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Schizophrenia 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.
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. Download PDF Introduction Over six decades following antipsychotic drug discovery, efforts continue to better understand the mechanisms of action of antipsychotic drugs APD. Clinical efficacy in the reduction of psychotic symptoms, such as hallucinations, delusions, and disorganized thought, as well as motor side effects have been associated with blockade of D2-like dopamine receptors.
The D3 receptor 1 , 2 , also a D2-like receptor, has both pre- and post-synaptic localization in regions consistently associated with alteration in schizophrenia, such as the limbic cortex, Islands of Calleja, striatum, prefrontal cortex, striatum, and hippocampus 3 , 4 , 5 , 6 , 7. Further, the D3 receptors are involved in cognitive, social, and motor functions 3 , many of which are impaired in individuals with schizophrenia.
Their preferential blockade with D3 receptor antagonist, S, has been associated with pro-cognitive effects in rats 4.
The D3 dopamine receptors are attractive targets for therapeutic intervention in neuropsychiatric disorders in which the dopamine system is dysregulated, such as schizophrenia; this is due to their influence on dopamine release and function, location, and positive effects on cognition 5. It is well established that APDs affect neurochemistry, however there is indication that they induce structural and circuit remodeling.
Longitudinal magnetic resonance imaging MRI studies on the neuroanatomy of individuals with schizophrenia suggest that chronic typical APD treatment - like haloperidol HAL - reduces gray matter volume and thickness of the frontal cortices 6 , 7 , 8. Striatal volume has been shown to increase following chronic typical APD treatment, but to decrease when patients are switched from typical APDs to clozapine CLZ , an atypical drug used for treatment resistant patients 9.
This may be due to differences in receptor binding and specificity Importantly, many of these APD effects are confounded by illness severity, duration, and chronicity, as well as the use of multiple medications in treatment. Further, alterations in these regions may exist prior to APD administration as many of these regions are known to be altered in drug naive schizophrenia patients 8 , 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 Furthermore, alterations in shape of the hippocampus have also been reported following chronic HAL or olanzapine treatment Many of these studies were performed at lower image resolution, which may limit the ability to detect more subtle changes.
Furthermore, the role of the D3 receptor in mediating volume changes has never been investigated in previous work. 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 However, little is known about the role of the D3 dopamine receptor.
As in our previous study, HAL was chosen as it is the most commonly used typical APD, and has been shown to induce structural changes in both clinical and preclinical studies. CLZ was chosen as it is an atypical drug used for treatment resistant patients; it can have severe metabolic side effects, however its effects on brain structure remain unclear. We have chosen to focus our baseline analyses or regions in which the D3 receptor is highly expressed that could be resolved through our atlas-based segmentation and in which we later conducted our longitudinal analyses, such as the striatum, nucleus accumbens, globus pallidus, prelimbic area, hippocampus, and hypothalamus 19 , We focused our longitudinal analyses on total brain volume TBV , anterior cingulate cortex ACC; prelimbic [PL] area specifically , striatum STR , and hippocampus HP following chronic APD administration as these regions have been consistently associated with structural remodeling in both clinical and preclinical studies 6 , 12 , Furthermore, these areas are implicated in the pathology of schizophrenia, and do receive dopaminergic innervation.
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. Figure 1 Brain volume differences due to D3 dopamine receptor knockdown. 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.
Total brain volume Analysis of TBV over 9 weeks of treatment revealed no statistically significant differences due to either genotype or treatment Fig. All graphs represent percent volume change over time per group. These results confirm observations made in the full model.
Zoom in of prelimbic area of the anterior cingulate cortex to show differences between glial and neuronal cells.
Zoom in of STR to show differences between glial and neuronal cells. Discussion The D3 dopamine receptor is highly expressed in the limbic system, and is of particular interest as a potential mediator of aberrant dopaminergic neurotransmission. It plays a critical role in cellular and synaptic plasticity throughout brain development.
Although the D2 dopamine receptor is more highly expressed in the brain, and is the main target of APDs, careful investigation of APD affinity through PET imaging demonstrates that both D2 and D3 receptor binding is necessary for reaching therapeutic effects Although D3 receptor function is important, its role in modulating brain morphology in development as well as due to chronic blockade via APD treatment had not been investigated.
The availability of transgenic dopamine D3KO mice allow us to study interactions between the receptor and brain anatomy. This is the first study to investigate neuroanatomical alterations due to deletion of the D3 receptor, and how this deletion interacts with chronic APD treatment.
Firstly, we observed an increase of striatal volume in D3KO mice, independent of total brain volume changes. The striatum is a region in which the D3 receptor would typically be expressed, thus it is possible that in its absence disrupts certain developmental processes, creating an increase in cell proliferation or density. However, the limited structural alterations we observe in D3KO mice may be due to the relatively sparse and heterogeneous expression of the receptor throughout the brain 19 , Striatal volume increase was accompanied by an overall increase in glial and neuronal cell density in all three treatment groups.
The fact that we do not observe a similar effect in this study suggests that D3 receptor removal prevents APDs from altering glial density. This is of interest since D3 receptors are more densely expressed in glia than neurons, suggesting that the D3 receptor may play a critical role in modulating APD effects on glial cells Typical APD treatment has consistently been shown to increase striatal volume in both clinical and preclinical literature, using both MRI and post-mortem investigations 7 , 9 , 12 , Thus, it is unsurprising that HAL treatment increased striatal volume in WT mice; the increase observed in D3KO mice is of interest, suggesting that the D3 dopamine receptor is not necessary for this structural remodeling.
These changes may therefore be more D2 receptor dependent, as in our previous study, we did observe trending striatal volume increases following chronic HAL treatment in WT, but not D2KO mice.
These volumetric findings were not backed up by histological findings, however these volume differences might be more subtle than the bulk increases in glial and neuronal cell density due to D3 receptor knock down. Previous work from both rodent and non-human primate studies has shown that chronic HAL and olanzapine treatment actually increases PL area glial cell density both astrocytes and microglia , coupled with decreases in volume 12 , 21 , Therefore, these studies suggest that the volume decreases observed may be due to a loss of dendritic arborization, and not necessarily a loss in cell number.
We also do not observe HAL induced changes to neuronal or glial cell density in the PL, which is surprising given that in our previous study HAL did increase glial cell density in WT mice mice only It is possible that if we investigated astrocyte- and microglia- cell density separately we would have seen similar effects. We were surprised to observe a decrease in PL area volume due to HAL treatment only in the D3KO mice, as both clinical and preclinical studies have shown that chronic typical APD treatment reduces frontal cortex volume 6 , It is important to consider this study in light of some limitations.
We observe interesting effects, however many are at a subthreshold level, possibly due to our modest sample size of 6 mice of mixed sex per group.
Furthermore, the mice were fairly old at the start of treatment and the ages were not perfectly matched between groups range from 20—28 weeks. Therefore, it is possible that APD treatment may have affected mice differently based on their age, even though all mice were adults, and fully developed at the time of treatment initiation. In future work, it would be important to determine whether an inducible D3KO mouse model occurring in adulthood , would result in a similar response to chronic APD administration, to rule out any compensatory mechanisms.
We do observe subtle volume changes at baseline in the D3KO mice, so it is possible that certain neurodevelopmental compensations are occurring, however previous work has shown that these mice do develop normally, achieve fertility, and have only subtle behavioural alterations in comparison to their WT littermates, such as transient locomotor hyperactivity in a novel environment 28 , Additionally, as discussed in our previous paper 18 , daily intraperitoneal injections may have affected D2-like receptor occupancy, and stress levels differently than a constant infusion via osmotic minipumps would have.
However, the majority of our results are consistent with those observed in other clinical and preclinical findings investigating interactions between chronic APD treatment and brain anatomy.
PET studies in humans observed that high levels of D2 occupancy are reach shortly after drug administration, but that levels drop after 12 hours of injection Conversely, when similar doses were administered via osmotic minipump D2 receptor occupancies were stable throughout the day, but perhaps lower than clinically therapeutic levels It is possible that given the stability of D2 occupancy achieve via osmotic minipump use, this method is more clinically comparable, however it is unclear whether constant D2-receptor blockade is necessary for clinical occupancy.
In fact, Remington and Kapur suggest that more intermittent blockade could be beneficial Finally, although HAL is the most classically used typical APD, and CLZ is of interest for treatment resistant individuals, it would have been interesting to investigate an APD that targets D2 and D3 receptors more specifically, such as amisulpride Obviously the D3 dopamine receptor is not the main target of APDs, although it is part of the D2-like family.
This has been investigated to some degree in human studies. Girgis and colleagues found that the risperidone, an atypical APD, does bind to the D3 receptor in regions like the substantia nigra and the ventral tegmental area Conversely, Mizrahi and colleagues found that patients treated with atypical APDs did not seem to have D3 receptor occupancy due to treatment, however they did have an upregulation of D3 receptor following short-term treatment In future work it would be interesting to investigate how the degree of D3 receptor binding of different drugs affects brain morphology.
Additionally, an investigation of other regions expressing the D3 receptors would be of interest. We did not observe baseline differences in a D3 rich region like the nucleus accumbens, however it is possible that histological investigation would show more subtle alterations. Furthermore, chronic clozapine, but not haloperidol treatment in rats was shown to increase c-fos mRNA in both the prelimbic and infralimbic cortices In future work, it would also be interesting to investigate volume changes at the voxel-level; this was not performed in the current study, as we were not sufficiently powered with modest group sizes and many treatment-genotype subgroups of mixed sex.
A similar study with larger groups of male and female mice would allow for thorough investigation of sex differences; this would be appropriate and of interest given known sex differences in symptomatology in schizophrenia, and in response to APD treatment. Furthermore, a thorough comparison of treatment with continuous drug infusion using osmotic mini-pumps or daily single injections would further our understanding of the relationship between brain volume changes and consistent vs.
In conclusion, we present evidence for the role of the D3 dopamine receptor in modulating plasticity of the striatum, both at the volume and cellular level. The D3 receptor may offer new therapeutic targets for drug treatments, therefore a better understanding of how APDs interact with the D3 dopamine receptor is important for furthering our understanding of how APD treatment affects the brain.
Upon sexing and weaning, tail snips were collected from each mouse and used for genotyping to assess the presence of the Drd3 gene homozygotes, heterozygotes, or wild-type using polymerase chain reaction PCR. Drugs were administered daily via intraperitoneal i. Following the last scan, brains were fixed by paraformaldehyde PFA via intracardiac perfusion, and were extracted for histological assessment of neuronal and glial cell populations details in Sections 2.
Every 3 days, an aliquot was diluted in NaCl 0. A Bruker — mm circularly polarized resonator and mouse head surface coil were used as transmit and receive antennas, respectively. Eight RF phase angles were used , 0, 90, , 45, , , and degrees to remove banding artifacts.
Body temperature was maintained by blowing warm air on the animal 40 minute scan timel. Final images used for analysis were root mean square RMS averages of the 8 acquisitions. This atlas does not label subregions of the frontal cortex, so we also performed the segmentation using the Dorr-Steadman-Ullman DSU atlas labeled regions to obtain volume of the anterior cingulate cortex sub-region, the prelimbic area PL , as it was one of our ROIs 46 ,
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