Prof Andy Ramage
Emeritus Professor of Systems Pharmacology
Div of Biosciences
Faculty of Life Sciences
- Joined UCL
- 1st Aug 1998
My research has focused on investigating the mechanisms involved in the modulation of chemical neurotransmission and how changes in its regulation affect the overall physiological outcome. This is focussed mainly on the central transmitter 5‑hydroxytryptamine (5-HT, serotonin), with particular reference to its involvement cardiovascular system and the control of micturition. These systems allow well-defined inputs to the CNS to be activated giving quantifiable outputs. Therefore, when interfering with transmission within the central nuclei involved in the integration of these inputs the physiological effect can be accurately assessed and related to changes in chemical transmission. Because an in vivo experimental approach is used, the overall physiological importance of such manipulations can be determined. The use of this experimental system has led to recognition of the importance of the role of 5-HT receptors and thus 5‑HT‑containing neurones in central autonomic regulation. 5-HT was identified as a major central transmitter involved in the control of parasympathetic outflow to the heart, airways and bladder via activation of 5-HT1A and 5-HT7 receptors. In addition, 5-HT3 receptors were identified as playing a critical role in the control of afferent input into the nucleus tractus solitarius involving glutamate release by visceral sensory afferents which terminate in this nucleus. Furthermore, the regulation of sympathetic outflow was demonstrated to involve central 5-HT2 receptors which cause sympathoexcitation. In addition, these receptors, via a central angiotensinergic pathway, control the release of vasopressin and this discovery led to the suggestion that this pathway plays an important role in blood volume regulation and that this circuit is also involved in the development of DOCA-salt hypertension in rats. Another major breakthrough using this approach has been the recognition that vagal afferents cause the release of 5-HT at their site of termination in the nucleus tractus solitarius (NTS). As this also occurs along with the release of glutamate, the role of co-transmission in neurotransmission can be investigated in this system. This discovery has further led to an interest in how transmitter release is controlled and the problems of studying such release in vivo and in real time. At present we are using the technique of fast cyclic voltammetry to detect 5-HT release in response to vagal afferent stimulation. Surprisingly, the release of 5‑HT that we detected in response to increasing afferent input in the NTS was unaffected by blockade of the 5-HT transport (5-HTT or SERT) but was potentiated by blockade of the low affinity transporter, originally known as uptake2 but now identified to be either the organic cation transporter 3 (OCT3) or plasma monoamine membrane transporter (+PMAT). Our present data suggests that it is PMAT. This has now been confirmed in slice experiments, in which 5-HT is released spontaneously or evoked by vagal afferent stimulation and activates 5-HT3 receptors to enhance glutamate release from these afferents. The evoked release of 5‑HT was found to be regulated by PMAT not by 5‑HTT/SERT. This has led us to an interest in the role volume transmission reflex regulation of the cardiovascular system. Intriguingly this has open up an interest into the role of glial cells in chemical transmission and to whether volume transmission can be demonstrated.
- University of Manchester
- Doctorate, Doctor of Science | 2003
- University of Manchester
- Doctorate, Doctor of Philosophy | 1977
In 1970 I was awarded a BSc in Physiology and Biochemistry from the University Southampton and in 1973 a M.Phil. on the effects of cholinergic and monoaminergic inputs onto identified neurones in the brain of the garden snail Helix aspersa. This led to the discovery that octopamine may be a transmitter in this system (Experientia, 28, 1173, 1972). This research was carried out under the supervision of Robert Walker. In 1972 I had the privilege, although briefly (9 months), to work with David Brown at Bart's Pharmacology Department studying nicotine receptors and sodium movement in sail neurones. In October of that year I took up a Research Fellowship in the Department of Pharmacology at the University of Manchester and completed my PhD (1977) on the effects of chemical irritants/riot gases on somatosensory receptors. This research lead to the demonstration that capsaicin and related chemicals selectively activated polymodal nociceptors and indicated that these somatosensory receptors were responsible for the cutaneous axon reflex (Neuropharmacol., 20,191-198, 1981). My supervisor was Bob Foster. I also had the privilege, during this period, of having the single C-fibre recording technique demonstrated to me by Prof. A. Iggo. In 1976 Prof. Eleanor Zaimis invited me to take up a lectureship in Pharmacology at the Royal Free Hospital School of Medicine to study the effects of antihypertensive drugs on the central regulatory mechanisms involved in the control of blood pressure. On her retirement in 1980 I built up my own research area, with the technical support of Steve Wilkinson, in systems neuropharmacology investigating the role of monoamines, with special reference to 5-HT, in central autonomic regulation. During this period, I developed a long-term collaboration with David Jordan in the Physiology Department, who sadly died prematurely in 2007. In 2007 (1st August) I moved from the Royal Free Campus to the Pharmacology Department in the Medical Sciences Building at the Bloomsbury Campus. This department in 2007 became part of the Research Department of Neuroscience, Physiology & Pharmacology. I took retirement 31st July 2015 and became Emeritus Professor working part-time until June 2018. In September 2019 I became a press editor for the British Journal of Pharmacological.