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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 91 records · Page 5Linked to original sources
PubMed1999

Autoradiographical and behavioural effects of a chronic infusion of antisense to the alpha2D-adrenoceptor in the rat.

1. The aims of this study were, firstly to use receptor autoradiography to investigate the effect of antisense oligonucleotides to the alpha2D-adrenoceptor on receptor binding and, secondly to measure behavioural and physiological parameters to determine whether the chronic antisense infusion had any effect on alpha2-adrenoceptor function in vivo. 2. A 3 day infusion of antisense to the alpha2D-adrenoceptor significantly reduced specific [3H]-RX821002 binding in the septum (20 - 30%) and anterior hypothalamic area (20 - 30%). beta-Adrenoceptor expression was unaffected in those brain areas examined, indicating the antisense knockdown was specific to the alpha2-adrenoceptors. 3. On the second day of the infusion, the hypothermic response to UK 14,304 was significantly attenuated in the antisense-treated group compared with both vehicle and mismatch controls. The effect was fully reversible and a similar decrease in body temperature was observed in all the treatment groups 4 days after the end of infusion. 4. During the second day of the infusion, the effects of UK 14,304 on behaviour were reduced in the antisense-treated rats, but were not significantly lower than those of the vehicle and mismatch, UK 14, 304 controls. These trends were not observed 4 days after the end of the infusion. 5. In conclusion, antisense has been shown to selectively knockdown alpha2-adrenoceptor expression in specific brain areas. The consequence of this knockdown is a significant attenuation of UK 14,304-induced hypothermia and a reduction in its sedative actions. These changes were fully reversed 4 days after the end of the infusion.

Animals↗
PubMed1999

In vitro and in vivo approaches to the characterization of the alpha2-adrenoceptor.

1. In order to more fully understand the role of the alpha2-adrenoceptor in brain function, a combination of in vitro and in vivo techniques were utilized including radioligand binding, autoradiography, brain microdialysis and antisense oligonucleotides. 2. Binding studies showed the tritiated form of the selective alpha2-adrenoceptor antagonist, RX821002 (methoxy-idazoxan) labelled an apparent single population of sites in rat brain membranes with high affinity (1 nM), for which prazosin had low affinity (1107 nM). Similar studies in rabbit brain membranes found that prazosin and oxymetazoline were able to displace [3H]-RX821002 in a biphasic manner indicating the presence of subtypes of alpha2-adrenoceptors. 3. Receptor autoradiography revealed a distribution of [3H]-RX821002 binding in rat brain consistent with the labelling of all alpha2-adrenoceptor subtypes, namely alpha(2A/D-), alpha2B and alpha2C. 4. In rat, in vivo brain dialysis experiments demonstrated peripherally administered RX821002 elevated basal noradrenaline in frontal cortex and also, although to a lesser extent, in ventral hippocampus. RX821002 was also able to elevate extracellular dopamine in the striatum. 5. A 7-day i.c.v. infusion of an antisense oligonucleotide targeting the alpha(2A/D)-adrenoceptor, resulted in a significant reduction in the autoradiographic density of [3H]-RX821002 binding in specific brain areas, notably the lateral septal nuclei and anterior hypothalamic area. 6. Several years of research by our group has extended our knowledge of the pharmacology and function of the alpha2-adrenoceptor and has provided evidence of the roles of this receptor in the control of monoamine turnover. The successful use of antisense technology to knockdown expression of the alpha(2A/D) subtype provides future opportunities to explore the physiology of this receptor subtype.

Adrenergic alpha-Antagonists↗
PubMed1999

The effects of idazoxan on reaction times, eye movements and the mood of healthy volunteers and patients with upper respiratory tract illnesses.

An experiment was carried out to determine whether idazoxan, a drug which increases the turnover of central noradrenaline, removes the malaise (reduced alertness, slower psychomotor performance) associated with upper respiratory tract illness (URTI). Eighty-one volunteers were tested when healthy and 17 returned to the laboratory when they developed URTIs. Those who remained healthy were then recalled as a control group. Volunteers were tested before and after receiving either idazoxan (40mg) or a lactose placebo. Idazoxan removed the URTI-induced slowing in a simple reaction time task and this group performed at a comparable level to the healthy group. No significant stimulant effect of idazoxan was found in the healthy subjects. The results suggest that at least part of the malaise induced by URTIs may reflect reductions in central noradrenaline and that this can be reversed by compounds such as idazoxan.

Adrenergic alpha-Antagonists↗
PubMed1999

Evaluation of severe insomnia in the general population: results of a European multinational survey.

The epidemiology of severe insomnia and its effect on quality of life and healthcare consumption was assessed in a survey of the general population of five northern European countries. Applying established consumer sampling techniques, insomnia sufferers were selected from the general population using a questionnaire, conducted by face-to-face interview, and severity of insomnia was ranked (severe, mild/moderate, no sleep complaint) using a specific algorithm. Population samples were matched according to case control methodology for age, gender and geographical region. A second questionnaire gathered information on sleep problems, quality of life (SF-36 scores) and healthcare consumption. The prevalence of severe insomnia ranged from 4% to 22%, was higher in females than in males, but did not increase significantly with age. Patients with severe insomnia had been experiencing sleeping problems for a median of 2-6 years. In all countries, insomnia had a negative impact on quality of life, and the degree of impairment in quality of life was directly related to the severity of insomnia. Individuals with severe insomnia also showed a higher level of healthcare consumption. Despite this, severe insomnia did not appear to feature prominently in the doctor-patient relationship.

Adult↗
PubMed1999

Home cage presentation of complex discrimination tasks to marmosets and rhesus monkeys.

The study reported here demonstrates the feasibility of presenting cognitive tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to either marmosets or rhesus monkeys in their home cages. This location of testing offers opportunities for the measurement of additional indices, for example spontaneous behaviour (Prowse et al. 1995) and electrophysiology (Pearce et al. 1998) as well as facilitating repeated test presentation. Results from 12 marmosets and 4 rhesus monkeys which have completed several sequences of an eight-stage discrimination task involving simple discriminations, compound discriminations and reversals are reported. The paradigm developed has application in long-term studies. Tests from CANTAB have been used extensively in normal humans (Robbins et al. 1994) as well as a range of patient groups (Owen et al. 1992, Elliott et al. 1995) and to assess drug effects (Coull et al. 1996). Additionally some of these tests have been presented to marmosets (Roberts et al. 1988) to examine neuropsychological functioning. This comparative approach facilitates meaningful cross species comparison, particularly in the study of the effects of pharmacological intervention.

Animals↗
PubMed1999

Care of depressed patients with anxiety symptoms.

Anxiety frequently coexists with depression, either as a comorbid anxiety disorder or as anxiety symptoms accompanying a primary depressive disorder. Effective therapy for the treatment of depressive illness must include a consideration of anxiety symptoms, since anxiety has been estimated to be present in up to 96% of patients with depressive illness. Available data also indicate that depressed patients with significant anxiety may be at greater risk for suicide. Of particular clinical importance are symptoms of somatic anxiety: they are present in up to 86% of depressed patients, and the failure to treat them effectively can diminish the ability of a patient to function. Since the overall prognosis for recovery from a major depressive episode is less than optimal in patients with significant anxiety, treatments that can provide an effective and early relief of both depressive and anxiety symptoms are of paramount importance. Drugs with serotonin reuptake inhibition (such as selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs]) may produce transient increases in anxiety symptomatology presenting as jitteriness, agitation, insomnia, and gastrointestinal symptoms when treatment is initiated. Mirtazapine has intrinsic receptor-blocking properties (in particular, serotonin-2 [5-HT2] receptor blockade) that can be linked to an early relief of anxiety symptoms during the treatment. The available data show that mirtazapine is superior to placebo in depressed patients with high baseline anxiety and/or agitation. Furthermore, mirtazapine was statistically significantly superior to both citalopram and paroxetine in alleviating anxiety symptoms early in treatment as assessed by changes from baseline on the Hamilton Rating Scale for Anxiety or the Hamilton Rating Scale for Depression anxiety/somatization factor, respectively. Mirtazapine provides early and effective relief of both depressive and anxiety symptoms, reducing the need for polypharmacy. These therapeutic actions of mirtazapine persist throughout the course of treatment.

Antidepressive Agents, Tricyclic↗
PubMed1998

Characterisation and localisation of [3H]2-(2-benzofuranyl)-2-imidazoline binding in rat brain: a selective ligand for imidazoline I2 receptors.

In rat whole brain homogenates, saturation binding analysis revealed that both [3H]2-BFI (2-(2-benzofuranyl)-2-imidazoline) and [3H]idazoxan (in the presence of 5 microM rauwolscine) bound with high affinity to an apparent single population of sites. However, the Kd for [3H]2-BFI (1.74+/-0.14 nM) was significantly (P < 0.01) less than that for [3H]idazoxan (10.4+/-2.68 nM). In competition studies idazoxan, 2-BFI, BU224 (2-(4,5-dihydroimidaz-2-yl)-quinoline), amiloride and guanabenz displayed high affinity (Ki values = 7.32, 1.71, 2.08, 21.80 and 14.90 nM, respectively) for 70-80% of sites, and low microM affinity for the remaining 20-30% of sites labelled by [3H]2-BFI. In contrast, several alpha2-adrenoceptor, imidazoline I1 receptor and histamine receptor ligands exhibited only micromolar affinity for the [3H]2-BFI labelled site. Quantitative receptor autoradiography revealed high binding by [3H]2-BFI to discrete brain nuclei, notably the area postrema, interpeduncular nucleus, arcuate nucleus, mammillary peduncle, ependyma and pineal gland. These data indicate that [3H]2-BFI recognises imidazoline I2 receptors in rat brain with higher affinity and selectivity than [3H]idazoxan and thus represents a superior radioligand to [3H]idazoxan for the study of imidazoline I2 receptors.

Animals↗
PubMed1998

Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study.

BACKGROUND: Positron emission tomography (PET) allows the measurement of benzodiazepine-gamma-aminobutyric acidA (GABA(A)) receptor kinetics. We employed flumazenil radiolabeled with carbon 11, a radioligand that labels the benzodiazepine site on the GABA(A) receptor, and fully quantitative, high-sensitivity PET to test the hypothesis that central benzodiazepine site binding is decreased in medication-free patients with panic disorder. METHODS: We compared 7 patients with panic disorder who had been off medication for at least 6 months and who had never abused alcohol with 8 healthy controls. The resulting parametric voxel-by-voxel maps were analyzed by voxel-based and region of interest-based methods using both parametric and nonparametric statistics. RESULTS: The major finding was that there is a global reduction in benzodiazepine site binding throughout the brain in patients with panic disorder compared with controls. There were sex differences in the 2 samples, but a separate analysis excluding women led to the same conclusions. In addition, the loci with the largest regional decrease in binding (right orbitofrontal cortex and right insula) were areas thought to be essential in the central mediation of anxiety. CONCLUSION: These results must be considered preliminary but are congruous with previous clinical psychopharmacologic evidence of involvement of the benzodiazepine-GABA(A) receptor and demonstrate that decreased flumazenil binding at this site may underlie panic disorder.

Adult↗
PubMed1998

'Seeing through a glass darkly': casting light on imidazoline 'I' sites.

Although imidazoline sites have been the subject of research for several years, there is still controversy about their structure, diversity and physiology. The I1 site is thought to exist principally as a binding site and is widely purported to play a role in controlling systemic blood pressure, although this is still unclear. The majority of I2 sites are widely accepted as being allosteric sites on monoamine oxidase; however, even with selective ligands, their exact function remains to be determined. A putative I3 site modulates insulin secretion and could represent the first functional site to be pharmacologically defined with selective agonists and antagonists. The structure and relevance of the proposed endogenous ligand 'clonidine-displacing substance' remains elusive. A potential candidate for this substance is agmatine; however, although it is capable of displacing bound clonidine from imidazoline sites, it lacks the functionality ascribed to the clonidine-displacing substance. In this review, Richard M. Eglen and colleagues assess our knowledge of imidazoline sites in the light of recent data.

Adrenergic alpha-Agonists↗
PubMed1998

Potentiation of barbiturate-induced alterations in presynaptic noradrenergic function in rat frontal cortex by imidazol(in)e alpha2-adrenoceptor agonists.

1. In order to resolve the extent to which presynaptic noradrenergic mechanisms contribute to the anaesthetic-sparing effects of alpha2-adrenoceptor agonists in vivo microdialysis was used to investigate the combined effects of sodium pentobarbitone and imidazol(in)e alpha2-adrenoceptor agonists on extracellular levels of noradrenaline (NA) in the rat frontal cortex. 2. Dialysate levels of NA were markedly reduced by the addition of TTX (2 microM) or by the removal of calcium in the perfusate. These data imply that dialysate NA levels are ultimately dependent on exocytotic release mechanisms from afferent coeruleo-cortical neurones. 3. Systemic administration of sodium pentobarbitone (85 mg kg(-1), i.p.) induced general anaesthesia and reduced NA levels by 92% after 30 min. The restoration of basal levels 90 min later was closely associated with a return of the corneal blink reflex. 4. Basal NA levels in conscious animals were not affected by an intravenous infusion of equally radioactive solutions of either imidazoline (clonidine) or imidazole (mivazerol) alpha2-adrenoceptor agonists. The dose rate employed for each compound was 2 microg kg(-1) h(-1) over 2 h. 5. The co-administration of intravenous clonidine or mivazerol, each at 2 microg kg(-1) h(-1) for 2 h, with sodium pentobarbitone (85 mg kg(-1), i.p.), produced a marked and prolonged reduction in NA efflux. After 2 h, NA levels remained suppressed by 95% (clonidine) and 80% (mivazerol) and animals remained deeply anaesthetized. 6. The accumulation of tritium in brain tissue was 42-73% lower across all brain regions examined after [3H]-mivazerol administration than after [3H]-clonidine administration. Sodium pentobarbitone did not alter the accumulation of tritium in brain tissue after the administration of either alpha2-adrenoceptor agonist. 7. These data demonstrate that alpha2-adrenoceptor agonists potentiate the inhibitory effects of sodium pentobarbitone on extracellular levels of NA in the frontal cortex. Further studies will be necessary to establish a causal role of noradrenergic mechanisms in the potentiation of anaesthesia by selective alpha2-adrenoceptor agonists.

Adrenergic alpha-Agonists↗
PubMed1998

Integrating the cognitive and physiological aspects of craving.

'Craving is generally considered a significant factor in opiate addiction that is associated with drug-dependence and in relapse to drug use after treatment'-ARC expert consensus (Pickens and Johanson, Drug and Alcohol Dependence 30: 127-131). There are however difficulties in defining craving and urges to use drugs and in associating craving with drug use and relapse. Tiffany [Psychological Review 97(2): 147-168] has reviewed a considerable number of studies that associated reports of craving with consumption measures of drugs and revealed only an overall modest correlation of 0.4. These findings call into question the general assumption that subjective cravings are invariably associated with drug use. Furthermore, it led to Tiffany's provocative argument that cravings are not necessary for drug use. We have addressed these issues by using a range of complementary techniques derived from research in related fields such as the cognitive psychology of anxiety and depression, physiological response measurements and positron emission tomography (PET) neuro-imaging. Initially we developed computerized assessments to probe cognitive dysfunction in addiction that related to biased processing of automatic thoughts and beliefs about craving and drug use in opiate-dependent subjects and alcoholics. Subsequently in an attempt to develop a reliable method of inducing craving we explored an imagery-based technique that relied on the memory of craving experiences. These experiments were conducted both in opiate addicts who had achieved abstinence and in those undergoing detoxification. Finally, we have begun a study to understand the neural mechanisms of craving using imagery-based procedures at the same time as performing PET studies of regional blood flow using the O15-labelled water technique.

Alcoholism↗
PubMed1998

Sertraline, a selective serotonin reuptake inhibitor modulates extracellular noradrenaline in the rat frontal cortex.

The selective action of selective serotonergic reuptake inhibitors (SSRIs) on 5-hydroxytryptamine (5-HT) neurotransmission underlies the therapeutic effectiveness of this class of drugs. Yet there is increasing evidence that changes in extracellular 5-HT content may result in changes in the regulation of other neurotransmitter systems. The present study examines the effects of acute and chronic administration of the SSRI sertraline on release of endogenous noradrenaline (NA) in the frontal cortex and hippocampus of the rat using in vivo microdialysis. Acute administration of sertraline did not significantly alter NA release in either the cortex or the hippocampus. However, 24 h after chronic (14 days) administration of the drug (10 mg/kg i.p. once daily), NA release in the cortex but not hippocampus was significantly enhanced. The lack of an effect on NA release following a challenge with the alpha2-antagonist idazoxan suggests that chronic drug treatment has reduced the sensitivity of cortical pre-synaptic alpha2-adrenoceptors, activation of which would normally inhibit further NA release. The possible mechanisms underlying the regional specificity of the effect of chronic and not acute sertraline administration and the implications of these results for our understanding of depression are discussed.

Animals↗
PubMed1998

Serotonin and panic.

BACKGROUND: Tricyclic (TCA) and monoamine oxidase inhibitor (MAOI) antidepressants are effective in the treatment of panic disorder. Two selective serotonin reuptake inhibitors (SSRIs) have also been licensed in the UK for this indication and studies with three other SSRIs have recently been completed. These provide further evidence for the role of serotonin in panic. METHOD: Review of clinical, animal and laboratory studies. RESULTS: SSRIs have been shown to be effective in the treatment of panic disorder. The reported rates of improvement of 60-70% of patients taking SSRIs are similar to those seen with TCAs and greater than placebo. Other serotonergic agents do not appear to be effective. Animal work and human studies including measures of 5-HT in plasma, cerebrospinal fluid and platelets, challenge paradigms and tryptophan depletion show that the relationship between 5-HT and anxiety is complex. CONCLUSION: Clinical trials have shown that of all the serotonergic agents only the SSRIs are effective in panic disorder. They are as beneficial as the TCAs and seem to be better tolerated which may be particularly significant in view of the chronic nature of the condition. Serotonin plays a role in panic disorder and serotonergic dysfunction, however the results and evidence do not fit one theory alone. It is also likely that different brain regions and 5-HT receptors are involved in specific ways.

Animals↗
PubMed1998

Efficacy of mirtazapine in clinically relevant subgroups of depressed patients.

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) with a novel mode of action that differs from other antidepressants that are currently available. Clinical trials have demonstrated it to have good antidepressant efficacy and excellent tolerability. Analysis of the results of placebo-controlled trials in moderately or severely depressed patients have shown mirtazapine to be effective in clinically important subgroups of depressed patients, particularly anxious patients, patients with sleep disturbance, retarded patients, and agitated patients. The efficacy and tolerability of mirtazapine are attributable to its pharmacological profile. It is likely that the overall antidepressant activity arises from its dual action, enhancing both noradrenergic and 5-HT1 receptor-mediated serotonergic neurotransmission, while the anxiolytic and sleep-improving properties of mirtazapine are attributable to the specific blockade of 5-HT2 and 5-HT3 receptors.

Adrenergic alpha-Antagonists↗
PubMed1998

Antidepressants in panic disorder: clinical and preclinical mechanisms.

Advances have been made in understanding the biology of panic disorder and the role of the underlying serotonergic dysfunction. This review summarizes the biological evidence for the involvement of serotonin in the pathogenesis of panic disorder and considers the 2 opposing theories that are currently prevalent (5-HT excess and 5-HT deficit). The serotonin selective reuptake inhibitors are increasingly considered as first-line treatment for panic disorder, and the interaction of these agents with the serotonergic system is considered.

Antidepressive Agents↗