- Email: [email protected]
Distribution of dopamine receptor subtypes in the post-mortem human brain
S-45 Chemical Neuroanatomy of the Human Brain; Post-Mortem Strategies
I8-44-5/ Antidepres~ant Drug-Induct;d Modulation of Serotonerglc Gene Expression KP. Lesch, A. Heils, H.I. Degen, P. Riederer, D. Bengel. Department of Psychiatry, University ofWurzburg, Wurzburg, Germany Several lines of evidence indicate that genes related to the centra 5-HT system are modulated during chronic treatment with tricyclics and SSRIs, In order to further investigate mechanisms of receptor-dependent signal transduction during psychotropic drug treatment, the regulation and expression of 5-HT receptors, their coupled G proteins and effector enzymes as well as the 5-HT transporter were studied during acute and chronic treatment with antidepressant and antibipolar drugs. The findings indicate that 5-HT receptors, their associated signal transduction components, and the 5-HT transporter are important targets for antidepressant drugs. Adaptational changes in response to long-term drug administration may occur at the level of gene expression and/or by posttranslational modification. Moreover, variant 5' -flanking regulatory sequences of serotonergic genes may respond differently to activation of the intracellular signal transduction cascades. Studies of receptor responsivity in conjunction with the assessment of G protein, effector system, and transporter expression therefore facilitates the investigation of the integrity of transmembrane and intracellular signaling in depression and related disorders and its role in the mode of action of antidepressants, Through an improved understanding of the modulation of receptor-dependent signal transduction pathways and neurotransmitter transporters in the brain, it may be possible to identify the molecular factors under!ying both the predisposition to and the pathogenesis of affective illness. Given the increasing evidence that the currently available antidepressants affect gene expression, the development of novel drugs targeting transcription factors or cis-acting elements remains an attractive prospect for the future.
I8-44-S!lntracellular Signaling System as a NewDirection in Affective Disorders Research S. Yamawaki. Departmentof Psychiatry and Neurosciences, Hiroshima
University SchoolofMedicine, Hiroshima. Japan As a neurochemical basis of affective disorders, monoamine hypothesis has been proposed since 1950's. The deficiency of serotonin (5-HT) has been suggested to be related to depressive mood and suicidal behavior from the findings that the low level of 5-HT and/or 5-hydroxyindoleacetic acid was observed in the cerebrospinal fluid of depressive patients and the postmortem brain of suicide victims, In 1980's, the 5-HT-2A receptor supersensitivity theory of depression has been proposed from the observation of the down-regulation of the receptors after repeated administration of antidepressant drugs and of the up-regulation of the receptors in postmortem brain of depressed patients, Recently this supersensitivity is under investigation in view of intracellular signaling systems such as Caz+, Another line of evidence also suggests the importance of intracellular components as targets of antidepressant drugs and mood stabilizers. Such intracellular signaling systems include GTP binding protein, phosphorylation by protein kinase C or MAP kinase, and gene expression. In this symposum, the importance of these intracellular signaling systems as a new direction in affective disorders research will be discussed,
157
in man is still fragmentary. To further explore such relationships clinical studies will ultimately be required. An important prerequisite for this analysis will be the detailed exploration of the biochemical anatomy of the human brain, Post mortem brain material is an indispensible tool in this analysis. Thus, systematic comparison of deviations in the biochemical anatomy of the brain in patient groups with neuropsychiatric disorders may give clues to pathophysiological mechanisms for these brain disorders. Since molecular components of brain monoaminergic and peptidergic signalling systems appear to be important targets for most of the currently known psychiatric agents, the exploration of the molecular anatomy of these signaling systems appears most pertinent. This symposium will present new aspects on post mortem strategies to explore molecular components related to monamine, glutamate and neuropeptide signaloling in the human brain. Histochemical, radioligand binding and in situ hybridization techniques will be presented and discussed in this symposium. The development of computerized biochemical information banks for the human brain is another important strategic aspect of this work,
I
8-45-2 1 Distribution of Dopamine Receptor SUbtypes in the Post-Mortem Human Brain
H. Hall, YL. Hurd, M. Suzuki, L. Farde, C. Halldin, G, Sedvall,
Karolinska Institutet, Dept, Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden During the 1970s two types of dopamine receptors, termed D 1 and D z, were identified. Recent studies using molecular biology techniques have revealed two Dr-like receptors (D I and D5 ) and at least three receptor subtypes in the Dz-dopamine receptor family, (D z, D 3 and D4 ) . Using autoradiography with new radioligands (eH1NNC-112, Z5 Ilepidepride and eHJPD128907) and in situ hybridization with rihoprobes we have performed detailed semiquantitative studies of the distributions of 0 I, Dz and D 3 receptors and their mRNAs in cryosectioned whole hemispheres of the post-mortem human brain. Although all receptor subtypes and their mRNA were found in the basal ganglia, they had different distributions within these regions. Both D 1 and D2 receptors and mRNAs were found in high densities throughout the basal ganglia. The D3 receptors were more densely labelling ventral striatum such as the nucleus accumbens. D z receptors were also found extra-striatally in the external pallidum, thalamic nuclei, amygdala and substantia nigra. Low densities of D z receptors were distinctly localized in neocortical layers and these differred between neocortical regions, Receptors of the 0 1 receptor family were found in high densities throughout the cerebral cortex. The 0 3 receptors had very low density in the human neocortex. Detailed quantitative and qualitative regional studies with these new, selective radioligands as well as with the riboprobes may be useful to reveal changes in dopamine receptor subtypes in different psychiatric disorders,
e
IS-45-31
Mapping and Characterizing SHT Receptors in the Human Brain
I.M, Palacios, Abstract not available at time of publication,
15-451 Chemical Neuroanatomy of the Human Brain; Post-Mortem Strategies
I
8-45-4 1 Excitatory Amino Acids in the Human Brain
M,A. Young. Abstract not available at time of publication.
I 8-45-1 I Chemical Neuroanatomy of the Human Brain, Post Mortem Strategies Goran C. Sedvall. Dept of Clinical Neuroscience. Karolinska Institute & Hospital, S-I7/ 76 Stockholm, Sweden Practically all of the currently used neuropsychopharmacological agents have been shown to bind to biochemical targets in the brain that mediate their actions. Knowledge concerning the causal relationships between such drag effects on targets and the psychodynamic effects of the drugs
8-45-5!lmaging the Gene Expression of Opioid Peptides in the Post-Mortem Human Brain Y.L. Hurd, S, Pauli, G. Sedvall. Departmentof Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
1
Opioid neuropeptides serve as the brain's natural endorphins and are critical for neural mechanisms related to analgesia, drug dependence, memory, motivation, mood, and motor behavior. Such peptides which
I8-44-5/ Antidepres~ant Drug-Induct;d Modulation of Serotonerglc Gene Expression KP. Lesch, A. Heils, H.I. Degen, P. Riederer, D. Bengel. Department of Psychiatry, University ofWurzburg, Wurzburg, Germany Several lines of evidence indicate that genes related to the centra 5-HT system are modulated during chronic treatment with tricyclics and SSRIs, In order to further investigate mechanisms of receptor-dependent signal transduction during psychotropic drug treatment, the regulation and expression of 5-HT receptors, their coupled G proteins and effector enzymes as well as the 5-HT transporter were studied during acute and chronic treatment with antidepressant and antibipolar drugs. The findings indicate that 5-HT receptors, their associated signal transduction components, and the 5-HT transporter are important targets for antidepressant drugs. Adaptational changes in response to long-term drug administration may occur at the level of gene expression and/or by posttranslational modification. Moreover, variant 5' -flanking regulatory sequences of serotonergic genes may respond differently to activation of the intracellular signal transduction cascades. Studies of receptor responsivity in conjunction with the assessment of G protein, effector system, and transporter expression therefore facilitates the investigation of the integrity of transmembrane and intracellular signaling in depression and related disorders and its role in the mode of action of antidepressants, Through an improved understanding of the modulation of receptor-dependent signal transduction pathways and neurotransmitter transporters in the brain, it may be possible to identify the molecular factors under!ying both the predisposition to and the pathogenesis of affective illness. Given the increasing evidence that the currently available antidepressants affect gene expression, the development of novel drugs targeting transcription factors or cis-acting elements remains an attractive prospect for the future.
I8-44-S!lntracellular Signaling System as a NewDirection in Affective Disorders Research S. Yamawaki. Departmentof Psychiatry and Neurosciences, Hiroshima
University SchoolofMedicine, Hiroshima. Japan As a neurochemical basis of affective disorders, monoamine hypothesis has been proposed since 1950's. The deficiency of serotonin (5-HT) has been suggested to be related to depressive mood and suicidal behavior from the findings that the low level of 5-HT and/or 5-hydroxyindoleacetic acid was observed in the cerebrospinal fluid of depressive patients and the postmortem brain of suicide victims, In 1980's, the 5-HT-2A receptor supersensitivity theory of depression has been proposed from the observation of the down-regulation of the receptors after repeated administration of antidepressant drugs and of the up-regulation of the receptors in postmortem brain of depressed patients, Recently this supersensitivity is under investigation in view of intracellular signaling systems such as Caz+, Another line of evidence also suggests the importance of intracellular components as targets of antidepressant drugs and mood stabilizers. Such intracellular signaling systems include GTP binding protein, phosphorylation by protein kinase C or MAP kinase, and gene expression. In this symposum, the importance of these intracellular signaling systems as a new direction in affective disorders research will be discussed,
157
in man is still fragmentary. To further explore such relationships clinical studies will ultimately be required. An important prerequisite for this analysis will be the detailed exploration of the biochemical anatomy of the human brain, Post mortem brain material is an indispensible tool in this analysis. Thus, systematic comparison of deviations in the biochemical anatomy of the brain in patient groups with neuropsychiatric disorders may give clues to pathophysiological mechanisms for these brain disorders. Since molecular components of brain monoaminergic and peptidergic signalling systems appear to be important targets for most of the currently known psychiatric agents, the exploration of the molecular anatomy of these signaling systems appears most pertinent. This symposium will present new aspects on post mortem strategies to explore molecular components related to monamine, glutamate and neuropeptide signaloling in the human brain. Histochemical, radioligand binding and in situ hybridization techniques will be presented and discussed in this symposium. The development of computerized biochemical information banks for the human brain is another important strategic aspect of this work,
I
8-45-2 1 Distribution of Dopamine Receptor SUbtypes in the Post-Mortem Human Brain
H. Hall, YL. Hurd, M. Suzuki, L. Farde, C. Halldin, G, Sedvall,
Karolinska Institutet, Dept, Clinical Neuroscience, Karolinska Hospital, Stockholm, Sweden During the 1970s two types of dopamine receptors, termed D 1 and D z, were identified. Recent studies using molecular biology techniques have revealed two Dr-like receptors (D I and D5 ) and at least three receptor subtypes in the Dz-dopamine receptor family, (D z, D 3 and D4 ) . Using autoradiography with new radioligands (eH1NNC-112, Z5 Ilepidepride and eHJPD128907) and in situ hybridization with rihoprobes we have performed detailed semiquantitative studies of the distributions of 0 I, Dz and D 3 receptors and their mRNAs in cryosectioned whole hemispheres of the post-mortem human brain. Although all receptor subtypes and their mRNA were found in the basal ganglia, they had different distributions within these regions. Both D 1 and D2 receptors and mRNAs were found in high densities throughout the basal ganglia. The D3 receptors were more densely labelling ventral striatum such as the nucleus accumbens. D z receptors were also found extra-striatally in the external pallidum, thalamic nuclei, amygdala and substantia nigra. Low densities of D z receptors were distinctly localized in neocortical layers and these differred between neocortical regions, Receptors of the 0 1 receptor family were found in high densities throughout the cerebral cortex. The 0 3 receptors had very low density in the human neocortex. Detailed quantitative and qualitative regional studies with these new, selective radioligands as well as with the riboprobes may be useful to reveal changes in dopamine receptor subtypes in different psychiatric disorders,
e
IS-45-31
Mapping and Characterizing SHT Receptors in the Human Brain
I.M, Palacios, Abstract not available at time of publication,
15-451 Chemical Neuroanatomy of the Human Brain; Post-Mortem Strategies
I
8-45-4 1 Excitatory Amino Acids in the Human Brain
M,A. Young. Abstract not available at time of publication.
I 8-45-1 I Chemical Neuroanatomy of the Human Brain, Post Mortem Strategies Goran C. Sedvall. Dept of Clinical Neuroscience. Karolinska Institute & Hospital, S-I7/ 76 Stockholm, Sweden Practically all of the currently used neuropsychopharmacological agents have been shown to bind to biochemical targets in the brain that mediate their actions. Knowledge concerning the causal relationships between such drag effects on targets and the psychodynamic effects of the drugs
8-45-5!lmaging the Gene Expression of Opioid Peptides in the Post-Mortem Human Brain Y.L. Hurd, S, Pauli, G. Sedvall. Departmentof Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
1
Opioid neuropeptides serve as the brain's natural endorphins and are critical for neural mechanisms related to analgesia, drug dependence, memory, motivation, mood, and motor behavior. Such peptides which