Techniques

    Metabolic mapping of cerebral function using quantitative (rat) and semi-quantitative 2-deoxyglucose autoradiographic imaging.

    Quantification of cerebrovascular perfusion using iodoantipyrine autoradiographic imaging.

    Analysis of cerebral flow-metabolism coupling using (1) and (2).

    Measurement of blood-brain barrier integrity using quantitative α-aminoisobutyric acid autoradiographic imaging.

    Mapping of protein synthesis using radiolabelled leucine autoradiographic imaging.

    Mapping of neurotransmitter receptor distributions using radioligands and quantitative autoradiographic imaging.

    Cytochrome oxidase histochemistry

     

Neuropharmacology Research Interests
The overall aim of our work is to characterise the mechanisms by which both genetically-determined and environmentally-induced alterations in central serotonergic function (including cerebrovascular function) might contribute to the aetiology of affective disorders. It is anticipated that from a greater understanding of the interaction between the serotonergic system (the current target for most antidepressant treatments) and other neurotransmitter systems in the brain, novel targets for therapeutic intervention may be identified.

Specifically, the objectives are:
1. To characterise brain function in the offspring of dams previously exposed to the psychostimulant drug, methylenedioxymethamphetamine (MDMA, “Ecstasy”).
2. To characterise brain function in animals where genetic modification alters central serotonergic systems, either directly or indirectly.
3. To characterise the mechanisms by which altered cerebrovascular physiology might contribute to changes in brain function induced by both genetic and environmental manipulation of central serotonergic systems.

The link between pathological cerebrovascular dysfunction and the development of affective disorders is well established. Less well established is any physiological link whereby cerebrovascular insufficiency might contribute to either the aetiology or symptomology of affective disorders, or conversely how the neurochemical imbalances of affective disorders might impinge upon cerebrovascular control.

Over the past 10 years, our research group has worked in this field as part of two European research consortia, funded under the 5th and 6th Framework Programmes. Most recently, we were part of a major collaboration between 13 academic groups in 10 EU countries, together with 2 Small/Medium Enterprises. This grouping represented an integrated clinical - basic science project that is capitalising on state-of- the-art neuroscience expertise across the EU, including molecular genetics and functional brain imaging.

The contribution to this integrated programme from our laboratory concentrated on models of altered serotonin transporter function including:

Current Research
More recently we have extended this work to examine the interaction between serotonin and corticotrphin-releasing factor in the aetiology of stress disorders using urocortin 3 over-expressing, or CRF receptor type 2 knock-out mice.

Future Research
Drug abuse is generally associated with psychiatric illness but it is not clear whether exposure to recreational drugs is a cause, a trigger, or merely contributes to pre-existing conditions. Certainly The association between cannabis and psychosis has long been recognised, but it remains controversial and the mechanisms unknown.

In preliminary studies we have examined the effects of  recreational drugs of upon brain function in mice with a genetic predisposition to either schizophrenia-like (DISC1 L100P mutants) or depression-like (DISC1 Q31L mutants) behaviours. Brain activity was investigated using autoradiographic imaging in wild-type mice and the two DISC1 (Disrupted In SChizophrenia) mutants, treated acutely with either saline or MDMA or vehicle or THC . In wild-type mice, MDMA produced both localised increases in brain activity, and some decreases. Similar effects were found in L100P mutants but here the effects (both increases and decreases) were potentiated and the decreases were more widespread. In Q31L mutants the effects of MDMA were slightly attenuated compared to wild-type. In wild type and Q31L the dose of THC used had no measurable effect but decreases were found in L100P mice suggesting that they are more susceptible to THC.


Key Publications
RUTTEN, K., VAN DONKELAAR, E.L., FERRINGTON L., BOLLEN, E., STEINBUSCH, H.W.M., BLOKLAND, A., KELLY P.A.T., and PRICKAERTS, J.H.H.J.  Phosphodiesterase inhibitors enhance object memory independent of cerebral blood flow and glucose utilization in rats.  Neuropsychopharmacol. 34, 1914-1925 (2009). (IF 6.685)
DAWSON, N., FERRINGTON, L., OLVERMAN, H.J., HARMAR, A.J. and KELLY, P.A.T.  Gender influences the effect of a life-long increase in serotonin transporter function on cerebral metabolism.  J. Neurosci. Res. 87, 2375-2385 (2009). (IF 2.986)
VAN DONKELAAR E.L., FERRINGTON, L., BLOKLAND, A., STEINBUSCH, H.W.M., PRICKAERTS, J., and KELLY, P.A.T.  Acute tryptophan depletion in rats alters the relationship between cerebral blood flow and glucose metabolism independent of central serotonin.  Neuroscience 163, 683-694 (2009). (IF 3.292)
VAN DONKELAAR E.L., BLOKLAND, A., LIEBEN, C.K., KENIS, G., FERRINGTON, L., KELLY, P.A., STEINBUSCH, H.W., and PRICKAERTS, J.  Acute tryptophan depletion in C57BL/6 mice does not induce central serotonin reduction or affective behavioural changes  Neurochemistry International 56, 21-34 (2010). (IF 3.541)
ANDÓ, R.D., ÁDORI, C., KIRILLY, E., KOVACS, G.G., FERRINGTON, L., KELLY. P.A.T., and BAGDY, G.  Acute SSRI-induced anxiogenesis and brain metabolic effects are attenuated despite partial recovery of serotonergic terminals six months after initial MDMA-induced depletion.  Behav. Brain Res. 207, 280-289 (2010). (IF 3.220)
VAN DONKELAAR E.L., KELLY, P.A.T., DAWSON, N., BLOKLAND, A., PRICKAERTS, J., STEINBUSCH, H.W.M., and FERRINGTON, L.  Acute tryptophan depletion potentiates 3,4-methylenedioxymethamphetamine-induced cerebrovascular hyperperfusion in adult male Wistar rats.  J. Neurosci. Res. 88, 1557-1568 (2010). (IF 2.986)
DAWSON, N., FERRINGTON, L., LESCH, K.-P. and KELLY, P.A.T. Cerebral metabolic responses to 5-HT2A/C receptor activation in mice with genetically modified serotonin transporter (SERT) expression. European Neuropsychopharmacol. 21, 117 – 128 (2011). (IF 3.684)
VAN DONKELAAR E.L., BLOKLAND, FERRINGTON, L., KELLY, P.A.T., STEINBUSCH, H.W.M. and PRICKAERTS, J.  Mechanism of acute tryptophan depletion: Beyond the serotonin system. Molecular Psychiatry 16, 695-713 (2011). (IF 15.470)
NEUFELD-COHEN, A., KELLY, P.A.T., PAUL, E.E., SKINNER, E., OLVERMAN, H.J., VAUGHAN, J.M., ISSLER, O., LOWRY, C.A., VALE, W.W., SECKL, J.R., CHEN. A., and JAMEISON, P.M. Chronic activation of CRF type 2 receptors reveals a key role for 5-HT1A receptor responsiveness in mediating behavioral and 5-HT responses to stressful challenge. Biol. Psychiatry, 72, 437-447 (2012).
ISSLER, O., CARTER, R.N, PAUL, E.D., KELLY, P.A.T, OLVERMAN, H.J., LOWRY, C.A., SECKL, J.R., CHEN. A., and JAMIESON, P.M. The role of the CRF receptor type 2 in stress recovery is mediated via modulation of serotonergic circuits in the lateral septum and subiculum. (Biology of Mood & Anxiety Disorders in press 2013).