Kennett A.,University of Bath |
Heal D.J.,RenaSci Consultancy Ltd |
Wonnacott S.,University of Bath
Nicotine and Tobacco Research | Year: 2012
Introduction: Noradrenergic mechanisms in frontal cortex and hippocampus are relevant to attentional and stress-related aspects of addiction, respectively. Nicotinic receptors (nAChRs) modulate the release of noradrenaline (NA) in these tissues. This study determined if similar subtypes of nAChR regulate NA release in rat frontal cortex and hippocampus. Methods: The release of [3H]-NA from rat tissue prisms was characterized in a 96-well plate assay. In vivo microdialysis was used to monitor NA overflow from rat frontal cortex and hippocampus in conscious freely moving rats. Results: [3H]-NA release from frontal cortex prisms was more sensitive to nicotinic agonists than release from hippocampal prisms. The β2-selective agonist 5-iodo-A-85380 was 1000-fold more potent in frontal cortex compared with hippocampus. Agonist-evoked [3H]-NA release was inhibited by the β2-selective antagonist dihydro-beta-erythroidine (DHβE) in frontal cortex, whereas in hippocampal tissue, DHβE had no effect. In vivo, 5-iodo-A-85380 (1, 100 μM) applied locally via the dialysis probe, significantly increased NA overflow, compared with basal release, in frontal cortex but not in hippocampus. Conclusions: These data support the modulation of NA release by different nAChR subtypes in frontal cortex and hippocampus. The pharmacological profile for rat hippocampus is consistent with previous studies, implicating α3β4* nAChRs in the modulation of NA release in this tissue. nAChRs having this function in frontal cortex are pharmacologically distinct and correspond to β2-containing nAChRs. © The Author 2012. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.
Bolea-Alamanac B.,University of Bristol |
Nutt D.J.,Imperial College London |
Adamou M.,South West Yorkshire Trust |
Asherson P.,Institute of Psychiatry |
And 9 more authors.
Journal of Psychopharmacology | Year: 2014
Attention deficit hyperactivity disorder (ADHD) is a common condition with a high societal burden. The present guidelines summarise current literature, generating expert consensus recommendations for the treatment of ADHD in children and adults. These guidelines also provide a review of recent research in the fields of neuroimaging, neuropsychology and genetics of ADHD. Novel discoveries in these areas have informed physiological models for the disease. Since the publication of the previous British Association for Psychopharmacology guidelines in 2008, new drugs have been licensed and further compounds are being investigated. The publication of randomised controlled trials of psychological interventions has contributed to the range of treatment options for ADHD. As the disorder has been diagnosed more frequently there has been greater focus on comorbid conditions and how they impact treatment. Services have continued to develop for the treatment of ADHD in adults and care agreements have been introduced to facilitate access to treatment. © 2014 The Author(s).
Klein T.,Boehringer Ingelheim |
Niessen H.G.,Boehringer Ingelheim |
Ittrich C.,Boehringer Ingelheim |
Mayoux E.,Boehringer Ingelheim |
And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2012
The effects of linagliptin on fat content in diet-induced obese rats were compared with those of the appetite suppressant sibutramine. Female Wistar rats fed a high-fat diet (HFD) for 3months received vehicle, linagliptin (10mg/kg) or sibutramine (5mg/kg) treatment orally, once daily for 6 additional weeks, while continuing the HFD. Magnetic resonance spectroscopy analysis of fat content was performed at baseline and at the end of the 6-week treatment period. Linagliptin treatment profoundly reduced hepatic fat compared with vehicle, with an effect comparable to that of sibutramine. The vehicle-corrected mean change (95% CI) from baseline in hepatic fat and intramyocellular lipid was -59.0% (-104.3%, -13.6%; p=0.015) and -62.1% (-131.6%, 7.4%; p=0.073), respectively, for linagliptin compared with -54.3% (-101.5%, -7.1%; p=0.027) and -72.4% (-142.4%, -2.4%; p=0.044), respectively, for sibutramine. © 2012 Blackwell Publishing Ltd.
Vickers S.P.,RenaSci Consultancy Ltd |
Clifton P.G.,University of Sussex
Neuropharmacology | Year: 2012
Obesity has reached epidemic proportions globally with an increasing incidence not just in Western cultures but also Mexico, Brazil, China and parts of Africa. In terms of pharmacological intervention, the track record of drug treatments for obesity is poor, especially in the case of centrally acting medicines, and there remains an unmet need for the development of safer compounds delivering superior efficacy. Animal models are of importance not only in detecting changes in food intake, energy expenditure and body weight but also providing confidence that these changes are behaviourally specific and not a result of drug-induced side effects. We review animal models of feeding behaviour that are used to aid our understanding of the control of body weight and energy regulation with special reference to CNS-acting drugs. The use of such models in the discovery of new drugs for the treatment of obesity is given particular emphasis. This article is part of a Special Issue entitled 'Central Control of Food Intake'. © 2012 Elsevier Ltd. All rights reserved.
Heal D.J.,RenaSci Consultancy Ltd |
Smith S.L.,RenaSci Consultancy Ltd |
Findling R.L.,Case Western Reserve University
Current Topics in Behavioral Neurosciences | Year: 2012
The stimulants, amphetamine and methylphenidate, have long been the mainstay of attention-deficit hyperactivity disorder (ADHD) therapy. They are rapidly effective and are generally the first medications selected by physicians. In the development of alternative pharmacological approaches, drug candidates have been evaluated with a wide diversity of mechanisms. All of these developments have contributed real progress in the field, but there is still much room for improvement and unmet clinical need in ADHD pharmacotherapy. The availability of a wide range of compounds with a high degree of specificity for individual monoamines (dopamine and noradrenaline) and/or different pharmacological mechanisms has refined our understanding of the essential elements for optimum pharmacological effect in managing ADHD. In this chapter, we review the pharmacology of the different classes of drug used to treat ADHD and provide a neurochemical rationale, predominantly from the use of in vivo microdialysis experiments, to explain their relative efficacy and potential to elicit side effects. In addition, we will consider how predictions based on results from animal models translate into clinical outcomes. The treatment of ADHD is also described from the perspective of the physician. Finally, the new research development for drugs to treat ADHD is discussed. © Springer-Verlag Berlin Heidelberg 2011.