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 [+]-α-HTBZ) elicited efficacy comparable to conventional antipsychotics in pre-pulse 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.
Significance Statement Antipsychotics effectively reduce psychotic symptoms and are often necessary and life-changing medications; however, these benefits are at the expense of a high side effect burden. This study shows that combining these postsynaptic dopaminergic modulators with a presynaptic dopamine modulator (VMAT2 inhibitor) potentiates efficacy synergistically in animal models of schizophrenia without potentiating weight gain. Our data suggest that adding a VMAT2 inhibitor may be a viable therapeutic strategy for reducing antipsychotic side effects by lowering antipsychotic dose while maintaining therapeutic efficacy.
- © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.