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Biomedical subjects

D J Nutt

Publications and source records attributed to D J Nutt.

At least 109 records · Page 6Linked to original sources
PubMed1998

Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in panic disorder and guide clinical practice with recommendations for appropriate pharmacotherapy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Four faculty invited by the chairman also participated: David S. Baldwin, Johan A. den Boer, Siegfried Kasper, and M. Katherine Shear. EVIDENCE: The consensus statement is based on the 6 review papers that are published in this supplement and on the scientific literature relevant to these issues. CONSENSUS PROCESS: There were group meetings held during a 2-day period. On day 1, the group discussed each review paper and the chairman and discussant (Dr. Kasper) identified key issues for further debate. On day 2, the group discussed these key issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chairman and approved by all attendees. CONCLUSIONS: The consensus statement provides standard definitions for response and remission and identifies appropriate strategy for the management of panic disorder in a primary care setting. Serotonin selective reuptake inhibitors are recommended as drugs of first choice with a treatment period of 12 to 24 months. Pharmacotherapy should be discontinued slowly over a period of 4 to 6 months.

Antidepressive Agents↗
PubMed1998

Brain mechanisms of social anxiety disorder.

The neurobiology of social anxiety disorder is poorly understood, although preliminary research has suggested several possible biological abnormalities. Challenge studies have demonstrated that subjects with social anxiety disorder have a sensitivity to carbon dioxide, cholecystokinin, and caffeine somewhere between that of panic disorder patients and normal controls. Serotonergic pathways may play a role in social anxiety disorder, as shown by the clinical effectiveness of selective serotonin reuptake inhibitors, plus fenfluramine and m-chlorophenylpiperazine challenge studies. Dopaminergic function and striatal dopamine uptake appear to be reduced in social anxiety disorder. There is also evidence for cardiovascular and adrenergic abnormalities. Recently, positron emission tomography has begun to identify brain regions that appear to be uniquely activated in this condition. These results offer the promise of an understanding of the brain mechanisms of social anxiety disorder, but much further research is needed to fully elucidate the neurobiological cause(s) that exist.

Animals↗
PubMed1998

Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety.

OBJECTIVE: The goal of this consensus statement is to provide primary care clinicians with a better understanding of management issues in social anxiety disorder (social phobia) and guide clinical practice with recommendations for appropriate pharmacotherapy. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty invited by the chair were Julio Bobes, Deborah C. Beidel, Yukata Ono, and Herman G. M. Westenberg. EVIDENCE: The consensus statement is based on the 7 review papers published in this supplement and on the scientific literature relevant to the issues reviewed in these papers. CONSENSUS PROCESS: The group met over a 2-day period. On day 1, the group discussed each review paper, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees. CONCLUSIONS: The consensus statement underlines the importance of recognizing social anxiety disorder and provides recommendations on how it may be distinguished from other anxiety disorders. It proposes definitions for response and remission and considers appropriate management strategies. Selective serotonin reuptake inhibitors are recommended as first-line therapy, and effective treatment should be continued for at least 12 months. Long-term treatment is indicated if symptoms are unresolved, the patient has a comorbid condition or a history of relapse, or there was an early onset of the disorder.

Anxiety Disorders↗
PubMed1997

Identification of ligands selective for central I2-imidazoline binding sites.

Using radioligand binding techniques, several compounds selective for mammalian brain imidazoline 2 receptors have been identified. In rabbit brain membranes, a series of 6 and/or 7 aromatic-substituted derivatives of the alpha 2-adrenoceptor antagonist idazoxan were found to show moderate affinity for I2 receptors over alpha 2-adrenoceptors, in particular 6,7-dichloroidazoxan, which was 41 fold selective in favour of I2 receptors. Modification of the benzodioxan ring of idazoxan could also result in affinity and selectivity, which was moderate (2.7 nM, 161 fold) in the case of the 1,3-benzodioxan isomer of idazoxan (2-(1,3-benzodioxanyl)-2-imidazoline), and high (1.3 nM, 2873 fold) in the case of 2-(2-benzofuranyl-2-imidazoline) (2-BFI). Analogues of 2-BFI with halogenic substitutions of the aromatic ring were also found to retain high affinity and moderate to high selectivity for I2-sites. In particular, the 7-chloro (Ki 2.8 nM, 2192 fold) and the 4,6-dibromo (Ki 6.1 nM, 361 fold) analogues of 2-BFI. These new ligands should prove invaluable for investigating the pharmacology and physiology of I2 receptors.

Adrenergic alpha-Antagonists↗
PubMed1997

Analysis of dynamic radioligand displacement or "activation" studies.

We present a simple way of assessing dynamic or time-dependent changes in displacement during single-subject radioligand positron emission tomography (PET) activation studies. The approach is designed to facilitate dynamic activation studies using selective radioligands. These studies are, in principle, capable of characterising functional neurochemistry by analogy with the study of functional neuroanatomy using rCBF activation studies. The proposed approach combines time-dependent compartmental models of tracer kinetics and the general linear model used in statistical parametric mapping. This provides for a comprehensive, voxel-based and data-led assessment of regionally specific effects. The statistical model proposed in this paper is predicated on a single-compartment model extended to allow for time-dependent changes in kinetics. We have addressed the sensitivity and specificity of the analysis, as it would be used operationally, by applying the analysis to 11C-Flumazenil dynamic displacement studies. The activation used in this demonstration study was a pharmacological (i.v. midazolam) challenge, 30 min after administration of the tracer. We were able to demonstrate, and make statistical inferences about, regional increases in k2 (or decreases in the volume of distribution) in prefrontal and other cortical areas.

Activation Analysis↗
PubMed1997

Behavioral and neuroendocrine responses to m-chlorophenylpiperazine in subtypes of alcoholics and in healthy comparison subjects.

OBJECTIVE: The purpose of this study was to explore central serotonergic functions in subgroups of alcoholics and in healthy comparison subjects. METHOD: The mixed serotonin (5-HT) agonist/antagonist m-chlorophenylpiperazine (m-CPP) was administered to male alcoholic patients who were classified according to the criteria of von Knorring et al. as type I alcoholics (late onset) (N = 16) or type II alcoholics (early onset with antisocial traits) (N = 24) and to 22 healthy comparison subjects. Psychological, physiological, and neuroendocrine measures were obtained before and after the m-CPP infusion. RESULTS: m-CPP elicited subtype-related differential effects among the alcoholics; the type I alcoholics reported more anger and anxiety, and the type II alcoholics reported increased euphoria and a greater likelihood of drinking. The healthy comparison subjects exhibited a greater increase in plasma ACTH response to the m-CPP infusion than the alcoholics regardless of subtype. CONCLUSIONS: Differences in certain 5-HT receptor functions may explain some of the clinical characteristics that differentiate the type II and type I subgroups of alcoholic patients. Furthermore, alcoholics may have reduced sensitivity of 5-HT2C receptors in comparison with healthy subjects.

Adrenocorticotropic Hormone↗
PubMed1997

Noradrenergic mechanisms in the prefrontal cortex.

There is growing evidence that noradrenergic inputs to the prefrontal cortex (PFC) play an important role in regulating its function. This paper reviews the pharmacological control of noradrenaline (NA) release in this region, with particular reference to our studies using brain microdialysis, and also describes how NA levels are modulated by antidepressant and antipsychotic drugs. The suggestion that atypical antipsychotics such as clozapine and risperidone may produce clinical benefits by their ability to increase NA release is discussed. Finally, a new class of drugs, which show selectivity for imidazoline receptors is described. These compounds are shown to similarly increase extracellular NA in the PFC. Their potential utility as clinical treatments is discussed.

Animals↗
PubMed1997

Antisense oligonucleotides in psychopharmacology and behaviour: promises and pitfalls.

Antisense oligonucleotides are used to study the expression and function of a diverse range of proteins. Areas for which antisense has been used for pharmacological investigation include receptors, neuropeptides and immediate early genes, particularly when specific ligands or markers are not yet available. Antisense oligonucleotides target a specific mRNA and block the expression of the protein by sequence specific hybridization. This technique has not only been shown to be a valuable pharmacological tool but also to have potential therapeutic applications. In this review we discuss the technology behind the technique including developments in methodology employed in antisense experiments. Although antisense provides a novel and highly specific tool, the reliability of the technique and many of the problems associated with antisense experiments are discussed. The main focus of this article is the use of antisense in psychopharmacology to investigate behavioural changes following antisense-mediated inhibition of the expression of specific brain proteins and receptors.

Animals↗
PubMed1997

Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

Adult↗
PubMed1996

Evaluation in rat of RS-79948-197 as a potential PET ligand for central alpha 2-adrenoceptors.

Tritium-labelled RS-79948-197 {(8aR,12aS,13aS)-5, 8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulphon yl)-6H-iso- quino[2,1-g][1,6]naphthyridine} was evaluated in rat brain as an in vivo ligand for central alpha 2-adrenoceptors, as a preliminary step in the development of a radioligand for positron-emission tomography (PET) studies. The maximal receptor-specific signal was achieved within 90-120 min after i.v. injection of [ethyl-3H]RS-79948-197 and was selective for the alpha 2- compared with the alpha 1-adrenoceptor, with no detectable binding to the imidazoline-I2 site. Estimates for binding potential (approximating to Bmax/Kd) ranged between 3.4 in entorhinal cortex and 0.5 in medulla oblongata. The results, which indicate a similarly localised but 2-fold increase in specific binding compared with that previously demonstrated using [3H]RX 821002 (2-methoxy-idazoxan), are sufficiently encouraging as to support further investment in the development of 11C-labelled RS-79948-197, or a close structural analogue, as a ligand for clinical PET.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1996

[3H]2-(2-benzofuranyl)-2-imidazoline: a new selective high affinity radioligand for the study of rabbit brain imidazoline I2 receptors.

This is the first study characterising the binding of the new imidazoline I2 receptor selective radioligand [3H]2-(2-benzofuranyl)-2-imidazoline (2-BFI) to rabbit brain membranes. [3H]2-BFI binding was found to be saturable and of high affinity identifying two binding sites with KD1 = 0.27 nM, Bmax = 111.2 fmol mg-1 protein and KD2 = 8.97 nM, Bmax = 268 fmol mg-1 protein. Specific binding represented greater than 90% of total binding. Kinetic studies revealed that the binding was rapid and reversible and also showed [3H]2-BFI interacted with these two sites or two affinity states. In competition binding studies against [3H]2-BFI (0.3-InM) idazoxan, 2-BFI, cirazoline, guanabenz, naphazoline, amiloride and BU224 (2-(4,5-dihydroimidaz-2-yl-quinoline) displaced with high affinity. In contrast the alpha 2-adrenoceptor antagonists efaroxan and rauwolscine, the I1 site selective drug moxonidine, the monoamine oxidase-A inhibitor clorgyline and the proposed endogenous imidazoline receptor ligand, agmatine, were weak at displacing [3H]2-BFI binding. These findings are consistent with [3H]2-BFI recognising imidazoline receptors of the I2 subtype in rabbit brain.

Affinity Labels↗
PubMed1996

Imidazoline binding sites in Huntington's and Parkinson's disease putamen.

Binding of [3H]2-(2-benzofuranyl)-2-imidazoline ([3H]BFI) to the imidazoline I2 receptor was determined in putamen taken post mortem from patients with two extrapyramidal motor disorders, Parkinson's and Huntington's diseases, and age-matched control subjects. No deficit of binding was apparent in Parkinson's disease, indicating that the receptors are not present on nigrostriatal terminals. A significant loss (by 56%) in imidazoline I2 receptor binding was observed in Huntington's disease, consistent with the receptors being sited on degenerating neurons.

Adrenergic alpha-Antagonists↗
PubMed1996

Estimating the synaptic concentration of norepinephrine in dentate gyrus which produces beta-receptor mediated long-lasting potentiation in vivo using microdialysis and intracerebroventricular norepinephrine.

Norepinephrine in the hippocampus of urethane anesthetized rats was monitored by microdialysis prior to, and following, an intracerebroventricular injection of 5 micrograms [-]NE in 2 microliters of ACSF. The perforant path evoked potential in dentate gyrus was concurrently monitored by a microelectrode adjacent to the dialysis probe. NE levels 30 x basal values or greater at the recording site were related to long-lasting potentiation of the perforant path-evoked population spike. Increases of 3 x to 6 x basal NE values were not accompanied by any potentiation. NE in the midline ventricles alone did not produce potentiation. These results suggest effective NE concentrations for beta-receptor activation of long-term potentiation would only occur near the NE release site.

Action Potentials↗