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.

Striatal Volume Increase After Six Weeks of Selective Dopamine D2/3 Receptor Blockade in First-Episode, Antipsychotic-Naïve Schizophrenia Patients

“…Notably, when chronically exposed to the same antipsychotics as wild-type mice, no additional basal ganglia volume increases were found. Taken together, these data strongly support that volume increases following antipsychotic exposure are mediated via the dopamine D 2 -like receptor (Guma et al, 2018(Guma et al, , 2019, rather than depending on the drug-class ('typical' vs. 'atypical' antipsychotic).…”

“…Both drugs, however, have low affinity toward dopamine D 2 -like receptors, whereas typical antipsychotics have high affinities (Creese et al, 1976;Kusumi et al, 2015;Jorgensen et al, 2016). Dopamine D 2 -like receptor knock-out mice also show striatal volume increases, mirroring the effects of chronic exposure (9 weeks) to different APDs (Guma et al, 2018(Guma et al, , 2019. Notably, when chronically exposed to the same antipsychotics as wild-type mice, no additional basal ganglia volume increases were found.…”

“…Nevertheless, longitudinal studies on antipsychotic-naïve patients as well as meta-analyses studies have reported associations between antipsychotic exposure and volumetric increase in basal ganglia (Glenthoj et al, 2007;Ebdrup et al, 2013;Jorgensen et al, 2016;Huhtaniska et al, 2017;Di Sero et al, 2019). Studies on rodents have replicated the basal ganglia volume increase in response to antipsychotic treatment (Vernon et al, 2012), and investigations in dopamine D 2 or D 3 receptor knock-out-and wild-type mice provide evidence that this increase is likely to be mediated through D 2 -like receptors (Guma et al, 2018(Guma et al, , 2019.…”

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…shows the effect of a preferential D3 partial agonist Cariprazine on gamma oscillations in hippocampal slides further supporting the general assumption that gamma waves could predict psychosis and in vitro NMDA hypofunction, and that D3 functional reduction can stabilize the alterations of the signal caused by NMDA hypofunction ( Meier et al., 2020 ). Treatment response to antipsychotics may be predicted looking at the effect on hippocampal- cortical connections and again these changes could be in part D3 related ( Guma et al., 2019 ; Blessing et al., 2020 ). The observed hippocampal alterations in some SCZ patients (psychotic) also support the presence of hippocampal immaturity at least in a subgroup of SCZ patients ( Alvarez et al., 2020 ; Cachia et al., 2020 ).…”

Dual-acting agents for improving cognition and real-world function in Alzheimer’s disease: Focus on 5-HT6 and D3 receptors as hubs

“…-in mice, rats and primates, upon single and repeated administration, in tests incorporating measures of attention, working memory, long-term memory and executive function, as well as procedural memory and conditioned learning, and in procedures monitoring social cognition, in particular social recognition (op cit); -upon direct introduction of D3 ligands into specific brain regions, principally the frontal cortex, but with potential roles for other cortical zones (like the cingulate cortex) as well as the nucleus accumbens, midbrain and hippocampus (Chang et al, 2020;Choi et al, 2010;Cole et al, 2012;Glickstein et al, 2005;Guma et al, 2019;Loiseau and Millan, 2009;Papp et al, 2019;Watson et al, 2012).…”