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Imaging in neuropsychopharmacology
s91
Plenary lectures
(Lp.2) Driving forces in brain research
ILp.31 Imaging in neuropsychopharmacology
H. Miihler. Institute of Pharmacology and Toxicology, University of Ziirich and Dept. Applied Biosciences, ETH Ziirich, Winterthurerstrasse 190, 8057 Ziirich, Switzerland
D.J. Nutt. University of Bristol, Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol BS8 ITD, UK
Brain research is an integrative science which draws on the methodological and conceptual advances made in multiple domains such as psychiatry, cognitive psychology, neurology as well as clinical and basic neuroscience. It’s goal is to identify the neural mechanisms of normal cognitive processes and behaviour and understand how these mechanisms are injured in disease (1). In basic and clinical neuroscience the major driving forces in improving the understanding of brain function continue to be genetics, brain imaging and molecular biology possibly supplemented in the future by cell-therapy: Genetic dissection of complex traits: Genetics has sparked a revolution in medical science on the basis of the seemingly improbable notion that on can discover the genes causing inherited diseases without any prior biological clue on how they function. Genome sequencing and the identification of genome markers have accelerated this process. Brain imaging has given unprecedented insights into the modular operation of the brain in performing various cognitive and emotional tasks. Molecular biology permits the identification of building blocks of brain function and the development of new animal models of disease. For instance, the recognition of a GABAA receptor deficit in patients with panic anxiety has lead to a new animal model of anxiety behaviour (2). Similarly, the genetic dissection of the benzodiazepine pharmacology (3) permitted the identification of more selective drug targets to improve the possibility to treat anxiety disorders (4). In the future new developments such as cell-therapy (5) are expected to contribute to the advance in brain research.
Neuroimaging techniques are set to revolutionise the way brain function and dvsfunction are understood. Thev allow us to address at least six different questions in neuropsychbpharmacology. 1. They contribute to the diagnostic process. Examples of this include differential changes in cerebral blood flow between Alzheimer’s Disease and Loewy body dementia and the development of new tracers to identify sites of inthunmation in the brain such as multiple sclerosis and other inflammatory diseases. 2. They allow the definition of brain circuits underlying changes in psychological state such as anxiety, depression, hallucinosis and addiction. For example, there are newer studies which have shown the role for the limbic system including its cortical projections in both anxiety and depressive disorders. There is growing evidence that similar regions but extending into the orbit0 frontal cortex may be involved in processes in addiction such as craving. 3. The radioactive imaging techniques of PET and SPECT allow identification of receptors in the brain, and possible changes in disease states and response to treatment. Currently available tracers allow us to image members of the dopamine, 5-HT, GABA, opioid, substance-P and acetylcholine receptor families. There are also tracers available for measuring either number or function of 5-HT, dopamine and noradrenaline transporters. These studies have already thrown considerable light on the GABA receptor abnormality in conditions such as the anxiety disorders and epilepsy and the role of ~-HT~A receptors in depression and D2 receptors in schizophrenia. New ligands for receptor subtypes are under development, eg the a5 GABA subtype. 4. Imaging techniques also offer the opportunity for accelerating drug development. They allow dose ranging studies of brain receptor occupancy to be performed for the first time and are being developed to explore interactions of new treatments with brain circuits. 5. Several PET tracers are now available to explore enzyme activity in the brain. For instance, choline acetyltransferase function can be assessed using a PET labelled substrate, and binding tracers for both MAO-A and MAO-B have been developed. The latter have been used to show, for example, smoking inhibits MAO-B function in humans. 6. Finally, and perhaps the most exciting new development is the use of PET and SPECT tracers as probes for endogenous neurotransmitter release. The principle here is that if a tracer has a binding affinity not dissimilar to that of the endogenous neurotransmitter, then altering the level of transmitter will alter the tracer binding. Thus, for example, 1 IC raclopride has been used successfully to estimate the synaptic release of dopamine, and it has been shown that drugs which increase dopamine
References PI Andreasen, N.C. Linking mind and brain in the study of mental illnesses: a project for a scientific psychopathology. Science 275, 1586 1592, 1997. PI Crestani, F., Lore+ M., Baer, K., Es&h, Ch., Benke, D., Laurent, J.P.
Belzung, C., Fritschy, J.-M., Ltischer, B. and Miihler, H. Impairment of GABAA-recentor clustering results in enhanced anxietv resoonses and a cognitive bjas for threat-cues. Nature Neurosci. 2, 833-839 (1999)
(reviewed in News and Views, Nature Neurosci. 2, 780-782, 1999 and Nature Medicine 5, 1131-l 132, 1999) [31 Rudolph, U., Crestani, F., Benke, D., Briinig, I., Benson, LA., Fritschy, J.-M., Martin, J.R., Blinhmann, H. and Mohler, H. Betuodiazepine actions mediated by specific y-aminobutyric acidA receptor subtypes. Nature 401, 796800 (1999) (reviewed in News and Views, Nature 401, 751-752, 1999 and The Lancet 354, 1451, 1999) [41 Low, K., Crestani, E, Keist, R., Benke, D., Brilnig, I., Benson, LA., Fritschy, J.M., Riilicke, Th., Bluethmann, H., Mdhler, H., and Rudolph, U. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131-134 (2000) (reviewed in News of the Week, Science 290, 23-25, 2000 and New Engl. J. Med.) [51 Huber, A., Padrun, V, Deglon, N., Aebischer, P, Miihler, H. and Boison, D. Grafts of adenosine relasing cells suppress seizures in kindling epilepsy. Proc. Natl. Acade. Sci. USA 98, 7611-7616, 2001)
S92
Plenary lectures
release such as amphetamine, will decrease raclopride binding. Interestingly, psychological experiments which increase motivation and suggest reward have also been shown to increase dopamine release using a similar paradigm. Mv oresentation will examine the utilitv of itnarrine in all of these fx domains, giving examples fro& my o& &d others research. References
[l] General reading: Journal of Psychopharmacology (1999) volwne 13, number 4. r21 Malizia. AL.. Forse. G.. Haida. A.. Gunn. R.. Melichar. J.. Poole. K.. L a Bateman, D.,‘Fahy, D., Schnorr~L.; Drown, D., Rhodes; d, Nutt,‘DJ.; Jones, T. (1995) A new human @sycho)pharmacologytool: the multiple ;Fc;orincidences counter (MGCC). J Psychopharmacology 9 (4): [3] Mahzia, AL., Gumt, RN., Wilson, SJ., Waters, SH., Bloomtield, PM., Cunningham, VJ., Nutt, DJ. (1996) Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in viva. Neurophatmacology 35 (9/10): 1483-1491.
[4] Friston, KJ., Malizia, AL., Wilson, SJ., Cunningham, VJ., Jones, T., Nutt, DJ. (1997) The analysis of dynamic radioligand displacement or ‘activation’studies. J Cerebral Blood Flow and Metabolism 17: 80-93. [5] Malizia, AL., Melichar, JK., Brown, D., Gunn, R., Reynolds, A., Jones, T., Nutt, DJ. (1997) Demonstration of clomipramine and venlafaxine occuoation at serotonin reuotake sites in man in viva. J Psvchoohar- L macdogy11 (3): 279-281. I [6] Malizia, AL., Cunningham, VJ., Bell, CJ., Liddle, PF., Jones, T., Nutt, DJ. (1998) Decreased brain GABAA-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET stud? Archives Gen Psychiatrv 55: 715-720. [7] Mahzia, AL., Mdlichar,~JK.,Rhodes, CG., Haida, A., Reynolds, AH., Jones, T., Nutt, DJ. (2000) Desipramine binding to noradrenaline reuptake sites in man in vivo. Eur J Pharmacol 391: 263-267.
Plenary lectures
(Lp.2) Driving forces in brain research
ILp.31 Imaging in neuropsychopharmacology
H. Miihler. Institute of Pharmacology and Toxicology, University of Ziirich and Dept. Applied Biosciences, ETH Ziirich, Winterthurerstrasse 190, 8057 Ziirich, Switzerland
D.J. Nutt. University of Bristol, Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol BS8 ITD, UK
Brain research is an integrative science which draws on the methodological and conceptual advances made in multiple domains such as psychiatry, cognitive psychology, neurology as well as clinical and basic neuroscience. It’s goal is to identify the neural mechanisms of normal cognitive processes and behaviour and understand how these mechanisms are injured in disease (1). In basic and clinical neuroscience the major driving forces in improving the understanding of brain function continue to be genetics, brain imaging and molecular biology possibly supplemented in the future by cell-therapy: Genetic dissection of complex traits: Genetics has sparked a revolution in medical science on the basis of the seemingly improbable notion that on can discover the genes causing inherited diseases without any prior biological clue on how they function. Genome sequencing and the identification of genome markers have accelerated this process. Brain imaging has given unprecedented insights into the modular operation of the brain in performing various cognitive and emotional tasks. Molecular biology permits the identification of building blocks of brain function and the development of new animal models of disease. For instance, the recognition of a GABAA receptor deficit in patients with panic anxiety has lead to a new animal model of anxiety behaviour (2). Similarly, the genetic dissection of the benzodiazepine pharmacology (3) permitted the identification of more selective drug targets to improve the possibility to treat anxiety disorders (4). In the future new developments such as cell-therapy (5) are expected to contribute to the advance in brain research.
Neuroimaging techniques are set to revolutionise the way brain function and dvsfunction are understood. Thev allow us to address at least six different questions in neuropsychbpharmacology. 1. They contribute to the diagnostic process. Examples of this include differential changes in cerebral blood flow between Alzheimer’s Disease and Loewy body dementia and the development of new tracers to identify sites of inthunmation in the brain such as multiple sclerosis and other inflammatory diseases. 2. They allow the definition of brain circuits underlying changes in psychological state such as anxiety, depression, hallucinosis and addiction. For example, there are newer studies which have shown the role for the limbic system including its cortical projections in both anxiety and depressive disorders. There is growing evidence that similar regions but extending into the orbit0 frontal cortex may be involved in processes in addiction such as craving. 3. The radioactive imaging techniques of PET and SPECT allow identification of receptors in the brain, and possible changes in disease states and response to treatment. Currently available tracers allow us to image members of the dopamine, 5-HT, GABA, opioid, substance-P and acetylcholine receptor families. There are also tracers available for measuring either number or function of 5-HT, dopamine and noradrenaline transporters. These studies have already thrown considerable light on the GABA receptor abnormality in conditions such as the anxiety disorders and epilepsy and the role of ~-HT~A receptors in depression and D2 receptors in schizophrenia. New ligands for receptor subtypes are under development, eg the a5 GABA subtype. 4. Imaging techniques also offer the opportunity for accelerating drug development. They allow dose ranging studies of brain receptor occupancy to be performed for the first time and are being developed to explore interactions of new treatments with brain circuits. 5. Several PET tracers are now available to explore enzyme activity in the brain. For instance, choline acetyltransferase function can be assessed using a PET labelled substrate, and binding tracers for both MAO-A and MAO-B have been developed. The latter have been used to show, for example, smoking inhibits MAO-B function in humans. 6. Finally, and perhaps the most exciting new development is the use of PET and SPECT tracers as probes for endogenous neurotransmitter release. The principle here is that if a tracer has a binding affinity not dissimilar to that of the endogenous neurotransmitter, then altering the level of transmitter will alter the tracer binding. Thus, for example, 1 IC raclopride has been used successfully to estimate the synaptic release of dopamine, and it has been shown that drugs which increase dopamine
References PI Andreasen, N.C. Linking mind and brain in the study of mental illnesses: a project for a scientific psychopathology. Science 275, 1586 1592, 1997. PI Crestani, F., Lore+ M., Baer, K., Es&h, Ch., Benke, D., Laurent, J.P.
Belzung, C., Fritschy, J.-M., Ltischer, B. and Miihler, H. Impairment of GABAA-recentor clustering results in enhanced anxietv resoonses and a cognitive bjas for threat-cues. Nature Neurosci. 2, 833-839 (1999)
(reviewed in News and Views, Nature Neurosci. 2, 780-782, 1999 and Nature Medicine 5, 1131-l 132, 1999) [31 Rudolph, U., Crestani, F., Benke, D., Briinig, I., Benson, LA., Fritschy, J.-M., Martin, J.R., Blinhmann, H. and Mohler, H. Betuodiazepine actions mediated by specific y-aminobutyric acidA receptor subtypes. Nature 401, 796800 (1999) (reviewed in News and Views, Nature 401, 751-752, 1999 and The Lancet 354, 1451, 1999) [41 Low, K., Crestani, E, Keist, R., Benke, D., Brilnig, I., Benson, LA., Fritschy, J.M., Riilicke, Th., Bluethmann, H., Mdhler, H., and Rudolph, U. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131-134 (2000) (reviewed in News of the Week, Science 290, 23-25, 2000 and New Engl. J. Med.) [51 Huber, A., Padrun, V, Deglon, N., Aebischer, P, Miihler, H. and Boison, D. Grafts of adenosine relasing cells suppress seizures in kindling epilepsy. Proc. Natl. Acade. Sci. USA 98, 7611-7616, 2001)
S92
Plenary lectures
release such as amphetamine, will decrease raclopride binding. Interestingly, psychological experiments which increase motivation and suggest reward have also been shown to increase dopamine release using a similar paradigm. Mv oresentation will examine the utilitv of itnarrine in all of these fx domains, giving examples fro& my o& &d others research. References
[l] General reading: Journal of Psychopharmacology (1999) volwne 13, number 4. r21 Malizia. AL.. Forse. G.. Haida. A.. Gunn. R.. Melichar. J.. Poole. K.. L a Bateman, D.,‘Fahy, D., Schnorr~L.; Drown, D., Rhodes; d, Nutt,‘DJ.; Jones, T. (1995) A new human @sycho)pharmacologytool: the multiple ;Fc;orincidences counter (MGCC). J Psychopharmacology 9 (4): [3] Mahzia, AL., Gumt, RN., Wilson, SJ., Waters, SH., Bloomtield, PM., Cunningham, VJ., Nutt, DJ. (1996) Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in viva. Neurophatmacology 35 (9/10): 1483-1491.
[4] Friston, KJ., Malizia, AL., Wilson, SJ., Cunningham, VJ., Jones, T., Nutt, DJ. (1997) The analysis of dynamic radioligand displacement or ‘activation’studies. J Cerebral Blood Flow and Metabolism 17: 80-93. [5] Malizia, AL., Melichar, JK., Brown, D., Gunn, R., Reynolds, A., Jones, T., Nutt, DJ. (1997) Demonstration of clomipramine and venlafaxine occuoation at serotonin reuotake sites in man in viva. J Psvchoohar- L macdogy11 (3): 279-281. I [6] Malizia, AL., Cunningham, VJ., Bell, CJ., Liddle, PF., Jones, T., Nutt, DJ. (1998) Decreased brain GABAA-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET stud? Archives Gen Psychiatrv 55: 715-720. [7] Mahzia, AL., Mdlichar,~JK.,Rhodes, CG., Haida, A., Reynolds, AH., Jones, T., Nutt, DJ. (2000) Desipramine binding to noradrenaline reuptake sites in man in vivo. Eur J Pharmacol 391: 263-267.