Efficacy of Vesicular Monoamine Transporter 2 Inhibition and Synergy with Antipsychotics in Animal Models of Schizophrenia

Abstract

Antipsychotic medications function by blocking postsynaptic dopaminergic signaling in the central nervous system. Dopamine transmission can also be modulated presynaptically by inhibitors of vesicular monoamine transporter 2 (VMAT2), which inhibit loading of dopamine into presynaptic vesicles. Here we investigated the combination of these mechanisms in animal models of schizophrenia and weight gain (a primary side effect of antipsychotics). When dosed alone, the highly selective VMAT2 inhibitor RRR-dihydrotetrabenazine (RRR-DHTBZ, also known as [1]-a-HTBZ) elicited efficacy comparable to conventional antipsychotics in prepulse inhibition and conditioned avoidance models without eliciting weight gain. In combination experiments, synergy was observed: subthreshold doses of RRR-DHTBZ and risperidone or olanzapine produced robust efficacy, and in dose response experiments, RRR-DHTBZ increased the antipsychotic potency in the efficacy models but did not affect weight gain. The combinations did not affect plasma compound concentrations. The synergy is consistent with VMAT2 inhibition blocking the counterproductive presynaptic stimulation of dopamine by antipsychotics. These results suggest a therapeutic strategy of adding a VMAT2 inhibitor to lower the antipsychotic dose and reduce the side effect burden of the antipsychotic while maintaining and potentially enhancing its therapeutic effects.