Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor

Elisa Guma, Jill Rocchetti, Gabriel A. Devenyi, Arnaud Tanti, Axel Mathieu, Jason P. Lerch, Guillaume Elgbeili, Blandine Courcot, Naguib Mechawar, M. Mallar Chakravarty, Bruno Giros

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. 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). 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. 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.