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SELF-FUNDING MSc BY RESEARCH PROJECT: Modulation of cyclic AMP level in astrocytes as a novel and alternative mechanism of action of antidepressants

School of Physiology and Pharmacology

About the Project

 Depression is a highly prevalent medical condition which may be life threatening. It also leads to disabilities and has extensive social implications for those affected and the society as a whole.

In spite of many years of research and a vast number of publications on this topic, there is no coherent theory of depression. Most of the current thinking pivots around insufficiency of central mono-amines, such as serotonin and noradrenalin which seems to be consistent with the fact that the most widely prescribed antidepressants block re-uptake of these monoamines, leading to the increase in their extracellular concentration in the brain. However, there too many facts which do not fit with this, apparently straightforward theory. For example, antidepressants which block reuptake of monoamines increase their concentration in the brain almost immediately, but it is widely known that it takes weeks for a clinical effect to develop. Why would that be? Moreover, genetically modified mice and rats which almost completely lack central serotonin are not showing obvious signs of depression and, when tested using accepted models of depression, still respond to the drugs, classified as “selective blockers of serotonin re-uptake”. What is then, the substrate of their action? There are many more such controversies. At the same time, long latency of the therapeutic effect is a major problem with the currently available antidepressants.

We are interested in testing a different theory which could explain how antidepressants work. It proposes that the key mechanism leading to depression is reduction of cAMP in brain cells and that antidepressants can increase the level of cyclic AMP in cells, in particular astrocytes, by a direct action on some G-proteins.

The project will use molecular tools and fluorescently tagged G proteins in combination with confocal imaging of living cells to investigate whether the antidepressants of various classes are able to induce translocation of alpha subunits of certain G-proteins. We will also test whether this effect is paralleled by increases in cAMP using FRET-based molecular sensors, viral vectors and other molecular tools.

Funding Notes

This project is for students who can fund the project themselves; there is no financial support.
Please apply to the Faculty of Life Sciences, School of Physiology and Pharmacology, selecting the programme 'MSc by Research'
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Reference List
1. Mizrahi C, Stojanovic A, Urbina M, Carreira I and Lima L. Differential cAMP levels and serotonin effects in blood peripheral mononuclear cells and lymphocytes from major depression patients. Int Immunopharmacol 4: 1125-1133, 2004.
2. Rasenick MM. Depression and Adenylyl Cyclase: Sorting Out the Signals. Biol Psychiatry 80: 812-814, 2016.
3. Singh H, Wray N, Schappi JM and Rasenick MM. Disruption of lipid-raft localized Galphas/tubulin complexes by antidepressants: a unique feature of HDAC6 inhibitors, SSRI and tricyclic compounds. Neuropsychopharmacology 43: 1481-1491, 2018.
4. Stewart RJ, Chen B, Dowlatshahi D, MacQueen GM and Young LT. Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium. Brain Res Bull 55: 625-629, 2001.

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