Long-term treatment with haloperidol modulates angiotensin I-converting enzyme (ACE) activity in transgenic animal model with construct validity for schizophrenia studies

Elevated angiotensin I-converting enzyme (ACE) activity has been correlated with worse cognitive performance in patients with first-episode psychosis (FEP) and chronic schizophrenia (SZ). In this study, we investigated ACE activity in drug-naïve transgenic rats overexpressing the full-length non-mutated human Disrupted-in-Schizophrenia 1 (tgDISC1) compared to wild-type (WT) controls, while we also assessed the effects of long-term treatment with typical antipsychotic haloperidol. Our findings indicated that untreated tgDISC1 rats show elevated serum ACE activity compared to WT animals, which is consistent with clinical observations in drug-naïve FEP patients. In contrast, baseline ACE activity in the brain of tgDISC1 was generally lower than in WT rats, with the exception of no difference in ACE activity observed in brain regions associated with learning, memory, and reward, such as the hippocampus and nucleus accumbens. Consistent with clinical observations in FEP patients following treatment with antipsychotics, 30-days of daily haloperidol-treatment significantly increased serum ACE activity in blood serum of both tgDISC1 and WT rats. However, ACE responses in brain were markedly different, as haloperidol treatment reduced ACE activity in most brain regions of both rat strains. These results support the existence of a central renin-angiotensin system (RAS) distinct from the peripheral RAS, suggesting that the treatment with a dopamine blocker exerts brain-specific effects on ACE activity, which was essentially opposite to that observed in the periphery. This region-specific alterations observed in cognition-related brain areas (notably with a relative stronger effect size in hippocampus and nucleus accumbens of tgDISC1 compared to WT rats) also suggest a critical interplay among dopamine homeostasis, ACE activity, and cognitive deficits in SZ. Understanding this interplay could help identifying novel biomarkers and/or therapeutic strategies for improving cognitive outcomes in SZ patients.