Extrastriatal Dopamine D2/3 Receptors in Schizophrenia

Several lines of studies on schizophrenia have suggested abnormalities in dopaminergic neurotransmission and dopamine receptor densities. The aim of this study was to evaluate putative alterations of the dopamine D2/3 receptor density in extrastriatal brain regions among drug‐naïve schizophrenic patients compared to healthy subjects, to compare drug‐ induced extrastriatal dopamine D2/3 receptor binding between different antipsychotic agents, as well as to investigate the relationship between extrapyramidal side‐effects and dopamine D2/3 binding. The densities of D2/3 receptors were studied in seven antipsychotic‐naïve patients with schizophrenia and seven healthy controls using single‐photon emission computed tomography (SPECT) ligand [123I]epidepride. The results indicated significantly reduced dopamine D2/3 receptor density in the temporal cortex and substantia nigra among patients compared with healthy subjects. Dopamine D2/3 receptor density correlated inversely with general psychopathological schizophrenic symptoms in the temporal cortex and thalamus. To determine dopamine D2/3 apparent binding potential and occupancy, [123I]epidepride SPECT imaging was performed on 13 schizophrenia patients treated with medication (seven with clozapine, four with olanzapine and two with haloperidol), six drug‐ naïve patients and seven healthy controls. The results suggested divergent dopamine D2/3 apparent binding potential and occupancy by different antipsychotics in substantia nigra, showing the lowest D2/3 binding indices for clozapine, followed by olanzapine, when compared to haloperidol. Extrapyramidal symptoms were also found to correlate negatively with antipsychotic‐induced D2/3 binding in substantia nigra among medicated patients. In the temporal cortex, D2/3 binding did not differ significantly between typical and second‐ generation antipsychotics. These imaging findings in extrastriatal D2/3 receptor density support the hypothesis on the dysfunction of mesocortical dopamine transmission underlying cognitive symptoms in schizophrenia, as well as emphasizing the role of thalamo‐cortical dopaminergic function in the pathophysiology. The observed decrease of D2 autoreceptors in the substantia nigra contributes to the dysregulation of dopamine neurotransmission in the striatum of schizophrenic patients. Furthermore, results from studies with medicated patients provide clues concerning the differences in clinical profile and therapeutic efficacy, as well as the side‐effects between different antipsychotic drugs. 1997‐2011. I want to express my warm gratitude to all patients participated in this study. I owe my deepest and sincere gratitude my supervisors, Professor Jari Tiihonen, Professor Heimo Viinamäki and Professor Jyrki T. Kuikka. Professor Jari Tiihonen introduced me to the world of neuroimaging in psychiatry. His excellent professional expertise and scientific guidance were invaluable during all phases of my thesis. Professor Heimo Viinamäki provided valuable advice on composing scientific articles. Without his …