Functional studies of specific imidazoline-2 receptor ligands.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
D J Nutt
Publications and source records attributed to D J Nutt.
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↗
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↗
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.
Explore the source record for details and available documents.
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↗
Investigation of the involvement of opioid receptors in the action of anticonvulsants.
This study investigates the possible involvement of opioid receptors in the action of a variety of anticonvulsant agents. The opioid antagonist naloxone (0.3, 1 mg/kg IP) and the selective mu-opioid antagonist cyprodime (3 mg/kg IP) significantly inhibited the increase in electroshock seizure threshold induced by phenytoin (3 mg/kg IP) in mice. The anticonvulsant effects of ethanol (1 g/kg IP) were also significantly antagonised by naloxone (1 mg/kg IP) but not by a 0.3 mg/kg IP dose or by cyprodime (3 mg/kg IP). The results with naloxone were confirmed using higher doses of phenytoin (10 mg/kg IP) and ethanol (1.5 g/kg IP). In contrast to the above findings, naloxone (0.3, 1 mg/kg IP) had no effect on the increase in seizure threshold induced by sodium valproate (200 mg/kg IP) or dizocilpine (MK801, 0.5 mg/kg IP) and paradoxically potentiated the increase in seizure threshold produced by phenobarbitone (15 mg/kg IP); carbamazepine (10 mg/kg IP) and the benzodiazepine agonist loprazolam (1 mg/kg IP), clearly differentiating these compounds from phenytoin and ethanol. These findings suggest that the anticonvulsant effects of phenytoin and ethanol (as assessed by their ability to prevent tonic hindlimb extension in the mouse electroshock model) may be mediated, at least in part, by the release of endogenous opioids and subsequent activation of opioid receptors (mu, in the case of phenytoin, but non-mu, in the case of ethanol) although direct activity at opioid receptors cannot be precluded.
Animals↗
Saccadic eye movement parameters in normal subjects.
The present study obtained saccadic eye movements from 122 normal subjects to establish normative values and test-retest reliability data, using a recently developed electrooculographic recording and analysis system. Factors that might affect saccade values, such as age, sex, and time of day when testing, were also assessed. Mean (+/- S.D.) peak velocity values over saccade angles of 15 degrees, 25 degrees and 35 degrees were in agreement with those previously reported. Repeat testing in 11 subjects on 4 separate occasions showed that saccade measurements were consistent across tests. Several saccade parameters were significantly negatively associated with age for 35 degrees saccades. The association between age and peak velocity was examined in greater detail over a range of saccade angles, and the greatest effect was observed for saccades of > or = to 35 degrees. Diurnal changes in performance were observed, with a tendency for slightly slower values in the early afternoon. There were no significant differences between males and females.
Adolescent↗
A single preexposure produces sensitization to the locomotor effects of cocaine in mice.
Sensitization to the locomotor effects of cocaine (10 mg/kg, IP) occurred in mice following preexposure to a single high dose (40 mg/kg, IP) of the drug on the previous day. Behavioral sensitization only occurred under certain experimental conditions; that is, in mice which were injected in a novel environment (i.e., the activity boxes) on day 1 and tested in the same environment on day 2. It did not occur in mice that were fully habituated to the test apparatus on both days of the experiment or in mice that were injected in the home cage on day 1. This model is consistent with studies in rats, and offers the opportunity for further characterization of the processes underlying cocaine sensitization.
Animals↗
Radioligands for PET studies of central benzodiazepine receptors and PK (peripheral benzodiazepine) binding sites--current status.
The status of the radiochemical development and biological evaluation of radioligands for PET studies of central benzodiazepine (BZ) receptors and the so-called peripheral benzodiazepine binding sites, here discriminated and referred to as PK binding sites, is reviewed against current pharmacological knowledge, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies, [N-methyl-11C]flumazenil for central BZ receptors, and [N-methyl-11C]PK 11195 for PK binding sites. Quality assurance and plasma metabolite analysis are also reviewed for these radioligands and practical recommendations are given on methodology for their performance.
Animals↗
Buprenorphine-cocaine interactions in mice: effect on locomotor activity and hole-dipping behaviour.
The effect of cocaine and the mixed mu-opioid partial agonist/kappa-antagonist buprenorphine on locomotor activity and hole-dipping behaviour was investigated in mice. The drugs were given alone and in combination. Cocaine (7.5, 15, 30 mg kg-1, i.p.) significantly increased locomotion in a dose-related manner in the hour following injection. The two highest doses also increased hole-dipping although this response was not consistently seen. Buprenorphine (0.5, 5 mg kg-1, i.p.) produced an increase in locomotion which occurred 30-60 min after injection but did not alter hole-dipping behaviour. A lower dose (0.05 mg kg-1) had no effect on either parameter. The locomotion induced by cocaine (15 mg kg-1, i.p.) was not modified by buprenorphine (0.05, 0.5, 1, 5 mg kg-1, i.p.; 5 min pretreatment). However, hole-dipping was almost completely abolished in animals given combinations of cocaine and buprenorphine (0.05-5 mg kg-1, i.p.), although neither drug decreased hole-dipping when given alone. This observation, which was not simply due to the emergence of stereotyped behaviour, suggests an interaction between buprenorphine and cocaine.
Animals↗
The approach to new anxiolytics.
Explore the source record for details and available documents.
Animals↗
Effects of benzodiazepine receptor inverse agonists on locomotor activity and exploration in mice.
This study investigates the effects of benzodiazepine receptor inverse agonists on the locomotor and exploratory behaviour of mice when tested in a familiar environment. The weak partial inverse agonist Ro 15-3505 (0.3, 1, 3 mg/kg i.p.) significantly increased locomotion and hole-dipping in habituated mice. However, the more efficacious partial inverse agonists Ro 15-4513 (0.3, 1, 3 mg/kg i.p.) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg i.p.) had no effect on these parameters. The benzodiazepine receptor antagonist flumazenil (3, 10, 20 mg/kg i.p.) also increased locomotion and hole-dipping in habituated mice, although like Ro 15-3505, these effects were of short duration occurring largely in the first 15 min following injection. Opposite effects were obtained with the partial benzodiazepine agonist Ro 17-1812 (1, 3, 10 mg/kg i.p.) which produced a longer-lasting significant decrease in hole-dipping behaviour in habituated mice without altering locomotion. Finally, in contrast to its effects in habituated animals, Ro 15-3505 (0.3, 1, 3 mg/kg i.p.) did not modify either locomotion or exploration in mice which were tested in a novel environment, showing that the effects of the inverse agonist were state-dependent. This demonstration that, under certain conditions, the weak benzodiazepine receptor inverse agonist Ro 15-3505 and the antagonist flumazenil, produce behavioural activation is in accordance with the work of others suggesting that these classes of compound may increase arousal and may therefore be of some value in treatment of memory disorders.
Animals↗