Biomedical subjects

David J Nutt

Publications and source records attributed to David J Nutt.

At least 37 records · Page 2Linked to original sources

PubMed2005

In vitro and ex vivo distribution of [3H]harmane, an endogenous beta-carboline, in rat brain.

The endogenous beta-carboline, harmane, has been shown to bind to monoamine oxidase A (MAO-A) and a separate, high affinity, non-MAO site. Research in our laboratory has shown that harmane is an active component of clonidine-displacing substance (CDS), the proposed endogenous ligand for imidazoline binding sites (IBS). In the present study we have investigated the distribution of [3H]harmane in rat brain, and related the binding profile to the distribution of the MAO-A selective ligand [3H]Ro41-1049 and the I2BS ligand [3H]2-BFI. The in vivo distribution of [3H]harmane following intravenous administration was also investigated. Receptor autoradiography revealed a highly significant correlation for the distribution of [3H]harmane and [3H]Ro41-1049, and a significant correlation for [3H]harmane and the I2BS ligand [3H]2-BFI. The in vivo distribution of [3H]harmane suggests that the ligand accumulates in the adrenal gland and throughout the brain with the primary route of excretion occurring via the duodenum. In conclusion, these studies have shown that [3H]harmane labels a population of binding sites that reflect the distribution of MAO-A. Further evidence for a non-MAO, IBS [3H]harmane population has not been shown but the high level of expression of the MAO-A site is likely to have masked the much smaller population of I2BS.

Animals↗

PubMed2005

Is there cognitive impairment in clinically 'healthy' abstinent alcohol dependence?

AIMS: The aim of this study was to determine neuropsychological performance in apparently cognitively, mentally, and physically healthy abstinent alcohol-dependent subjects compared with control subjects who were recruited for a number of different neuroimaging studies. METHODS: All subjects completed a battery of neuropsychological tests as part of the neuroimaging protocol. RESULTS: The group dependent on alcohol performed as well as controls on a non-verbal memory test and verbal fluency but performed worse in the verbal memory task, Trail A + B, and total IQ derived from Silverstein's short-form of the WAIS-R. However, the IQ performance of both groups was above average. In both groups, age was associated with slower performance on the Trail A + B task. In the alcohol-dependent group, severity of dependence and length of abstinence was not associated with performance of any task. CONCLUSIONS: In this apparently clinically healthy population of abstinent alcohol-dependent subjects, frontal lobe dysfunction was detectable using the Trail A + B and digit symbol tasks. This was despite above-average WAIS-R IQ scores. Consideration needs to be given to routine incorporation of cognitive testing in alcohol dependence since subtle deficits may not be easily apparent and may impact on treatment outcome.

Adult↗

PubMed2005

Characterisation of imidazoline I2 binding sites in pig brain.

The imidazoline I2 binding sites in the central nervous system have previously been described in several different species including rat, mouse, rabbit and frog. The present study has investigated the imidazoline I2 binding site, and its relationship to the monoamine oxidase isoforms, in pig whole brain and compared the results obtained with data from other species. Results from saturation binding studies revealed that the imidazoline I2-selective ligand, [3H]2BFI (2-(2-benzofuranyl)-2-imidazoline) labelled a single saturable population of sites with a KD=6.6 nM and Bmax=771.7 fmol/mg protein. The pharmacological characterisation of the sites was similar to that previously reported with a rank order of potency for the imidazoline I2 ligands of 2BFI>BU224>Idazoxan>BU226. Displacement by the imidazoline I1 ligands was low affinity and the monoamine oxidase inhibitors displaced with micromolar affinity. The majority of compounds displaced the binding in a monophasic manner, however, displacement by the putative endogenous ligand, harmane was biphasic. The relative populations of the two monoamine oxidase isoforms revealed a 10 fold greater expression of monoamine oxidase B relative to monoamine oxidase A. These data confirm the presence of imidazoline I2 binding sites in pig brain and show that their pharmacology is characteristic of that seen in other species. The proportion of monoamine oxidase A and B expressed in the pig brain is similar to that seen in the human brain therefore, given the association between imidazoline I2 binding sites and monoamine oxidase, the pig may provide a more useful model for human imidazoline I2 binding sites than other species such as the rat.

Animals↗

PubMed2005

The uptake of a fluorescently labelled antisense oligonucleotide in vitro and in vivo.

Antisense oligonucleotides have been used to target a range of different gene products in the CNS including neurotransmitter receptors. Previous studies using antisense oligonucleotides to target the rat alpha(2A/D)-adrenoceptor revealed changes in receptor expression in specific brain areas following i.c.v. administration but no reduction was observed following antisense treatment in primary cortical neurones. In order to resolve these discrepant results, the uptake and distribution of the antisense sequence has been determined. In vivo, the fluorescent signal was detected close to the site of injection (2-3 mm) and on the same side of the brain as the injection. Although the oligonucleotides (ODN) were distributed throughout the CSF, the ODN was not widely distributed within the mid or hindbrain parenchyma. In vitro uptake studies revealed the antisense was poorly taken up into primary cortical neurones but a higher level of fluorescence was detected in a small sub-population of cells. These studies demonstrate that antisense is rapidly taken up into cells in vivo but poorly taken up into primary cortical neurones in culture. These data provide further evidence for the uptake and distribution of antisense oligonucleotides in neuronal tissue in vivo.

Animals↗

PubMed2005

Behavioral and cardiovascular effects of 7.5% CO2 in human volunteers.

The study of carbon dioxide (CO2) inhalation in psychiatry has a long and varied history, with recent interest in using inhaled CO2 as an experimental tool to explore the neurobiology and treatment of panic disorder. As a consequence, many studies have examined the panic-like response to the gas either using the single or double breath 35% CO2 inhalation or 5-7% CO2 inhaled for 15-20 min, or rebreathing 5% CO2 for a shorter time. However, this lower dose regime produces little physiological or psychological effects in normal volunteers. For this reason we have studied the effects of a higher concentration of CO2, 7.5%, given over 20 min. Twenty healthy volunteers were recruited to a double blind, placebo-controlled study where air and 7.5% CO2 were inhaled for 20 min. Cardiovascular measures and subjective ratings were obtained. When compared to air, inhaling 7.5% CO2 for 20 min increases systolic blood pressure and heart rate, indicating increased autonomic arousal. It also increases ratings of anxiety and fear and other subjective symptoms associated with an anxiety state. The inhalation of 7.5% CO2 for 20 min is safe for use in healthy volunteers and produces robust subjective and objective effects. It seems promising as an anxiety provocation test that could be beneficial in the study of the effects of anxiety on sustained performance, the discovery of novel anxiolytic agents, and the study of brain circuits and mechanisms of anxiety.

Administration, Inhalation↗

PubMed2005

Estimation of endogenous noradrenaline release in rat brain in vivo using [3H]RX 821002.

Noradrenaline plays an important role in many normal brain functions, e.g., attention, memory, and emotion. Dysfunction in the noradrenergic system is thought to lead to a number of abnormal brain conditions. The lack of suitable in vivo tracers to monitor noradrenaline release, levels, and regulation has hampered our fully understanding the roles that it plays in the brain. Presented here are data showing that the in vivo binding of the alpha2-adrenoceptor antagonist [3H]RX 821002 is sensitive to endogenous noradrenaline. Elevation of extracellular noradrenaline, using three different pharmacological challenges in rat, led to a reduction in the binding potential (BP) of [3H]RX 821002 when compared with vehicle controls. The challenges used were i.p. administration of D-amphetamine, the imidazoline2 binding site-selective ligand BU224, and L-deprenyl. Of the cortical regions measured, the reduction in BP reached significance in the anterior cingulate cortex for all of these pharmacological challenges. These initial observations in rat indicate that labelling of the alpha2-adrenoceptors with RX 821002 can be used to estimate changes in extracellular noradrenaline concentration in the cortex. This has the potential to enable the investigation of the role that noradrenaline plays both in the normal and abnormal brain and, if the ligand can be radiolabelled with a suitable positron-emitting isotope at high specific radioactivity, it could be an invaluable PET tracer.

Adrenergic Uptake Inhibitors↗

PubMed2005

Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is the most prevalent childhood developmental disorder and is also of unclear neurobiological aetiology. However, recent advances in molecular genetics and brain imaging implicate dopaminergic hypofunction in the frontal lobes and basal ganglia in ADHD. Psychostimulants (e.g. methylphenidate and amphetamine, which are potent inhibitors of the dopamine transporter) are the first choice medication for ADHD and have a good acute efficacy and safety profile when used for this disorder. Whether long-term psychostimulant administration to adolescents alters neural development and behaviour or increases the risk of substance abuse is less certain. The precise molecular mechanism of action of psychostimulants is beginning to be established. Furthermore, preclinical studies have begun to use lower clinically relevant doses and oral administration of psychostimulants to determine their long-term effect on development, behaviour and neurochemistry, which is an important public health issue associated with chronic medication of adolescents with ADHD.

Adolescent↗

PubMed2005

Overview of diagnosis and drug treatments of anxiety disorders.

Anxiety disorders are common and often disabling. They fall into five main categories: panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder and posttraumatic stress disorder, each of which have characteristic symptoms and cognitions. All anxiety disorders respond to drugs and psychological treatments. This review will focus on drug treatments. Recent research has emphasized the value of antidepressants especially the selective serotonin reuptake inhibitors, benzodiazepines, and related sedative-like compounds. The common co-existence of depression with all of the anxiety disorders means that the selective serotonin reuptake inhibitors are now generally considered to be the first-line treatments but the benzodiazepines have some utility especially in promoting sleep and working acutely to reduce extreme distress.

Anti-Anxiety Agents↗

PubMed2005

Comparison of alterations in c-fos and Egr-1 (zif268) expression throughout the rat brain following acute administration of different classes of antidepressant compounds.

The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the c-fos literature, we demonstrated the utility of c-fos profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of c-fos or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased c-fos mRNA in the central amygdala, as previously shown, while c-fos was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered c-fos expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.

Acetylcholinesterase↗

PubMed2005

Acute tryptophan depletion. Part I: rationale and methodology.

OBJECTIVE: Acute tryptophan depletion (ATD) is an experimental technique that has been widely used over the last decade to investigate the role of serotonin (5-HT) in a variety of disorders. This review, the first of two articles, describes the rationale behind this technique and provides detail on how it is applied in research settings. METHOD: The authors outline the development of this technique with reference to the seminal literature and more recent findings from neuroimaging and neuroendocrine studies. This is supplemented by the authors' clinical experience of over 5 years of continuous experimental work with this paradigm in over 50 subjects. RESULTS: Acute tryptophan depletion is a method that significantly reduces central 5-HT in human subjects. Non-serotonergic explanations of the effects of ATD have not been confirmed, supporting the specificity of this method. CONCLUSIONS: The ATD technique is a valid method of manipulating central 5-HT levels. The second article in this series will review the application of ATD in depression, anxiety and other psychiatric conditions.

Blood-Brain Barrier↗

PubMed2005

Acute tryptophan depletion. Part II: clinical effects and implications.

OBJECTIVE: This is the second of two articles reviewing the modern dietary technique of acute tryptophan depletion (ATD), a method of transiently reducing central serotonin levels in both healthy volunteers and clinical populations. This article details the clinical studies to date and discusses the implications of this research methodology. METHOD: The authors present a review of clinical ATD studies collated from a MEDLINE search, unpublished communications and the authors' considerable experience with this paradigm. RESULTS: Following from the initial use of ATD in subjects with depressive illness, studies of anxiety disorders and other psychiatric illnesses have been reported. Sleep, aggressive and cognitive effects are also active areas of research and are reviewed here. CONCLUSIONS: Acute tryptophan depletion remains a useful psychiatric research tool. The findings from the clinical studies reviewed here are summarized and implications for future research detailed.

Alleles↗

PubMed2005

Gamma hydroxy butyrate abuse and dependency.

The recreational use of gamma hydroxy butyrate (GHB) has gained popularity over the last decade. GHB was initially sold as a safe body building and fat burning compound. It is now also widely abused by body builders and young ravers. GHB attracts young people due the euphoria that it initially produces, and the claimed increase in sociability and sexual function (it is also known as liquid Ecstasy). Over the last few years, there has been an increase in the number of cases of GHB intoxication, dependence and severe withdrawal, as reported in medical literature. The situation is complicated by the use of GHB analogues, other toxic chemicals that are easily converted into GHB. GHB has recently been classified as a class 'C' drug in the UK, but no provisions were made in relation to GHB analogues. GHB has been increasingly used in rape cases due to its capacity to produce intoxication and amnesia. The management of patients dependent on GHB is rather complicated due to the high doses of medication that they require to control withdrawal symptoms.

Adult↗

PubMed2005