Dopaminergic and glutamatergic models of psychosis show differential sensitivity to aripiprazole and a novel experimental compound modulating D2/5-HT receptor activity.

Dopamine type 2 receptors (D2Rs) constitute the main molecular target in the pharmacotherapy of schizophrenia. However, the second and third generation of antipsychotics comprises multi-target ligands, also binding serotonin type 3 receptors (5-HT3Rs) and other receptor classes as well. Here, we examined two experimental compounds (marked compound K1697 and K1700) from the group of 1,4-di-substituted aromatic piperazines, previously described in the study of Juza et al., 2021, and compared them with the chosen reference antipsychotic, aripiprazole. Their efficacy against schizophrenia-like behavior was tested in two different models of psychosis in the rat, induced by acute administration of either amphetamine (1.5 mg/kg) or dizocilpine (0.1 mg/kg), reflecting the dopaminergic and glutamatergic hypotheses of schizophrenia. The two models exhibited broadly similar behavioral manifestations: hyperlocomotion, disrupted social behavior and impaired prepulse inhibition of the startle response. However, they differed in their treatment responses as hyperlocomotion and prepulse inhibition deficit in the dizocilpine model were resistant to antipsychotic treatment, unlike the amphetamine model. One of the experimental compounds, K1700, ameliorated all the observed schizophrenia-like behaviors in the amphetamine model with an efficacy comparable to or greater than aripiprazole. Whereas social impairments caused by dizocilpine were strongly suppressed by aripiprazole, K1700 was less efficient. Taken together, K1700 showed antipsychotic properties comparable to those of aripiprazole, although the efficacy of the two drugs differed in specific domains of behavior and was also model-dependent. Our present results highlight the differences in these two schizophrenia models and their responsiveness to pharmacotherapy, and confirm compound K1700 as a promising drug candidate.