- Email: [email protected]
Dopamine autoreceptors in the human midbrain
688
FRIDAY, MAY 20
BIOLPSYCHIATRY 1994;35:615-747
rently emphasize activation with blood flow measures. However, there is lack of data on carefully screened unmedicated patients compared to socio-demographieally balanced healthy control subjects, with reliable q~'nitative measure of resting baseline metabolism. Thus, there is still debate on whether "hypofrontality" exists under this condition, or whether there are lateralized abnormalities. We measured glucose utilization using mF-fluoro-deoxyglucose (FIX;) and positron emission tornography (PET) in 42 unmedicated patients and 42 socio-demographitally balanced healthy controls. Subjects were screened for medical conditions affecting brain metabolism and controls were also screened for psychopathology in first-degree relatives. Measures were obtained during a standard resting baseline condition (eyes open, ears unoccluded). MRIs were also obtained. ROls for anatomically co-registered PET images ineluded caudate, insula, globus pallidus, lenticular rtu¢leus, thalamus, parahippoeampal gyms, uncus, hippocampus, amygdala, mammiilary bodies, ant.crier a ~ pose~rjor ¢~ngulum (subcortical regions), midfrontal, dorsolateral prefrontal, inferior frontal, orbitofrontal, rect. ! gyms, superior temporal, midtemporal, inferotemporal, parietal, sensorimotor, occipitotemporal, and occipital (cortical regions), and anterior and posterior corpus callosum, cerebellum and midbrain. Results showed a remarkable similarity of topography when regions were averaged between the two hemisphere. Indeed, the means for patients and controls were entirely overlapping. However, a laterality index (L-R) showed higher left hemispheric metabolism in patients for the superior temporal (p<,05) and mid. temporal cortex (p<,001), and lower left than right activity in thalamus and midbrain (p<.01). Thus, patients with schizophrenia have normal to. pography of resting brain activity, with no suggestion of "hypofrontality". The laterality fndings indicate relatively higher left hemispheric activation in cortical regions and a reverse effect for subeortical regions. This pattern will be related to clinical and neuropsychological data.
264. THE DEVELOPMENTAL PLASTICITY OF THE DOPAMINE SYSTEMS IN THE RODENT BASAL GANGLIA P.A. Frohna & J.N. Joyce Departments of Psychiatry and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Neonatal 6-OHDA lesions have allowed us to study the developmental plasticity of the dopamine (DA) systems of the rodent basal ganglia. Recent studies have found pre- and postsynaptic changes in adult animals that had received intrastriatal 6OHDA lesions on postnatal day ! (PI). In the ventral mesencepbalon of these animals, we found a significant loss of tyrosine hydroxylase frH) n~qNA in the substantia nigra pars compacta (SNpc) and pars lateralis (SNpl), and a compensatory upregulation of TH mRNA levels in ventral tegmental area (VTA). In ag~ement with these findings is the presynaptic loss of DA uptake sites from the dorsal and medial caudate-putamen. Striatal DA receptor changes differ from those seen following adult 6-OHDA lesions and include a loss ofDA Di-recep. tors and no change in DA D2-receptors. Surprisingly, an increase in DIreceptor mRNA was found in striatai regions that showed a decrease of Di receptors. D2-receptor mRNA expression was unchanged in these animals. These findings suggest that DA DI, but not D2, receptors/mRNA are developmentally regulated by DA. The present experiments will determine the timecourse of the pre- and post-synaptic changes described above using quantitative receptor autoradiography and in-situ hybridization histochemistry in PI 6-Of-IDAlesioned rats at PT, PI 4, i)30, and Pgo. These timepoints should allow us to determine if there is a temporal and/ or spatial correlation between the loss of nigrostriatal DA neurones and changes in I"1-1mRNA and DI receptor/mRNA expression. These studies should allow us to better understand the role of DA afferents in the normal development of the basal ganglia DA systems.
265. REGULATION OF IMMEDIATE EARLY GENREEXPRESSION IN THE CNS BY ANTIPSYCHOTICS P. Rogue & G. Vincendon CNRS Center for Neurochemistry, 5 rue Blaise Pascal Strasbourg 67084 France Dopamfne D2 receptors regulate the expression of a specific set of immediate early genes (lEG) in the rat striatum. A single injection I.P. ofhaloperidoi (2 mg/kg) or sulpiride (100 mg/kg) produces a rapid and transient increase in c-fos, c.jun,jun B and zif268 mRNA, but has no influence on the expression of ETRi or junD (Brain Res Bull 29, 449). These inductions are specifically blocked by pretreatment with a !:)2 agonist (I mg/kg quinelorane). We have further studied the effect of clozapine and dopamine D2 receptor antagonists on IEG expression in different regions of the CNS by northern analysis and ISH. Both clozapine (20 mg/kg) and haloperidol (2 mg/kg) induce zif268, c-fos, andjunB in the nucleus accumbens. However, only haloperidol induces all of these proto-oncogenes in the striatum, whereas in the frontal cortex clozapine induces c-fos but not zif268. The effects of these compounds on the expression of CRF.B and CREM mRNAs, as well as the effects of prolonged administration, will also be presented. The significance of these specific lEG activation patterns for the mode of action of antipsychotics will be discussed.
266. DOPAMINE AUTORECEPTORS IN THE HUMAN MIDBRAIN J. H. Meador-Woodruff, S. P. Damask, & S. J. Watson Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109-0720 The most extensive dopamine projections in the brain are the nigrostriatal and the mesocorticolimbic systems. The nigrostriatal system originates in the substantia nigra (SN), and these dopaminergic cells project to dopaminoceptive cells in the basal ganglia, subserving motor functions. The mesocorticolimbic system originates from cell bodies located in the ventral tegmental area (VTA), and these cells send projections rostrally to a number of limbic structures. Regulation of these systems can occur at many levels: "short.loop" regulation is via dopaminergic autoreceptors, which are encoded by and expressed on dopamine synthesizing cells and their processes. The dopaminergic autoreceptor, when stimulated, causes a number of intracellular effects, the net result of which are decreased dopaminergic activity. To examine the nature of the midbrain dopamine autoreceptors, we undertook this study using in situ hybridization to visualize specific mRNA molecules within these dopamine-synthesizing cells groups. Serial sections of rat and human midbrain were probed for either tyrosine hydroxylase (TH) mRNA (identifying dopamine-synthesizing cells), as well as for the mRNAs encoding the various dopamine receptors. As has been previously shown, the dopamine autoreceptors appear to belong to the D2-1ike family of dopamine receptors. In both the rat and the human, the overwhelming majority of encoded autoreceptors are of the D2 subtype; D3 and D4 receptors are also encoded in these regions, but at much lower levels, in the rat, most if not all of the TH-positive cells in both the SN and the VTA express dopamine receptor mRNA. Interestingly, in the human, while nearly all cells in the SN encode autoreceptors, very few if any cells in the VTA encode them. These results suggest that the mesocorticolimbic system in the human brain does not express a significant level of dopamine autoreceptors. This finding has significant ramifications for our understanding of human dopamine physiology and of the pathophysiology of disorders of dopamine neurotransmission such as schizophrenia, as well as for our use of psychopharmacological agents
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.
FRIDAY, MAY 20
BIOLPSYCHIATRY 1994;35:615-747
rently emphasize activation with blood flow measures. However, there is lack of data on carefully screened unmedicated patients compared to socio-demographieally balanced healthy control subjects, with reliable q~'nitative measure of resting baseline metabolism. Thus, there is still debate on whether "hypofrontality" exists under this condition, or whether there are lateralized abnormalities. We measured glucose utilization using mF-fluoro-deoxyglucose (FIX;) and positron emission tornography (PET) in 42 unmedicated patients and 42 socio-demographitally balanced healthy controls. Subjects were screened for medical conditions affecting brain metabolism and controls were also screened for psychopathology in first-degree relatives. Measures were obtained during a standard resting baseline condition (eyes open, ears unoccluded). MRIs were also obtained. ROls for anatomically co-registered PET images ineluded caudate, insula, globus pallidus, lenticular rtu¢leus, thalamus, parahippoeampal gyms, uncus, hippocampus, amygdala, mammiilary bodies, ant.crier a ~ pose~rjor ¢~ngulum (subcortical regions), midfrontal, dorsolateral prefrontal, inferior frontal, orbitofrontal, rect. ! gyms, superior temporal, midtemporal, inferotemporal, parietal, sensorimotor, occipitotemporal, and occipital (cortical regions), and anterior and posterior corpus callosum, cerebellum and midbrain. Results showed a remarkable similarity of topography when regions were averaged between the two hemisphere. Indeed, the means for patients and controls were entirely overlapping. However, a laterality index (L-R) showed higher left hemispheric metabolism in patients for the superior temporal (p<,05) and mid. temporal cortex (p<,001), and lower left than right activity in thalamus and midbrain (p<.01). Thus, patients with schizophrenia have normal to. pography of resting brain activity, with no suggestion of "hypofrontality". The laterality fndings indicate relatively higher left hemispheric activation in cortical regions and a reverse effect for subeortical regions. This pattern will be related to clinical and neuropsychological data.
264. THE DEVELOPMENTAL PLASTICITY OF THE DOPAMINE SYSTEMS IN THE RODENT BASAL GANGLIA P.A. Frohna & J.N. Joyce Departments of Psychiatry and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 Neonatal 6-OHDA lesions have allowed us to study the developmental plasticity of the dopamine (DA) systems of the rodent basal ganglia. Recent studies have found pre- and postsynaptic changes in adult animals that had received intrastriatal 6OHDA lesions on postnatal day ! (PI). In the ventral mesencepbalon of these animals, we found a significant loss of tyrosine hydroxylase frH) n~qNA in the substantia nigra pars compacta (SNpc) and pars lateralis (SNpl), and a compensatory upregulation of TH mRNA levels in ventral tegmental area (VTA). In ag~ement with these findings is the presynaptic loss of DA uptake sites from the dorsal and medial caudate-putamen. Striatal DA receptor changes differ from those seen following adult 6-OHDA lesions and include a loss ofDA Di-recep. tors and no change in DA D2-receptors. Surprisingly, an increase in DIreceptor mRNA was found in striatai regions that showed a decrease of Di receptors. D2-receptor mRNA expression was unchanged in these animals. These findings suggest that DA DI, but not D2, receptors/mRNA are developmentally regulated by DA. The present experiments will determine the timecourse of the pre- and post-synaptic changes described above using quantitative receptor autoradiography and in-situ hybridization histochemistry in PI 6-Of-IDAlesioned rats at PT, PI 4, i)30, and Pgo. These timepoints should allow us to determine if there is a temporal and/ or spatial correlation between the loss of nigrostriatal DA neurones and changes in I"1-1mRNA and DI receptor/mRNA expression. These studies should allow us to better understand the role of DA afferents in the normal development of the basal ganglia DA systems.
265. REGULATION OF IMMEDIATE EARLY GENREEXPRESSION IN THE CNS BY ANTIPSYCHOTICS P. Rogue & G. Vincendon CNRS Center for Neurochemistry, 5 rue Blaise Pascal Strasbourg 67084 France Dopamfne D2 receptors regulate the expression of a specific set of immediate early genes (lEG) in the rat striatum. A single injection I.P. ofhaloperidoi (2 mg/kg) or sulpiride (100 mg/kg) produces a rapid and transient increase in c-fos, c.jun,jun B and zif268 mRNA, but has no influence on the expression of ETRi or junD (Brain Res Bull 29, 449). These inductions are specifically blocked by pretreatment with a !:)2 agonist (I mg/kg quinelorane). We have further studied the effect of clozapine and dopamine D2 receptor antagonists on IEG expression in different regions of the CNS by northern analysis and ISH. Both clozapine (20 mg/kg) and haloperidol (2 mg/kg) induce zif268, c-fos, andjunB in the nucleus accumbens. However, only haloperidol induces all of these proto-oncogenes in the striatum, whereas in the frontal cortex clozapine induces c-fos but not zif268. The effects of these compounds on the expression of CRF.B and CREM mRNAs, as well as the effects of prolonged administration, will also be presented. The significance of these specific lEG activation patterns for the mode of action of antipsychotics will be discussed.
266. DOPAMINE AUTORECEPTORS IN THE HUMAN MIDBRAIN J. H. Meador-Woodruff, S. P. Damask, & S. J. Watson Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109-0720 The most extensive dopamine projections in the brain are the nigrostriatal and the mesocorticolimbic systems. The nigrostriatal system originates in the substantia nigra (SN), and these dopaminergic cells project to dopaminoceptive cells in the basal ganglia, subserving motor functions. The mesocorticolimbic system originates from cell bodies located in the ventral tegmental area (VTA), and these cells send projections rostrally to a number of limbic structures. Regulation of these systems can occur at many levels: "short.loop" regulation is via dopaminergic autoreceptors, which are encoded by and expressed on dopamine synthesizing cells and their processes. The dopaminergic autoreceptor, when stimulated, causes a number of intracellular effects, the net result of which are decreased dopaminergic activity. To examine the nature of the midbrain dopamine autoreceptors, we undertook this study using in situ hybridization to visualize specific mRNA molecules within these dopamine-synthesizing cells groups. Serial sections of rat and human midbrain were probed for either tyrosine hydroxylase (TH) mRNA (identifying dopamine-synthesizing cells), as well as for the mRNAs encoding the various dopamine receptors. As has been previously shown, the dopamine autoreceptors appear to belong to the D2-1ike family of dopamine receptors. In both the rat and the human, the overwhelming majority of encoded autoreceptors are of the D2 subtype; D3 and D4 receptors are also encoded in these regions, but at much lower levels, in the rat, most if not all of the TH-positive cells in both the SN and the VTA express dopamine receptor mRNA. Interestingly, in the human, while nearly all cells in the SN encode autoreceptors, very few if any cells in the VTA encode them. These results suggest that the mesocorticolimbic system in the human brain does not express a significant level of dopamine autoreceptors. This finding has significant ramifications for our understanding of human dopamine physiology and of the pathophysiology of disorders of dopamine neurotransmission such as schizophrenia, as well as for our use of psychopharmacological agents
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.