Elisa Guma1, Jill Rocchetti2, Gabriel A Devenyi3, Arnaud Tanti4, Axel Mathieu3, Jason P Lerch5, Guillaume Elgbeili2, Blandine Courcot3, Naguib Mechawar4, M Mallar Chakravarty6, Bruno Giros7. 1. Department of Psychiatry & Integrated Program in Neuroscience, McGill University, 845 Sherbrooke St W, Montreal, QC, H3A 0G4 Canada; Cerebral Imaging Center, Douglas Mental Health University Institute, Verdun, Quebec, H4H 1R3, Canada. 2. Department of Psychiatry & Integrated Program in Neuroscience, McGill University, 845 Sherbrooke St W, Montreal, QC, H3A 0G4 Canada. 3. Cerebral Imaging Center, Douglas Mental Health University Institute, Verdun, Quebec, H4H 1R3, Canada. 4. McGill Group for Suicide Studies, Department of Psychiatry, McGill University, Douglas Mental Health University Institute, Montreal, QC, Canada. 5. Mouse Imaging Center - Hospital for Sick Children, Department of Medical Biophysics -University of Toronto, Toronto, Ontario, M5T 3H7, Canada. 6. Department of Psychiatry & Integrated Program in Neuroscience, McGill University, 845 Sherbrooke St W, Montreal, QC, H3A 0G4 Canada; Cerebral Imaging Center, Douglas Mental Health University Institute, Verdun, Quebec, H4H 1R3, Canada; Department of Biological and Biomedical Engineering, McGill University, 845 Sherbrooke St W, Montreal, QC, H3A 0G4, Canada. 7. Department of Psychiatry & Integrated Program in Neuroscience, McGill University, 845 Sherbrooke St W, Montreal, QC, H3A 0G4 Canada; Sorbonne University, Neuroscience Paris Seine, CNRS UMR 8246, INSERM U 1130, UPMC Univ Paris 06, UM119, 75005, Paris, France. Electronic address: bruno.giros@mcgill.ca.
Abstract
BACKGROUND: Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2-like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2-like receptors has yet to be explored. METHODS: We undertook a preclinical longitudinal study to examine the effects of typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs in wild type (WT) and dopamine D2 knockout (D2KO) mice over 9-weeks using structural magnetic resonance imaging (MRI). RESULTS: Chronic typical APD administration in WT mice was associated with reductions in total brain (p = 0.009) and prelimbic area (PL) (p = 0.02) volumes following 9-weeks, and an increase in striatal volume (p = 0.04) after six weeks. These APD-induced changes were not present in D2KOs, where, at baseline, we observed significantly smaller overall brain volume (p < 0.01), thinner cortices (q < 0.05), and enlarged striata (q < 0.05). Stereological assessment revealed increased glial density in PL area of HAL treated wild types. Interestingly, in WT and D2KO mice, chronic CLZ administration caused more limited changes in brain structure. CONCLUSIONS: Our results present evidence for the role of D2 DA receptors in structural alterations induced by the administration of the typical APD HAL and that chronic administration of CLZ has a limited influence on brain structure.
BACKGROUND: Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2-like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2-like receptors has yet to be explored. METHODS: We undertook a preclinical longitudinal study to examine the effects of typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs in wild type (WT) and dopamine D2 knockout (D2KO) mice over 9-weeks using structural magnetic resonance imaging (MRI). RESULTS: Chronic typical APD administration in WT mice was associated with reductions in total brain (p = 0.009) and prelimbic area (PL) (p = 0.02) volumes following 9-weeks, and an increase in striatal volume (p = 0.04) after six weeks. These APD-induced changes were not present in D2KOs, where, at baseline, we observed significantly smaller overall brain volume (p < 0.01), thinner cortices (q < 0.05), and enlarged striata (q < 0.05). Stereological assessment revealed increased glial density in PL area of HAL treated wild types. Interestingly, in WT and D2KO mice, chronic CLZ administration caused more limited changes in brain structure. CONCLUSIONS: Our results present evidence for the role of D2 DA receptors in structural alterations induced by the administration of the typical APD HAL and that chronic administration of CLZ has a limited influence on brain structure.
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