Abstract
Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic [PL] area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.
Highlights
Over six decades following antipsychotic drug discovery, efforts continue to better understand the mechanisms of action of antipsychotic drugs (APD)
In a previous study from our group, we investigated the role of the D2 dopamine receptor in modulating APD induced brain volume changes by chronically treating D2 knockout (D2KO) mice and WT littermates with typical and atypical APDs, and found that the D2 receptor played a critical role[18]
We undertook a longitudinal magnetic resonance imaging (MRI) study with post-mortem histology to investigate the effects of chronic exposure to HALor CLZ on both wild-type and D3 knockout (D3KO) mice in order to characterize the role of the D3 dopamine receptor in brain remodeling induced by chronic APD treatment
Summary
Over six decades following antipsychotic drug discovery, efforts continue to better understand the mechanisms of action of antipsychotic drugs (APD). Rodent models offer an effective way to investigate the impact of APD administration on brain structure, affording precise control over drug exposure, without confounds of illness severity, duration, and other drugs Both longitudinal and cross-sectional preclinical studies investigating chronic haloperidol or olanzapine (an atypical APD) exposure in both rodents and non-human primates have observed decreased total brain, frontal and parietal cortical volume, and increased striatal volume[12,13,14,15,16] alterations in shape of the hippocampus have been reported following chronic HAL or olanzapine treatment[17]. A better understanding of how the dopaminergic system influences structural brain remodeling due to APD administration would aid in the understanding of APD action on the brain, and in the refinement of treatments for schizophrenia
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