenil was well tolerated and produced a significantly greater reduction in the number of epileptic transients during the first 40 minutes after injection than did placebo (p less than 0.05). This effect was similar to that of diazepam in magnitude and duration. When flumazenil (3 mg) was administered immediately after intravenous diazepam (10 mg), the reduction in interictal epileptic activity was not significantly different from that produced by diazepam alone. The results suggest that either flumazenil has intrinsic antiepileptic activity and in this respect acts as a partial agonist at the benzodiazepine receptor, or that it is antagonising an endogenous proconvulsant ligand in these patients.

Adult↗
PubMed1991

Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in six men.

OBJECTIVE: Excessive exposure to glucocorticoids can have neurotoxic effects. The behavioral, cognitive, and neurochemical changes observed following the cessation of heavy drinking, therefore, may be associated with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate HPA axis disturbances during the ethanol withdrawal syndrome, the authors examined diurnal changes in plasma cortisol in six alcohol-dependent men following the abrupt discontinuation of alcohol intake. METHOD: Plasma cortisol concentrations were quantified every 30 minutes for 24 hours in the early stage (1 day after cessation) and the middle to late stage (3 days after cessation) of the ethanol withdrawal syndrome as well as after the resolution of acute symptoms (8 days or more after cessation). RESULTS: Plasma cortisol concentrations were almost twice as high during acute withdrawal as they were following recovery. The duration of the cortisol diurnal cycle on the first day of withdrawal was negatively correlated with the severity of withdrawal. CONCLUSIONS: There is a marked activation of the HPA axis associated with the ethanol withdrawal syndrome. The authors hypothesize that this activation may account for some of the signs and symptoms of acute and subacute withdrawal. They discuss the potential long-term physiological effects of the episodic increases in cortisol associated with repeated episodes of ethanol withdrawal. The alterations in cortisol rhythmicity during early withdrawal may also have clinical implications.

Adult↗
PubMed1990

Body temperature discriminates between full and partial benzodiazepine receptor agonists.

The benzodiazepine full agonist loprazolam and the beta-carboline ZK 93423 produced hypothermia in mice (1-30 mg/kg i.p.). Maximal effects were seen at relatively low doses of these compounds. In contrast, the partial agonists Ro 17-1812 (a benzodiazepine) and ZK 91296 (a beta-carboline), did not modify rectal temperature at doses up to 30 mg/kg i.p. (which would be receptor saturating). Body temperature may therefore be a useful test for discriminating between full and partial agonists at the benzodiazepine receptor.

Animals↗
PubMed1990

Diazepam and Ro 15-1788 increase absence epilepsy in WAG/Rij rats chronically exposed to diazepam.

The mechanisms underlying tolerance to benzodiazepines were investigated by injecting diazepam (5 mg/kg) twice daily for 23 days in WAG/Rij rats (an animal model for non-convulsive absence epilepsy). After this the rats received either the agonist, diazepam, or the antagonist, flumazenil (Ro 15-1788). EEG analyses showed that both compounds increased the amount of absence epilepsy-like phenomena. This suggests that repeated administration of diazepam moves the benzodiazepine receptor spectrum towards the inverse agonist end.

Animals↗
PubMed1990

Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder.

The possibility that panic disorder might be due to abnormal activity of endogenous ligands of the benzodiazepine receptor was investigated with the use of the benzodiazepine antagonist flumazenil. Physiological and subjective psychological responses to this selective antagonist were measured in 10 patients with panic disorder and in 10 control subjects, by using a placebo-controlled crossover study design. Subjective anxiety responses after flumazenil infusion were significantly higher in the patient group with panic disorder than in the controls, and eight patients with panic disorder but no controls had panic attacks. This anxiogenic effect of flumazenil in the patients argues against the presence of endogenous anxiogenic (inverse agonist) ligands. Possible explanations include the differential production of an anxiolytic endogenous ligand or an altered benzodiazepine receptor "set-point." Such an abnormality may contribute to the pathogenesis of panic disorder.

Adolescent↗
PubMed1990

Regional neurotransmitter responses after acute and chronic electroconvulsive shock.

Regional neurotransmitter changes after acute and chronic electroconvulsive shock (ECS) were studied using the technique of repeated microdialysis. Microdialysis was carried out on alternate sides of the brains of anaesthetised rats before and during the first and the eighth ECS or sham (control) treatments. Extracellular fluid release of monoamines and their metabolites was measured in the frontal cortex, striatum and nucleus accumbens using HPLC with electrochemical detection. The first ECS produced selective regional responses, shown by increased concentrations of noradrenaline (NA) and dopamine (DA) in frontal cortex, by unchanged DA content in striatum, and by a small rise in NA and a fall in DA concentrations in nucleus accumbens. Concentrations of metabolites increased after ECS in all regions studied, and for homovanillic acid and dihydroxyphenylacetic acid, the temporal pattern of these changes did not resemble that of DA. Comparison of neurotransmitter responses as per cent of baseline release after the first and eighth ECS treatments showed they were identical. Basal release of monoamines and metabolites before the first ECS or sham treatment was similar in all regions studied. Prior to the eighth treatment, basal release of NA in the frontal cortex and DA in the striatum was elevated in the ECS-treated animals, while basal release of NA in the nucleus accumbens was reduced in both ECS- and sham-treated animals. These data suggest that acute and chronic ECS have different and region-specific effects on neurotransmitter release, although the overall pattern of these responses is not changed by chronic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Pharmacological mechanisms of benzodiazepine withdrawal.

The pharmacology of the benzodiazepine receptor is unusual in relation to other receptors in that there exist three types of ligand: agonists (e.g. diazepam), which are anxiolytic and anticonvulsant; antagonists (e.g. flumazenil), which are neutral; and inverse agonists (e.g. FG 7142), which are anxiogenic and proconvulsant. Chronic administration of agonists leads to tolerance and withdrawal, and produces a global shift in benzodiazepine receptor function with attenuation of agonist and enhancement of inverse agonist actions. These changes appear without alterations in receptor number or affinity, and may reflect a shift in efficacy, "withdrawal shift", at the receptor. Treatment with flumazenil during benzodiazepine agonist administration, or even in the period after the last dose, can prevent or reverse this efficacy shift as indicated by a lack of sensitization to inverse agonists. The clinical implications of these findings are discussed.

Animals↗
PubMed1990

Noradrenergic mechanisms appear not to be involved in cocaine-induced seizures and lethality.

In the present study we have investigated the effects of compounds which increase synaptic levels of noradrenaline on cocaine-induced seizures and lethality in mice. The noradrenaline uptake blocker desipramine (0.3, 3, 30 mg/kg i.p.; 1h pretreatment) and the alpha 2-antagonists idazoxan (0.05, 0.5, 5 mg/kg i.p.; 15 min) and RX811059A (0.01, 0.1, 1 mg/kg i.p.; 15 min) neither reduced nor increased the number of animals having convulsions in the 10 min following administration of cocaine (45, 60 mg/kg i.p.). None of these drugs increased lethality when assessed 10 minutes after 60 mg/kg cocaine and the alpha 2-antagonists did not protect against the lethal effects of a 90 mg/kg dose. On the other hand, desipramine significantly reduced the number of animals dying after this high dose of cocaine. These results suggest that noradrenergic mechanisms do not promote cocaine-induced convulsions and lethality - an important observation in light of the growing use of desipramine for initiation of abstinence in cocaine-dependent outpatients.

Adrenergic alpha-Antagonists↗
PubMed1990

The pharmacology of human anxiety.

The human pharmacology of anxiety disorders, including panic disorder, is detailed. The major theories center around the role of benzodiazepine receptor, noradrenergic and serotonergic dysfunction. The contribution that challenge tests with lactate, hyper- and hypocapnia, beta- and alpha-2-adrenoceptor agonists, peptides, pentylenetetrazol, and caffeine make to our understanding of the biological basis of anxiety and these major theories are described and discussed.

Animals↗
PubMed1990

The neurochemistry of anxiety: an update.

1. Recent neurochemical investigations have enhanced our understanding of the anxiety disorders. Emphasis has been placed on dysfunction in central benzodiazepine, serotonergic and noradrenergic systems. 2. Changes in activity of endogenous ligands for the benzodiazepine receptor or in benzodiazepine receptor sensitivity appear to modulate anxiety. 3. There is evidence of serotonergic involvement in anxiety, in that serotonin agonists may increase anxiety, whilst drugs that reduce serotonin function are anxiolytic. 4. Noradrenergic dysfunction, especially that of alpha-2-adrenoceptors, provides the strongest etiological evidence in the development of anxiety. 5. A number of testable hypotheses can be generated from our present knowledge. As a result, new and more specific treatments may become apparent for the anxiety disorders.

Anxiety↗
PubMed1990

A cerebrospinal fluid study of the pathophysiology of panic disorder associated with alcoholism.

In order to investigate the neurochemistry of panic disorder in alcoholics, we measured various cerebrospinal fluid (CSF) parameters in subjects with both conditions and compared them with an age- and sex-matched population of alcoholics and normal controls. When height, age and weight were covaried, subjects with panic disorder had higher levels of B-endorphin in CSF. There were no differences in other CSF measures between the groups. Alcoholics with panic disorder had higher plasma MHPG concentrations compared with alcoholics without panic disorder but these were not statistically different from controls.

Adult↗
PubMed1990

Alcoholism and panic disorder: is the comorbidity more than coincidence?

Studies on alcoholic patients have found a higher than expected prevalence of panic disorder, and suggest a positive correlation between the level of alcohol consumption and severity of anxiety. Conversely, there is an increased prevalence of alcoholism among patients with panic disorder and their blood relatives. A comparison of symptoms, physiological and neurochemical changes known to occur in both alcohol withdrawal and panic disorder reveals a degree of similarity between the 2 conditions. Based on the data, we propose that the chemical and cognitive changes occurring as the result of repeated alcohol withdrawals may kindle and condition coincidence of panic attacks in susceptible individuals. Implications of our postulates for treatment of alcohol withdrawal and panic disorder in alcoholics and for future studies are discussed.

Alcoholism↗
PubMed1990

Neuropharmacological and clinical aspects of alcohol withdrawal.

Abnormalities in the function or activity of several neurotransmitter systems have been demonstrated after acute and chronic, exposure to alcohol, and in alcohol withdrawal. The changes can be divided into alterations in function of inhibitory and excitatory systems. Inhibitory dysfunction is indicated by reduced gamma-aminobutyric acid and alpha-2-adrenoceptor activity. In conjunction with, and exacerbating this, is increased activity of excitatory systems, perhaps the most significant of which is the probable potentiation of N-methyl-D-aspartate activity by depletion of magnesium. There is additional, and possibly secondary, overactivity of catecholamine and corticotropin releasing factor neuronal systems. Other, less specific changes include increased numbers of calcium channels, which would increase neuronal excitability. The evidence for these changes is presented, and the implications for new treatment regimes for alcohol withdrawal are discussed.

Alcoholic Intoxication↗
PubMed1990

Carbamazepine retards the development of cocaine-kindled seizures but not sensitization to cocaine-induced hyperactivity.

The effects of chronic carbamazepine on cocaine-kindled seizures and behavioral sensitization were examined in this study. Rats were fed a diet containing carbamazepine or no drug and then repeatedly administered cocaine (40 and 50 mg/kg intraperitoneally [IP] [117.6 and 147.0 mumol/kg, respectively]). Carbamazepine markedly decreased the development of cocaine-kindled seizures and their associated lethality, but did not affect the development of sensitization of behavioral stereotypies. Carbamazepine consistently decreased the peak stereotypy ratings at the 40 mg/kg but not 50 mg/kg dose. In a 2-day sensitization paradigm chronic carbamazepine did not affect acute cocaine-induced hyperactivity (day 1; 40 mg/kg), nor did it affect sensitization to a low dose challenge of cocaine (day 2; 10 mg/kg [29.4 mumol/kg]). Sensitization of stereotypy and locomotor activity are thought to be related to the psychomotor stimulant properties of cocaine, while seizures may be associated with cocaine's local anesthetic effects. Our data suggest that carbamazepine is inhibiting mechanisms associated with local anesthetic kindling and only minimally affecting the psychomotor stimulant effects of cocaine.

Animals↗
PubMed1989

3-(Methoxycarbonyl)-amino-beta-carboline reduces both the sedative and anticonvulsant effects of diazepam.

The intrinsic effects of the benzodiazepine receptor ligand beta-CMC (3-(methoxycarbonyl)-amino-beta-carboline) and its interaction with the anticonvulsant and sedative effects of diazepam were assessed. beta-CMC (100 mg/kg i.p.) significantly elevated seizure threshold to bicuculline. beta-CMC (10 mg/kg) failed to alter the anticonvulsant action of diazepam (5 mg/kg i.p.), but significantly attenuated diazepam's sedative effect. A higher dose of beta-CMC (40 mg/kg) did attenuate diazepam's anticonvulsant action. The data suggest that beta-CMC is a partial agonist at benzodiazepine receptors.

Animals↗