Noradrenergic mechanisms in attention and response inhibition

Neuroscience research is one of the priority areas identified by the Government and leading health organisations. Recognition of the clinical need for new advances in therapeutic approaches to these diseases is particularly highlighted by statistics revealing an increase in the prevalence of psychiatric and neurodegenerative diseases. The focus of this research project is to investigate the biology of attention deficit hyperactivity disorder (ADHD), a prevalent and debilitating condition in children and adults. ADHD is responsible for significant social and economic costs to society and, although treatments are available, very little is known or understood about how or why they work. To address some of these issues, we can turn to animal models to enable us to dissect the specific brain mechanism that mediate the symptoms and treatment of this disorder. Animals provide a powerful method to study basic brain function and the methods we will use provide an excellent parallel with studies that are carried out in people. Using our animal models we will measure behaviours such as impulsivity, when an action is made that is not properly considered and has negative consequences, and inattention. The experiments will test how current treatments for ADHD act within the brain and isolate which brain areas and chemical processes are involved. The results that we obtained will help us to design future experiments to further refine our understanding of how the brain functions to control behaviour. Importantly, because our models relate closely to psychology test used in humans, we will be able to directly relate our results to the clinical situation. My research is closely linked with human disease and overall this project will identify new ways to alter brain function and improve the treatment of psychiatric conditions such as ADHD.

Psychiatric conditions such as attention deficit hyperactivity disorder (ADHD), schizophrenia and drug abuse are characterised by specific deficits in cognitive function and executive processes. Current therapeutic approaches for ADHD involve the use of stimulant and non-stimulant medications with improve symptoms such as inattention and enhance impulse control. There are fundamental problems when addressing the treatment of ADHD, however, as our understanding of the underlying neurobiology of the condition and mechanisms of action of drugs used therapeutically is severely limited. We have recently shown that the noradrenaline (NA) reuptake inhibitor, atomoxetine, improves three distinct forms of impulsivity in the rat. Our research as well as evidence from other groups supports, the hypothesis that cortical increases in catecholamines is an important mechanism by which improvements in impulse control and attention is achieved. Building on these studies and working from this hypothesis, the proposed project will investigate the mechanism of action of atomoxetine-induced improvements in impulse control using animal models of motor impulsivity (the 5-choice serial reaction time task and stop signal reaction time task) and impulsive choice (delay discounting paradigm). To isolate the role of the NA-ergic system in task performance and the efficacy of ADHD medications, a series of experiments are proposed, which utilise new developments in molecular approaches to induce NA-ergic specific neuronal silencing through viral-mediated transgene expression. The results from these experiments will be compared directly with data obtained from animals with neurotoxic lesions (6-hydroxydopamine) of the dorsal noradrenergic nerve bundle. Overall, the programme of research proposed will achieve four key objectives. I. Pharmacological characterisation of ATO-induced decrease in impulsivity, II. Determine the attentional effects of NaRI using modified 5CSRTT, III. Identify the neural basis of ATO-induced improvements in impulse control and IV. Establish the involvement of cortical NA innervations in impulsivity. The utilisation of the viral-vector methodology will also facilitate the development of new approaches to targeting the NA-ergic system in vivo. The results obtained from these experiments will be published in leading international behavioural neuroscience journals and, through this dissemination process and through links with the pharmaceutical industry, this project has the potential to provide an evidential basis for improved pharmacotherapies in ADHD.