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Guest lectures
GL.01 Dopamine in health and disease
  1. T W Robbins

    Trevor Robbins was appointed in 1997 as the Professor of Cognitive Neuroscience at the University of Cambridge. He was elected to the Chair of Expt. Psychology (and Head of Department) at Cambridge from October 2002. He is also Director of the newly-established Cambridge MRC Centre in Behavioural and Clinical Neuroscience, the main objective of which is to inter-relate basic and clinical research in Psychiatry and Neurology for such conditions as Parkinson's, Huntington's, and Alzheimer's diseases, frontal lobe injury, schizophrenia, depression, drug addiction and developmental syndromes such as attention deficit/hyperactivity disorder. He is a Fellow of the British Psychological Society and the Academy of Medical Sciences. He has been President of the European Behavioural Pharmacology Society (1992–1994) and he won that Society's inaugural Distinguished Scientist Award in 2001. He was also President of the British Association of Psychopharmacology from 1996 to 1997. He has edited the journal Psychopharmacology since 1980 and joined the editorial board of Science in Jan. 2003. He has been a member of the Medical Research Council (UK) and chaired the Neuroscience and Mental Health Board from 1995 to 1999. He has been included on a list of the 100 most cited neuroscientists by ISI. He has published nearly 500 full papers in scientific journals and has co-edited three books (Psychology for Medicine: The Prefrontal Cortex; Executive and Cognitive Function, and Disorders of Brain and Mind).

    Research interests: Functions of prefrontal-striatal systems, psychopharmacology of cognition and reinforcement. My research interests span the areas of cognitive neuroscience, behavioural neuroscience and psychopharmacology. My main work focuses on the functions of the frontal lobes of the brain and their connections with other regions, including the so-called brain reward systems which have been discovered in other animals. These brain systems are relevant to such psychiatric and neurological disorders as Parkinson's and Huntington's disease, dementia, schizophrenia, depression, drug addiction, obsessive-compulsive disorder and attention deficit/hyperactivity disorder, as well as frontal lobe injury. A variety of methods is used for studying these systems, including sophisticated psychological paradigms for investigating cognitive functions such as planning, decision-making and self-control (impulsivity) in both normal subjects and patients; these include the computerised CANTAB battery, which I co-invented. I also employ functional brain imaging using brain scanners that operate via magnetic resonance imaging or positron emission tomography to determine where in the human brain various cognitive operations are carried out. In addition, I am interested in establishing how drugs work to produce changes in brain chemistry, and how these affect behaviour. Two particular current interests are characterising beneficial effects of drugs on cognition, as may occur with “cognitive enhancing” drugs used clinically and deleterious effects of drugs of abuse, such as cocaine and amphetamine, which may lead to possible long-term intellectual impairment.

    Some recent publications:

    1. Chamberlain S, Muller U, Blackwell A, et al. Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 2006;311:861–3.

    2. Everitt BJ, Robbins TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 2005;8:1481–9.

    3. Ron M, Robbins TW, eds. Disorders of Mind and Brain 2. Cambridge: Cambridge University Press, 2003.

    4. Cools R, Robbins TW. Chemistry of the adaptive mind. Philosophical transactions. Philos Transact A Math Phys Eng Sci 2004;15:2871–88.

    5. Aron AR, Fletcher PC, Bullmore ET, et al. Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat Neurosci 2003;6:115–16.

    6. Turner DC, Robbins TW, Clark L, et al. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology 2003;165:260–9.

    7. Manes F, Sahakian BJ, Clark L, et al. Decision-making processes following damage to the prefrontal cortex. Brain 2002;125:624–39.

    8. Cardinal RN, Pennicott C, Sugathapala CL, et al. Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 2001;292:2499–501.

    9. Cools R, Barker R, Sahakian BJ, et al. Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands. Cerebral Cortex 2001;11:1136–43.

Abstract

The original synthesis of dopamine in the laboratories of H.E. Dale in South London, followed some 50 years later by the seminal mapping of the mesencephalic dopamine (DA) pathways into ramifying mesostriatal, mesolimbic and mesocortical projections, the identification of several DA receptors and their signalling pathways, and the discovery of phasic and tonic modes of dopaminergic activity, have led to important questions about the functions of this modulatory neurotransmitter. The triadic division of these projections has suggested discrete and even parallel functions in movement (eg, Parkinson's disease, dorsal striatum), reward (eg, drugs of abuse, nucleus accumbens) and cognition (eg, schizophrenia and attention deficit/hyperactivity disorder (ADHD), prefrontal cortex). However, several lines of evidence show that this division to be artificial, it also being important to consider interactions between prefrontal and striatal systems, between the various sectors of the striatum itself, and even its component “direct” and “indirect” pathways.

This lecture will provide several examples of how work performed in experimental animals has informed these functional considerations, while also having profound implications for understanding the functions of dopamine in health and disease. A prime example is the discovery that prefrontal cortical dopamine modulates cognitive functions such as working memory, which our own work has suggested to be a consequence of stabilising representations of the world via dopamine D1 receptor actions. This contrasts with findings that striatal dopamine often serves to promote behavioural switching, as occurs for example in Parkinson's disease, ADHD and stimulant abuse following dopaminergic therapy with l-dopa, methylphenidate, and a D2/3 agonist, respectively. The hypothesis that there exist optimal levels of dopamine activity for efficient cognitive functioning in the prefrontal cortex also has applicability in the sub-cortical brain, based for example on the discovery that optimal titration of dopaminergic therapy for motor function in Parkinson's disease can lead, not only to cognitive enhancement, but also behavioural dysregulation in certain domains, possibly arising as a consequence of an “over-dosing” of ventral striatal dopamine pathways with probable motivational consequences.

Such a motivational role is consonant with the discovery that rewarding effects of psychomotor stimulant drugs such as cocaine and amphetamine were mediated by dopamine-dependent functions of the nucleus accumbens in rats. Recent work has shown that addiction to such drugs is predicted by individual differences in the propensity for impulsive behaviour, associated with variations in dopamine receptor number in the ventral striatum. This impulsivity may reflect an aberrant engagement of pavlovian approach behaviour. However, work in animals has suggested that during the addictive process, there is a shift in control of drug-seeking behaviour from the ventral to dorsal striatum that is consistent with a role for dopamine in stimulus-response habit learning. Implications for recent findings in chronic drug abusers will also be discussed.

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