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Co-localization of neurotensin receptor mRNA within dopaminergic neurons
FRIDAY, MAY 20
in a rational fashion. Supported by MH008 ! 8 (JHMW) and MH4225 ! (SJW).
267. DOPAMINE RECEPTOR GENE EXPRESSION IN THE HUMAN MEDIAL TEMPORAL LOBE J. H. Meador-Woodruff ',2, S. P. Damaskl, K. Y. Little2,3, & S. J. Watson t,2 'Mental Health Research Institute and 2Department of Psychiatry, University of Michigan, Ann Arbor, MI; 3Ann Arbor Veterans Administration Medical Center, Ann Arbor, MI The medial temporal lobe contains a number of complex and interrelated structures, including the hippocampai formation and several distinct cortical areas. Several of these neuroanatomical structures have been implicated in the pathophysiology of schizophrenia. It has been assumed that the dopaminergic involvement in schizophrenia is likely in the mesocorticolimbic dopamine system, originating in the ventral tegmental area of the midbrain and projecting to a number of more rostral cortical and limbic regions. Among the recipients of this projection, a number of medial temporal lobe structures have been identified as dopaminoceptive regions of the limbic system. Because of these considerations, the par'pose of the present work was to examine the nature of dopamine receptor gene expression in the medial temporal lobe of normal human brain, by determining the concentrations of the mRNA molecules encoding each of the five dopamine receptors in the various structures in the medial temporal lobe. All five receptor mRNAs are present in temporal lobe structures, although their distributions are heterogeneous. Three general pauerns of distribution of dopamine receptor mRNA across region were observed. The first pattern was a Dl-specific distribution, which consisted of highest levels of mRNA expressed in the neocortex, with lowest levels in CA2-CA4 and in the presubiculum. The second observed pattern was a distribution unique to D2 receptor mRNA, in which all regions were noted to have similar levels of mRNA except the dentate gyms, in which higher levels were seen. The third pattern was seen for the D3, D4, and Ds receptors. This pattern consisted of relatively higher levels of expression in the dentate gyms, CA2, and the general area from the presubiculum through the entorhinal cortex. Interestingly, fi~is pattern is generally opposite the Di pattern: areas of relative abundance of I)3, D4, and Ds receptor mRNAs correspond to those areas in which D! receptor message was relatively scarce. These results provide a description of the distribution of these receptor mRNAs in normal humans, and suggest multiple levels of complexity as well as regulation of the medial temporal lobe dopamine projection. Supported by MH00818 (JHMW) and MH42251 (SJW).
268. CO-LOCALIZATION OF NEUROTENSIN RECEPTOR mRNA WITHIN DOPAMINERGIC NEURONS T. Cho, M. Yamada, Mi. Yamada, & E. Richelson Department of Psychiatry and Pharmacology, Mayo Clinic Jacksonville, Jacksonville, FL 32224 The tridecapeptide neurotensin (NT) is a putative neurotransmitter in the central nervous system. Studies with experimental animals show that NT interacts with dopaminergic neurons. Researchers propose that NT is involved in the pathophysiology of some neuropsychiatric disorders
BIOL PSYCHIATRY 689 1994;35:615-747
thought to be related to malfunction of dop .,tergic systems. The receptor for NT has been molecularly cloned from rat brain and human brain. In the'present study, we compared the distribution of NT receptor mRNA in rat midbrain to that of tyrosine hydroxylase (TH) immunoreactivity (marker for dopaminergic neurons in this region). We used "ABC" method for immunohistochemicai experiments. After immunostaining with anti-TH antibody, we examined the expression of NT receptor mRNA in the same brain sections using in situ hybridization techniques. We used an 35S-labeled antisense RNA probe (302 bp) complementary to this receptor eDNA. In both the substantia nigra and the ventral tegmental area, NT receptor mRNA was co-localized within the TH-inununoreactire (TH.IR) nenmns. These findings suggest that dopaminergic neurons in the substantia nigra and ventral tegmental area synthesize NT receptors and express them in their perikarya and, probably, after axonal transport, in the terminal regions of the nigrostriatal, mesocortical and mesolimbic dopaminergic pathways, not all of the TH.IR neurons expressed this mRNA. This suggests heterogeneity of the dopaminergic neurons in these regions of the rat midbrain. Our group previously found that two weeks of haloperidol (typical neuroleptic), but not clozapine. (atypical, without extrapyramidal side effects) increased NT receptor mRNA levels in the rat substantia nigra and ventral tegmental area. Increase of NT receptors in dopaminergic neurons of the substantia nigra and the ventral tegmental area after chronic haloperidol treatment may be involved with the pathophysiology of extrapyramidal side effects with haloperidol treatment. (Supported by Mayo Foundation and USPHS Grant MH27692).
269. THE EFFECTS OF NEUROLEPTIC DOSE ADJUSTMENT ON D2 RECEPTOR OCCUPANCY AND SCHIZOPHRENIC SYMPTOMATOLOGY, A STUDY USING IBZM SPECT T.P. Su, J. Hsiao, A.K. Malhotra, I.W. Chung, K. Hadd, J. Tuskan, R. Brenholtz, E. Wasky, L.S. Lee, J. Gorey, R. Coppola, D.R. Weinberger, & D. Pickar National Institutes of Health, National Institute of Mental Health, Experimental Therapeutics Branch, Clinical Brain Disorder Branch in vivo dopamine D2 receptor occupancy can be assessed by single photon emission computed tomography (SPECD using i 231 labelled iodobenzamide (IBZM) as a tracer. In an effort to investigate the relationship between 132 receptor occupancy and schizophrenic symptomatology, 13 patients with schizophrenia on stable (694 + 480 days) clozapine treatment had their doses reduced by 50-70% (from 510.4- 184 to 189 + 79 rag/day). Patients remained on the reduced dose for I to 4 weeks. IBZM SPECT studies were performed and clozap::.~ plasma level and behavioral measures were obtained during the sta01e and reduced dose conditions. During the reduced dose, 9 of 13 patients experienced worsening of symptoms. For the whole patient group, there were a significant decrease of clozapine plasma level (from 596 + 453 to 302 4- 261 ng/ml), and increases in schizophrenic symptoms and IBZM specific binding (decrease in D2 receptor occupancy) (p<0.01) when dose was reduced. However, patients with more severe schizophrenic symptoms had lower IBZM binding (higher D2 receptor occupancy), compared with patients with fewer symptoms.
in a rational fashion. Supported by MH008 ! 8 (JHMW) and MH4225 ! (SJW).
267. DOPAMINE RECEPTOR GENE EXPRESSION IN THE HUMAN MEDIAL TEMPORAL LOBE J. H. Meador-Woodruff ',2, S. P. Damaskl, K. Y. Little2,3, & S. J. Watson t,2 'Mental Health Research Institute and 2Department of Psychiatry, University of Michigan, Ann Arbor, MI; 3Ann Arbor Veterans Administration Medical Center, Ann Arbor, MI The medial temporal lobe contains a number of complex and interrelated structures, including the hippocampai formation and several distinct cortical areas. Several of these neuroanatomical structures have been implicated in the pathophysiology of schizophrenia. It has been assumed that the dopaminergic involvement in schizophrenia is likely in the mesocorticolimbic dopamine system, originating in the ventral tegmental area of the midbrain and projecting to a number of more rostral cortical and limbic regions. Among the recipients of this projection, a number of medial temporal lobe structures have been identified as dopaminoceptive regions of the limbic system. Because of these considerations, the par'pose of the present work was to examine the nature of dopamine receptor gene expression in the medial temporal lobe of normal human brain, by determining the concentrations of the mRNA molecules encoding each of the five dopamine receptors in the various structures in the medial temporal lobe. All five receptor mRNAs are present in temporal lobe structures, although their distributions are heterogeneous. Three general pauerns of distribution of dopamine receptor mRNA across region were observed. The first pattern was a Dl-specific distribution, which consisted of highest levels of mRNA expressed in the neocortex, with lowest levels in CA2-CA4 and in the presubiculum. The second observed pattern was a distribution unique to D2 receptor mRNA, in which all regions were noted to have similar levels of mRNA except the dentate gyms, in which higher levels were seen. The third pattern was seen for the D3, D4, and Ds receptors. This pattern consisted of relatively higher levels of expression in the dentate gyms, CA2, and the general area from the presubiculum through the entorhinal cortex. Interestingly, fi~is pattern is generally opposite the Di pattern: areas of relative abundance of I)3, D4, and Ds receptor mRNAs correspond to those areas in which D! receptor message was relatively scarce. These results provide a description of the distribution of these receptor mRNAs in normal humans, and suggest multiple levels of complexity as well as regulation of the medial temporal lobe dopamine projection. Supported by MH00818 (JHMW) and MH42251 (SJW).
268. CO-LOCALIZATION OF NEUROTENSIN RECEPTOR mRNA WITHIN DOPAMINERGIC NEURONS T. Cho, M. Yamada, Mi. Yamada, & E. Richelson Department of Psychiatry and Pharmacology, Mayo Clinic Jacksonville, Jacksonville, FL 32224 The tridecapeptide neurotensin (NT) is a putative neurotransmitter in the central nervous system. Studies with experimental animals show that NT interacts with dopaminergic neurons. Researchers propose that NT is involved in the pathophysiology of some neuropsychiatric disorders
BIOL PSYCHIATRY 689 1994;35:615-747
thought to be related to malfunction of dop .,tergic systems. The receptor for NT has been molecularly cloned from rat brain and human brain. In the'present study, we compared the distribution of NT receptor mRNA in rat midbrain to that of tyrosine hydroxylase (TH) immunoreactivity (marker for dopaminergic neurons in this region). We used "ABC" method for immunohistochemicai experiments. After immunostaining with anti-TH antibody, we examined the expression of NT receptor mRNA in the same brain sections using in situ hybridization techniques. We used an 35S-labeled antisense RNA probe (302 bp) complementary to this receptor eDNA. In both the substantia nigra and the ventral tegmental area, NT receptor mRNA was co-localized within the TH-inununoreactire (TH.IR) nenmns. These findings suggest that dopaminergic neurons in the substantia nigra and ventral tegmental area synthesize NT receptors and express them in their perikarya and, probably, after axonal transport, in the terminal regions of the nigrostriatal, mesocortical and mesolimbic dopaminergic pathways, not all of the TH.IR neurons expressed this mRNA. This suggests heterogeneity of the dopaminergic neurons in these regions of the rat midbrain. Our group previously found that two weeks of haloperidol (typical neuroleptic), but not clozapine. (atypical, without extrapyramidal side effects) increased NT receptor mRNA levels in the rat substantia nigra and ventral tegmental area. Increase of NT receptors in dopaminergic neurons of the substantia nigra and the ventral tegmental area after chronic haloperidol treatment may be involved with the pathophysiology of extrapyramidal side effects with haloperidol treatment. (Supported by Mayo Foundation and USPHS Grant MH27692).
269. THE EFFECTS OF NEUROLEPTIC DOSE ADJUSTMENT ON D2 RECEPTOR OCCUPANCY AND SCHIZOPHRENIC SYMPTOMATOLOGY, A STUDY USING IBZM SPECT T.P. Su, J. Hsiao, A.K. Malhotra, I.W. Chung, K. Hadd, J. Tuskan, R. Brenholtz, E. Wasky, L.S. Lee, J. Gorey, R. Coppola, D.R. Weinberger, & D. Pickar National Institutes of Health, National Institute of Mental Health, Experimental Therapeutics Branch, Clinical Brain Disorder Branch in vivo dopamine D2 receptor occupancy can be assessed by single photon emission computed tomography (SPECD using i 231 labelled iodobenzamide (IBZM) as a tracer. In an effort to investigate the relationship between 132 receptor occupancy and schizophrenic symptomatology, 13 patients with schizophrenia on stable (694 + 480 days) clozapine treatment had their doses reduced by 50-70% (from 510.4- 184 to 189 + 79 rag/day). Patients remained on the reduced dose for I to 4 weeks. IBZM SPECT studies were performed and clozap::.~ plasma level and behavioral measures were obtained during the sta01e and reduced dose conditions. During the reduced dose, 9 of 13 patients experienced worsening of symptoms. For the whole patient group, there were a significant decrease of clozapine plasma level (from 596 + 453 to 302 4- 261 ng/ml), and increases in schizophrenic symptoms and IBZM specific binding (decrease in D2 receptor occupancy) (p<0.01) when dose was reduced. However, patients with more severe schizophrenic symptoms had lower IBZM binding (higher D2 receptor occupancy), compared with patients with fewer symptoms.