Addiction: brain mechanisms and their treatment implications.
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Animals↗
Biomedical subjects
D J Nutt
Publications and source records attributed to D J Nutt.
Cognitive processing in post-traumatic stress disorder.
Recent research has suggested an abnormal attentional bias to threat in anxiety disorders. We have assessed the processing of thoughts of trauma, panic attacks, general fear and positive affect in a cohort of 15 war veterans with post-traumatic stress disorder (PTSD) and an age- and sex-matched normal control group. Subjects with PTSD showed delayed processing of self-referential sentences when the themes of the sentences were traumatic experiences or positive affect, compared with controls. However, they were more efficient than control subjects in the processing of sentences describing situations of panic attacks and general fear. It would therefore appear that in patients with PTSD, cognitive processing is hindered by personally relevant themes of past traumatic experiences, whereas it may be facilitated by information related to general threat or internal body sensations of panic.
Adult↗
TNF alpha mimics the endocrine but not the thermoregulatory responses of bacterial lipopolysaccharide (LPS): correlation with FOS-expression in the brain.
Thermoregulatory and plasma corticosterone responses to peripheral LPS and TNF alpha were compared and correlated with brain FOS protein expression. TNF alpha mimicked the corticosterone response evoked by LPS and the increase in FOS expression in the hypothalamic PVN. TNF alpha also mimicked LPS-activation of central noradrenergic and adrenergic neurones. TNF alpha did not induce a hypothermia which might reflect its failure to activate the vasopressin neurones of the BNST.
Animals↗
Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo.
To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last finding validates the use of other non-tomographic counting techniques (Malizia et al., 1995a) where an index of displacement can be obtained after the administration of less than 1% of the dose of radiation needed for a PET study. These studies are likely to be useful in human psychopharmacology, in particular in the assessment of tolerance and of putative changes in benzodiazepine sensitivity in anxiety disorders. The same principles can be applied to other ligand studies and will be useful to validate current PK/PD models.
Adult↗
Functional studies of specific imidazoline-2 receptor ligands.
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Animals↗
Behavioral and endocrine responses to clomipramine in panic disorder patients with or without alcoholism.
Central nervous system serotonin functions may differ between certain subgroups of alcoholics, patients with panic disorder, and healthy volunteers. To investigate these possibilities we administered the serotonin uptake inhibitor, clomipramine (12.5 mg, i.v.), to patients with alcohol dependence, patients with panic disorder with or without alcohol dependence, and healthy volunteers. Alcoholics did not differ from healthy volunteers in their neuroendocrine or behavioral responses. In contrast, patients with panic disorder exhibited marked dysphoric reactions and/or panic attacks following low-dose i.v. clomipramine, whereas their neuroendocrine responses were similar to the other two groups. Patients with panic disorder may have super-sensitive postsynaptic serotonin receptors in areas of their central nervous system, which are important for mood regulation.
Adrenocorticotropic Hormone↗
Idazoxan-induced reductions in cortical glucose use are accompanied by an increase in noradrenaline release: complementary [14C]2-deoxyglucose and microdialysis studies.
The autoradiographic [14C]2-deoxyglucose procedure was used to map function-related alterations in local cerebral glucose use following acute administration of the alpha 2-adrenoceptor antagonist, idazoxan (0.3-3 mg kg-1 s.c.). The most prominent feature of the results obtained was the significant reduction in glucose use in certain locus coeruleus projection areas. Thus, in various cortical, hippocampal and thalamic regions, as well as structures involved in auditory and visual function, idazoxan administration was associated with a 13-20% decrease in glucose use. In a complementary microdialysis study, the effect of idazoxan on extracellular noradrenaline levels in the frontal cortex of rats, manipulated in the same fashion as during the [14C]2-deoxyglucose procedure (i.e. following the application of surgery and partial restraint), was examined. Both surgery and restraint were associated with a modest but significant increase in basal noradrenaline release (+31% and +26%, respectively). Subsequent administration of idazoxan (3 mg kg-1 s.c.) evoked a further increase in noradrenaline release, the magnitude of which was the same as that observed following its administration to freely-moving rats (+113%). These combined data suggest that idazoxan-induced reductions in cerebral glucose use, at least in the frontal cortex, may occur as a consequence of the increase in noradrenaline release. In addition, it appears that surgery and partial restraint do not alter alpha 2-adrenoceptor tone in the frontal cortex.
Adrenergic alpha-Antagonists↗
The effects of flumazenil in neuropsychiatric disorders.
Flumazenil is a benzodiazepine receptor antagonist. It is currently used mainly in the anaesthetic and emergency rooms to reverse the effect of exogenous benzodiazepines. Its use in a variety of experimental animal models and in human neuropsychiatric disorders continues to generate a wealth of information on the possible role of the benzodiazepine-GABA(A) receptor complex in their pathogenesis. In addition, labelled with carbon-11, flumazenil has proved to be one of the most successful positron emission tomography ligands stimulating research on the role of the benzodiazepine receptor in these disorders. This review focuses on the current state of play of flumazenil as a therapeutic or investigative agent in neuropsychiatry, citing also the relevant animal models.
Animals↗
Use of selective serotonin reuptake inhibitors and other serotonergic drugs in the biological dissection of affective disorders.
The need to subtype patients with affective disorders on the basis of biological characteristics is well recognized, and much of the research in this area has focused on the serotonergic system. Biological subtyping can be approached using both peripheral and central markers. Peripheral markers include platelet serotonin concentrations, the density and affinity of platelet serotonin reuptake and platelet 5-HT2 receptors, and plasma serotonin concentrations. Central markers include cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations, and endocrine, psychological and body temperature responses to challenge tests with a number of serotonergic drugs. More recently, the role of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic drugs in sleep, and in the control of cardiovascular homeostasis, has been studied. This may provide a greater understanding of the mechanisms of serotonin dysregulation in affective disorders, and may ultimately improve treatment of these conditions.
Biomarkers↗
A comparison of the effects of phenelzine treatment with moclobemide treatment on cardiovascular reflexes.
The effects of treatment with phenelzine (n = 15) and moclobemide (n = 20) on heart rate variability and cardiovascular responses to standing were examined using non-invasive beat-to-beat blood pressure (BP) monitoring in an open cross-sectional study. Phenelzine markedly impaired the BP response compared with moclobemide, with 83% vs 15% of patients lacking the normal initial BP overshoot (p < 0.01). BP recovery to supine levels was delayed (median time for diastolic BP 14.5 s after phenelzine vs 4.9 s after moclobemide; p < 0.002). Standing BP at 1 min and its change from supine levels were also significantly lower in the phenelzine group (delta diastolic BP 4 mmHg vs 15 mmHg; p < 0.001). Heart rate responses and variability were preserved and did not differ between treatments. These findings are consistent with impairment of sympathetic function but preservation of parasympathetic responses after phenelzine treatment.
Adolescent↗
The cardiovascular and subjective effects of thyrotropin releasing hormone (TRH) and a stable analogue, dimethyl proline-TRH, in healthy volunteers.
1. The cardiovascular effects of TRH 0.5 mg and 1 mg and a stable TRH analogue, dimethylproline-TRH (RX77368) 1 mg, infused intravenously over 1 min were assessed in healthy volunteers in two randomised, double-blind, placebo controlled crossover studies. 2. Both doses of TRH produced significant but transient increases in blood pressure (peak delta systolic: 0.5 mg = 9.2 mm Hg, 1.0 mg = 5.2 mm Hg; peak delta diastolic: 0.5 mg = 6.4 mm Hg, 1.0 mg = 5.4 mm Hg). 3. Beat-to-beat Finapres monitoring demonstrated a rapid onset of effects of RX77368 1 mg, with significant blood pressure effects by 45-60 s from the start of the infusion (delta systolic BP: 14.2 mm Hg, delta diastolic BP: 15.8 mm Hg and delta heart rate: 8.9 mm Hg at 60 s). 4. The pressor effects of RX77368 1 mg recorded by Dinamap (peak delta systolic: 14.3 mm Hg; peak delta diastolic: 11.8 mm Hg) were sustained, with diastolic pressure still elevated (delta diastolic: 8.2 mm Hg) at 60 min. Heart rate was more transiently elevated (peak delta heart rate: 9.0 beats min-1) during the first 6 min post infusion. 5. Mild apprehension was reported for the first 6 min after RX77368 1 mg, whereas paraesthesiae were noted after TRH. Otherwise both drugs were similar in the type (flushing, nausea, acid taste, urethral sensations) and duration of subjective effects.
Adult↗
Effect of chloride or glucose on the incidence of lactate-induced panic attacks.
OBJECTIVE: This study was designed to test the hypothesis that the addition of chloride to a lactate infusion would reduce the frequency of panic attacks. METHOD: The subjects included 14 healthy volunteers and 20 patients meeting the DSM-IV criteria for panic disorder. All subjects received an infusion of lactate dissolved in 0.9% sodium chloride and an infusion of lactate dissolved in 5% dextrose in water on separate days in a random-order, double-blind procedure. Blood pressure, heart rate, and panic symptoms were measured at 3-minute intervals during the infusions. The occurrence of panic attacks was ascertained through the subjects' reports of losing control, panicking, or "going crazy" and the presence of at least four Research Diagnostic Criteria symptoms of a panic attack. RESULTS: Fifteen (75%) of the patients with panic disorder reported a panic attack during one of the infusions or both; no healthy volunteers had a panic attack. The patients with panic disorder were significantly more likely to have a panic attack during the lactate/sodium chloride infusion than during the infusion of lactate/5% dextrose in water. The number of panic attack symptoms reported at 3-minute intervals did not differ between the two types of infusion. CONCLUSIONS: The coadministration of glucose resulted in a reduced sensitivity to the panicogenic effects of lactate. The hypothesis that adding chloride to the infusion would reduce the frequency of lactate-induced panic attacks was not supported.
Blood Glucose↗
Benzodiazepine receptor function in anxiety disorders.
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Anxiety Disorders↗
Neuroendocrine and clinical effects of electroconvulsive therapy and their relationship to treatment outcome.
Two groups of variables, endocrine and clinical, have been reported to have predictive value in determining response to electroconvulsive therapy (ECT) in depressed patients. Baseline levels of oxytocin associated neurophysin (OAN) and peak OAN response to ECT may predict clinical outcome, while the presence of delusional symptoms may indicate favourable initial response to ECT. The purpose of this study was to examine the relationship between these variables on initial and longer term response over a course of ECT, using a direct measure of plasma oxytocin concentrations. A substantial and immediate increase in oxytocin was seen after the first ECT, with significantly attenuated responses after the third and fifth ECTs. Increased plasma vasopressin concentrations were seen after all ECT treatments, each response being of similar magnitude. No associations were found between either endocrine baseline levels or peak responses, and clinical outcome. Only clinical variables predicted outcome, as patients with psychotic symptoms had more rapid initial response to ECT, and patients who had relapsed 2 months after the end of ECT had significantly higher depression ratings at day 14 of treatment than treatment responders.
Aged↗
A pharmacodynamic study of the alpha 2-adrenergic receptor antagonist ethoxyidazoxan in healthy volunteers.
Ethoxyidazoxan, a potent and highly selective alpha 2-adrenergic receptor antagonist, was administered intravenously to six healthy male volunteers in a double-blind, placebo-controlled, dose-rising design. Doses of 6 micrograms/kg and 8 micrograms/kg infused intravenously over 30 minutes produced significant elevations of plasma norepinephrine and body temperature and inhibited norepinephrine-induced platelet aggregation. Central activity was shown by reversal of the slowing of saccadic eye movements and an increase in saccade peak velocity at the higher dose. Modest increases in blood pressure were produced without change in heart rate. Ethoxyidazoxan was well tolerated, with slight changes in subjective alertness and sedation.
Adrenergic alpha-Antagonists↗
Alcohol: the drug.
The purpose of this chapter is to bring together some of the recent research that has significantly increased our knowledge of the mechanisms underlying the actions of alcohol in the body, including absorption and metabolism. One particular field of growth is that of the actions of alcohol in the brain. In the past few years there have been a number of important advances in our understanding of the mechanisms by which alcohol produces sedation, intoxication and pleasure as well as those processes which contribute to its addictive properties. Progress has also been made in unravelling the mechanisms of tolerance and physical withdrawal and these studies have also thrown light on the basis of the neurotoxic effects of alcohol. Similarly in the periphery new ideas about the toxic tissue damaging properties of alcohol have been developed.
Biogenic Monoamines↗
Successful treatment of night terrors and somnambulism with paroxetine.
A patient with a 30-year history of somnambulism and night terrors is described. The use of a home ambulatory sleep electroencephalogram (EEG) recording in clarifying the diagnosis and in monitoring the results of treatment is illustrated and successful treatment using a selective serotonin re-uptake inhibitor is reported.
Clonazepam↗
Central alpha-2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm.
Clonidine produces an interoceptive discriminative stimulus or "cue" in rat drug discrimination studies. This cue may be mediated by its alpha-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg-1, IP) or a saline vehicle. The alpha-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg-1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selective alpha-2 adrenoceptor antagonists RX811059 (2.5 mg kg-1) and fluparoxan (3 mg kg-1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated by alpha-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally acting alpha-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.
Adrenergic alpha-2 Receptor Agonists↗