Function and pharmacology of monoamine neurotransmitters

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Dr S. Clare Stanford
Reader in Experimental Psychopharmacology
Tel: 020 7679 3731
Email: c.stanford@ucl.ac.uk

Lab members:

  • Ms Liz Ash
  • Ms Carrie Yan

Clare Stanford graduated in physiology from UCL and then carried out research for a DPhil in the University Laboratory of Physiology at Oxford university. She was awarded a university scholarship to enable her to stay on as a postdoc and to continue her research on the regulation of central and peripheral noradrenergic transmission. This was followed by a Demonstratorship in the same department and her appointment as the first woman Fellow of Exeter College. She has held a visiting research fellowship at the University of Bergen, Norway and was appointed to a tenured lectureship in pharmacology at The Middlesex Hospital Medical School. She moved to this department in 1987 and is currently a Reader in Experimental Psychopharmacology. She is a member of the Senate and also of Council of the University of London where she represents the Subject Area Board in Life Sciences. She has edited four books, contributed nearly 20 chapters to other books and has been a senior author on over 60 peer-reviewed papers.

As well as being immediate Past President of the British Association for Psychopharmacology (BAP), she is a member of Council (and a former Vice President) of the Laboratory Animal Science Association (LASA) and represents the British Pharmacological Society on Council of the Research Defence Society. She is an Editor of several international journals (British Journal of Pharmacology, Pharmacology Biochemistry and Behavior, Journal of Psychopharmacology, International Journal of Neuropsychopharmacology) and has served on the National Centre for the 3Rs (NC3Rs) grant panel for the last three years. She represents LASA on the Boyd Group and is a member of working groups, set up by the NC3Rs and the ABPI, whose remit is to advise on regulatory policy and practice in animal research (both nationally and internationally).

Clare was also responsible for setting up a series of training (CPD) modules, leading to the BAP Certificate in Preclinical Psychopharmacology. This pioneering and highly successful programme (now in its 7th year and emulated by other societies) attracts delegates from all over Europe, as well as the UK. It receives financial support from the BBSRC and is aimed at postgraduate students, postdoctoral workers and established scientists moving into psychopharmacology from other disciplines (for more information, see: www.bap.org.uk).

She is invited regularly to give talks on welfare and ethics in psychopharmacology but also often talks to schools and other groups (e.g., clinicians, the police and the DANA centre) to encourage public interest in psychopharmacology. She has made many media appearances including ITV, Channel 4, Sky TV, Radio 4 and the World Service.

Research

The so-called 'monoamine neurotransmitters', which include dopamine, noradrenaline, adrenaline and serotonin, are released from neurones in both the brain and peripheral nervous system. The function of the monoamines is not at all clear but they are thought to have a crucial role in arousal, emotion and cognition. Certainly, drugs that augment the effects of monoamines on their target tissues, are used to treat psychiatric disorders such as anxiety, depression and schizophrenia. The major aim of our research is to explain how the brain regulates monoamine transmission and to understand their influence on mood and behaviour.

We apply a wide range of techniques in vitro and in vivo to tackle these questions. At present, much of our work depends on 'in vivo microdialysis'. This technique enables us to monitor changes in the rate of release of neurotransmitters in the brain of rodents at the same time as recording their behaviour. Currently, we are one of only a handful of academic groups (<three?) in the UK experienced in using this technique to study mice. With the increasing use of mutant mice in biomedical research, our experimental approach is increasingly in demand in the industrial sector. 

In the past, a major focus of our research has been to understand the role of monoamine transmitters in the therapeutic effects of antidepressants. Our key findings revealed that antidepressants (even drugs known as ‘Selective Serotonin Reuptake Inhibitors’) actually modify the function of both serotonin and noradrenaline in vivo, regardless of their selectivity in vitro. This fundamental shift in emphasis, from serotonin as a key factor in ‘antidepression’, to the importance of interactions between all three monoamines, and their downstream consequences, is still a major focus of research in this field.

We have also compared changes in monoamine transmission induced by the anti-obesity drug (and the monoamine releasing agent), d‑amphetamine, and the reuptake inhibitor, sibutramine. We have characterised not only qualitative differences in the effects of these two drugs but also striking differences in latency of the monoamine responses to these compounds. We believe that these differences in latency explain why d‑amphetamine is addictive but sibutramine is not. This work made a vital contribution to an application for a product licence submitted (to the FDA and, subsequently, worldwide) by our industrial sponsor. Sibutramine is the only centrally-acting drug that is still licenced for treatment of obesity.

Recently, we have investigated the neurochemical and behavioural abnormalities of NK1R-/- mice, which lack functional receptors for the neuropeptide, substance P. We were interested in these mice because their behaviour resembles that of wildtype mice that have been given an antidepressant drug. In the course of this work, which was carried out in collaboration with Professor Stephen Hunt of this department, we made the exciting discovery that NK1R‑/- mice express the core features of Attention Deficit Hyperactivity Disorder (ADHD). These include hyperactivity, which is prevented by d-amphetamine, and striking abnormalities in monoamine transmission in the brain. This work in mice has been complemented by genetic studies of patients with ADHD (carried out in collaboration with Professor Hugh Gurling, Molecular Psychiatry). This translational research, which has linked directly our findings in mice and humans, has led to the discovery of a novel target for drug treatment of ADHD. This will be a major focus of our future research.

We have also used microdialysis to study the regulation of glutamate transmission in the prefrontal cortex, a brain region believed to have a pivotal role in perception, arousal and response control. We have discovered that the glutamate response to an experimental challenge differs systematically along its rostral / caudal axis. Specifically, the glutamate responses in different subregions of the prefrontal cortex are organized in a characteristic on/off pattern. In the future, we intend to test our proposal that this asymmetric regulation of glutamate transmission explains how different regions of the prefrontal cortex make different contributions to the emotional and behavioural responses to external stimuli.

References:

Book chapters

  • STANFORD S.C. & MARSDEN C.A (2005) Regional specialisation in the central noradrenergic response to unconditioned and conditioned environmental stimuli. Handbook of Stress and the Brain. 145: 487-501.
  • STANFORD S.C. (2005) Adrenaline and noradrenaline: Introduction. In: Encyclopaedia of Life Sciences. John Wiley & Sons Ltd, Chichester, UK (update of previous review (2001): published electronically, only).

Papers:

  • STANFORD S.C. (2007) Open fields (unlike wheels) can be any shape but still miss the target. J Psychopharmacol. 21: 144.
  • STANFORD S.C. (2007) The Open Field Test – Reinventing the wheel. J Psychopharmacol. 21: 134-135
  • ASH E.S., HEAL D.J., STANFORD S.C. (2007) The glial (GLT-1) transporter has different roles in the regulation of the glutamate response to d‑amphetamine in different subregions of the rat anterior cingulate cortex. Prize poster at the annual meeting of the British Association for Psychopharmacology, July 2007.
  • FISHER A.S., STEWART, R.J., YAN T., HUNT S.P., STANFORD S.C. (2007) Disruption of noradrenergic transmission and the behavioural response to a novel environment in NK1R-/- mice. Eur. J. Neurosci. 25: 1195-1204.
  • KELLETT D.O., STANFORD S.C., MACHADO B.H., JORDAN D., RAMAGE A.G. (2005) Effect of 5-HT depletion on cardiovascular vagal reflex sensitivity in awake and anesthetised rats. Brain Res. 1054: 61-72
  • HERPFER I., HUNT S.P., STANFORD S.C. (2005) A comparison of neurokinin1 knock-out (NK1-/-) and wildtype mice: exploratory behaviour and extracellular noradrenaline concentration in the cerebral cortex of anaesthetised subjects. Neuropharmacol. 48: 706-719.
  • GÉRANTON S.M., HEAL D.J., & STANFORD S.C. (2004) 5-HT has contrasting effects in the frontal cortex, but not the hypothalamus, on changes in noradrenaline efflux induced by the monoamine-releasing agent, d-amphetamine, and the reuptake inhibitor, BTS 54 354. Neuropharmacol. 46: 511-518.
  • GÉRANTON S.M., HEAL D.J. & STANFORD S.C. (2003) Noradrenaline clearance differs in the frontal cortex and hypothalamus: a dual-probe microdialysis study in the rat. Neurosci. Lett. 350: 157-160.
  • GÉRANTON S.M., HEAL D.J. & STANFORD S.C. (2003) Differences in the mechanisms that increase noradrenaline efflux after administration of d-amphetamine: a dual-probe microdialysis study in rat frontal cortex and hypothalamus. Br. J. Pharmacol. 139: 1441-1448.
  • STRICKLAND S.S., VEENA G.V., HOUGHTON P.J., STANFORD S.C. & KURPAD A.V. (2003) Areca nut, energy metabolism and hunger in Asian men. Annals Hum. Biol.30:26-52
  • McQUADE R. & STANFORD S.C. (2001) Differences in central noradrenergic and behavioural responses of Maudsley NonReactive and Maudsley Reactive inbred rats on exposure to an aversive novel environment. J. Neurochem. 76: 21-28.
  • SALMON P., STANFORD S.C., MIKHAIL G., ZIELINSKI S. & PEPPER J.R. (2001) Hemodynamic and emotional responses to stress after cardiac transplantation. J. Psychosomatic Res. 63:289-299.
  • STANFORD B.J. & STANFORD S.C. (2000) Postoperative delirium indicating an adverse drug interaction involving the selective serotonin reuptake inhibitor, paroxetine? A reply to the response from JL Palmer. J Psychopharmacol. 14: 186-187.
  • McQUADE R. & STANFORD S.C. (2000) A microdialysis study of the noradrenergic response in rat frontal cortex and hypothalamus to a conditioned cue for aversive naturalistic environmental stimuli. Psychopharmacol. 148: 201-208. (author list appears in most databases as: ‘M c-Quade R’, only)