Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration

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.

Figure 1

Brain volume differences due to D3 dopamine receptor knockdown. (A) Total brain volume was no different between WT and D3KO mice. (B) D3KO mice had significantly larger striatal volume following Bonferroni correction (p = 0.0005***). Volume differences are displayed in box plots where the midline represents the median, the box represents the first and third quartiles, and the vertical lines represent the end range of the data.

Figure 2

Differences between WT and D3KO mice in response to 9 weeks of APD treatment. All graphs represent percent volume change over time per group. Curves for treatment group represented as follows: saline (SAL in red), haloperidol (HAL in blue) and clozapine (CLZ in green) for D3KO mice and WT littermates. (A) Total brain volume was not significantly affected by either HAL and CLZ relative to SAL in either WT or D3KO mice. (B) Prelimbic area volume was significantly increased in WT mice for CLZ treated relative to SAL mice (t = −2.335, p = 0.021; green asterix). Volume was reduced in D3KO mice at a trend level at 3 weeks (t = −2.098, p = 0.038) and significant at 6 weeks of treatment relative to SAL (this was not observed in WT mice; t = −2.544, p = 0.012, blue asterix). (C) HAL increased striatal volume in WT and D3KO mice relative to SAL (t = 2.623, p = 0.010; blue asterix). CLZ increased STR volume in WT mice relative to SAL (t = −2.004, p = 0.048; green asterix). (D) Hippocampal volume changes were not differentially affected by HAL or CLZ relative to SAL for either WT or D3KO mice. All significant three way interactions were decomposed by testing WT and D3KO mice separately, and Bonferroni corrected (corrected p < 0.025).

Figure 3

Chronic typical and atypical APD treatment differentially affects neuronal and glial cell density in the prelimbic area and striatum of WT and D3KO mice. (A) Representative Nissl stained coronal section at AP = + 1.98 from bregma taken from a WT-SAL treated mouse (Figure 14 from page 40 of the Franklin & Paxinos Mouse Brain Atlas 3rd edition). Zoom in of prelimbic area of the anterior cingulate cortex to show differences between glial and neuronal cells. Glial and neuronal cell density of PL for each treatment group saline (SAL in red), haloperidol (HAL in blue) and clozapine (CLZ in green) for D3KO mice and WT littermates. (B) Glial cell density is significantly greater following HAL compared to CLZ treatment in D3KO mice (+18%, p = 0.048). (C) D3KO mice tend to have higher neuronal density following either SAL or HAL treatment (p = 0.09). (D) Representative Nissl stained coronal section at AP = +0.38 from bregman taken from a WT-SAL treated mouse (Figure 28 from page 55 of the Franklin & Paxinos Mouse Brain Atlas 3rd edition). Zoom in of STR to show differences between glial and neuronal cells. (E) D3KO mice had significantly greater glial cell density (+20.3%; p < 0.00001). (F) D3KO mice had significantly greater neuronal cell density (+12.5%; p < 0.007).