- Email: [email protected]
In vivo dopamine receptor gene transfer using an adenoviral vector
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contrast, extracellular 5HIAA levels were increased by ketamine administration in both drug naive and were further enhanced in ketamine pre-treated animals but without a change in basal 5HIAA levels while GABA levels were unaffected by either single or repeated ketamine. These findings provide new evidence for a differential effect of single and repeated ketamine on mPFC dopamine, serotonin and GABA transmission and suggest a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of elevated basal dopamine levels, the ketamine induced increase in dopamine is attenuated and the increase in 5HIAA is enhanced. Thus, ketamine pretreatment appears to reduce the dynamics of mPFC dopaminergic transmission thereby altering the balance between dopamine and serotonin transmission.
IN VIVO DOPAMINE RECEPTOR GENE
TRANSFER USING AN ADENOVIRAL VECTOR A.H,C. Wong, M. Knapp, H . H . M . Van Tol Clarke Institute of Psychiatry, 250 College Street, Toronto, ON, M5T 1R8, Canada Objective: The aim of this project is to develop an animal model of altered dopamine (DA) receptor expression to study the mechanism of neuroleptic drug action, and the neurophysiology of psychotic symptoms in illnesses such as schizophrenia. Method." Recombinant El deleted, Ad5 vectors containing DA D2 and D4 receptor genes were constructed. DA receptor expression mediated by these vectors has been assessed in vitro in established and primary cell cultures. The modification of DA receptor expression in vivo, is accomplished through stereotactic microinjection of our adenoviral vectors into selected areas of Sprague-Dawley rat brains including: caudateputamen, frontal cortex, and hippocampus. The resulting change in expression is assayed by autoradiography using [3H] raclopride (D2) and, in the presence of excess unlabelled raclopride, [3H] emonapride (D4). Gliosis is assessed with autoradiography using PKlI195. Behavioural measures will include: stereotypy, activity, and catalepsy measured with and without dopaminergic stimulation. Results: We have established that the D2-1ike receptors are reliably overexpressed in vitro as shown by [3H] spiperone and [3H] raclopride binding assays. The /Lgalactosidase marker gene is consistently expressed in vivo using our adenovirus. We will present the results of the autoradiography and behavioural experiments described above. Conclusion. Using a recombinantly engineered, replicationdeficient adenovirus to induce overexpression of dopamine receptors in vitro is a feasible technique which can now be applied for in vivo gene transfer by stereotactic microinjection to modify dopamine receptor expression in experimental animals. These experiments may provide greater understanding of the function of dopamine receptors in normal neurophysiology, schizophrenia, and as a therapeutic target.
THE COCHRANE SCHIZOPHRENIA GROUP: PRODUCING, MAINTAINING AND DISSEMINATING REVIEWS OF CARE C.E. A d a m s (Co-ordinating Editor, C o c h r a n e Schizophrenia G r o u p ) Cochrane Schizophrenia Group, Summertown Pavilion, Middle Way, OxJord OX2 7LG, UK The Cochrane Schizophrenia Group, established in the Winter Workshop of 1994, now maintains the world's largest Register of randomised trials (published and unpublished) relevant to the care of those with schizophrenia. This has been constructed from meticulous searching of commercial and noncommercial databases, hand searching of relevant journals (1948-present) and scanning of conference proceedings (50% of trials in conference proceedings fail to be fully written up). This register is the basis of the systematic reviews that are being produced, and maintained, within the Cochrane Library (electronic publication for details please see http://archie.cochrane.co.uk/info/). Reviewers, from many different countries and disciplines, are trained, produce a protocol and then a review. Every three months, after lay input (to ensure that all information is accessible), these reviews and protocols are published in the Cochrane Library. Abstracts are available on the internet (http://archie.cochrane.co.uk/info/ abstracts/abidx.hmtm#G06@). Quantitative reviews on new antipsychotics, other well established drugs, ECT, and community care policies are now available. The work of the Cochrane Schizophrenia Group will be described and demonstrated.
A COMPARISON BETWEEN SCHIZOPHRENIA AND TEMPORAL LOBE EPILEPSY: A PROTON MAGNETIC RESONANCE SPECTROSCOPY STUDY M. Maier 1, M.A. R o n 2, J. Mellers 3, B. Toone 3, M. Trimble 2 1Imperial College o[ Science, Technology and Medicine, Charing Cross Hospital London," 21nstitute of Neurology, Queen Square, London; 3The Royal Bethlem & MaudshLv Hospital, London, UK Schizophrenia is characterised by diffuse cortical volume reduction, ventricular enlargement together with temporal lobe pathology, especially on the left side. Temporal lobe pathology is also a cardinal feature of temporal lobe epilepsy (TLE). Previously we found that there is a significant reduction in N acetyl aspartate (NAA) in the left hippocampi of schizophrenics thought to reflect neuronal loss as part of a neurodevelopmental process. We have now used MR imaging and spectroscopy to study two groups of patients with TLE; one group of 12 patients had a schizophreniform psychosis as a result of their TLE and the second group of 12 patients did not. The groups were matched for age, gender and side of epileptic focus. The schizophrenic group showed a significant reduction of NAA in
contrast, extracellular 5HIAA levels were increased by ketamine administration in both drug naive and were further enhanced in ketamine pre-treated animals but without a change in basal 5HIAA levels while GABA levels were unaffected by either single or repeated ketamine. These findings provide new evidence for a differential effect of single and repeated ketamine on mPFC dopamine, serotonin and GABA transmission and suggest a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of elevated basal dopamine levels, the ketamine induced increase in dopamine is attenuated and the increase in 5HIAA is enhanced. Thus, ketamine pretreatment appears to reduce the dynamics of mPFC dopaminergic transmission thereby altering the balance between dopamine and serotonin transmission.
IN VIVO DOPAMINE RECEPTOR GENE
TRANSFER USING AN ADENOVIRAL VECTOR A.H,C. Wong, M. Knapp, H . H . M . Van Tol Clarke Institute of Psychiatry, 250 College Street, Toronto, ON, M5T 1R8, Canada Objective: The aim of this project is to develop an animal model of altered dopamine (DA) receptor expression to study the mechanism of neuroleptic drug action, and the neurophysiology of psychotic symptoms in illnesses such as schizophrenia. Method." Recombinant El deleted, Ad5 vectors containing DA D2 and D4 receptor genes were constructed. DA receptor expression mediated by these vectors has been assessed in vitro in established and primary cell cultures. The modification of DA receptor expression in vivo, is accomplished through stereotactic microinjection of our adenoviral vectors into selected areas of Sprague-Dawley rat brains including: caudateputamen, frontal cortex, and hippocampus. The resulting change in expression is assayed by autoradiography using [3H] raclopride (D2) and, in the presence of excess unlabelled raclopride, [3H] emonapride (D4). Gliosis is assessed with autoradiography using PKlI195. Behavioural measures will include: stereotypy, activity, and catalepsy measured with and without dopaminergic stimulation. Results: We have established that the D2-1ike receptors are reliably overexpressed in vitro as shown by [3H] spiperone and [3H] raclopride binding assays. The /Lgalactosidase marker gene is consistently expressed in vivo using our adenovirus. We will present the results of the autoradiography and behavioural experiments described above. Conclusion. Using a recombinantly engineered, replicationdeficient adenovirus to induce overexpression of dopamine receptors in vitro is a feasible technique which can now be applied for in vivo gene transfer by stereotactic microinjection to modify dopamine receptor expression in experimental animals. These experiments may provide greater understanding of the function of dopamine receptors in normal neurophysiology, schizophrenia, and as a therapeutic target.
THE COCHRANE SCHIZOPHRENIA GROUP: PRODUCING, MAINTAINING AND DISSEMINATING REVIEWS OF CARE C.E. A d a m s (Co-ordinating Editor, C o c h r a n e Schizophrenia G r o u p ) Cochrane Schizophrenia Group, Summertown Pavilion, Middle Way, OxJord OX2 7LG, UK The Cochrane Schizophrenia Group, established in the Winter Workshop of 1994, now maintains the world's largest Register of randomised trials (published and unpublished) relevant to the care of those with schizophrenia. This has been constructed from meticulous searching of commercial and noncommercial databases, hand searching of relevant journals (1948-present) and scanning of conference proceedings (50% of trials in conference proceedings fail to be fully written up). This register is the basis of the systematic reviews that are being produced, and maintained, within the Cochrane Library (electronic publication for details please see http://archie.cochrane.co.uk/info/). Reviewers, from many different countries and disciplines, are trained, produce a protocol and then a review. Every three months, after lay input (to ensure that all information is accessible), these reviews and protocols are published in the Cochrane Library. Abstracts are available on the internet (http://archie.cochrane.co.uk/info/ abstracts/abidx.hmtm#G06@). Quantitative reviews on new antipsychotics, other well established drugs, ECT, and community care policies are now available. The work of the Cochrane Schizophrenia Group will be described and demonstrated.
A COMPARISON BETWEEN SCHIZOPHRENIA AND TEMPORAL LOBE EPILEPSY: A PROTON MAGNETIC RESONANCE SPECTROSCOPY STUDY M. Maier 1, M.A. R o n 2, J. Mellers 3, B. Toone 3, M. Trimble 2 1Imperial College o[ Science, Technology and Medicine, Charing Cross Hospital London," 21nstitute of Neurology, Queen Square, London; 3The Royal Bethlem & MaudshLv Hospital, London, UK Schizophrenia is characterised by diffuse cortical volume reduction, ventricular enlargement together with temporal lobe pathology, especially on the left side. Temporal lobe pathology is also a cardinal feature of temporal lobe epilepsy (TLE). Previously we found that there is a significant reduction in N acetyl aspartate (NAA) in the left hippocampi of schizophrenics thought to reflect neuronal loss as part of a neurodevelopmental process. We have now used MR imaging and spectroscopy to study two groups of patients with TLE; one group of 12 patients had a schizophreniform psychosis as a result of their TLE and the second group of 12 patients did not. The groups were matched for age, gender and side of epileptic focus. The schizophrenic group showed a significant reduction of NAA in