Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression

Abstract

Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. In a rodent model of chronic depression induced by corticosterone exposure, daily administration of this compound, H2-cyanome, induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased VTA dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome also modulated in a similar way than fluoxetine several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of long-term antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.

General Overview of Organic Cation Transporters in Brain

“…Sophisticated experiments in rodents have indicated the impact of organic cation transporters on complex cerebral functions like anxiety, mood control, and motor activity and on their modulatory functions during medical treatment of psychiatric disorders. These data implicate the possibility of developing a new generation of more effective psychoactive drugs that inhibit monoamine neurotransmitter reuptake by high and low affinity neurotransmitter transporters (Orrico-Sanchez et al 2020). By critically appraising previous achievements and calling attention to the incompleteness of the current data basis, we hope to stimulate future investigations in this research area.…”

MPP+-Induced Changes in Cellular Impedance as a Measure for Organic Cation Transporter (SLC22A1-3) Activity and Inhibition

“…However, on some occasions these DDIs might be beneficial to prevent localized toxicity, e.g., nephrotoxicity of chemotherapeutic agents can be prevented by coadministration of OCT2 inhibitors [25] and OCT3 inhibitors were shown to counteract cardiac toxicity [9,12]. In addition, selective targeting of OCTs is currently explored as a strategy to potentiate antidepressant effects [26][27][28]. Unfortunately, there are not that many OCT inhibitors, and they tend to have low selectivity.…”

Metabonomic Profile and Signaling Pathway Prediction of Depression-Associated Suicidal Behavior

“…Bile salt sulfotransferase 1 (SULT2A1) was associated with inflammation response, immune regulation and lipid metabolism in patients with major depressive disorder (66). Organic acid transportation that contributes to depression has been found, and a blocking therapy of organic cation transporter has shown antidepressant efficacy in patients with depression (67). In addition, several transporters of mental ions such as copper and zinc have been confirmed to promote the development of depression (68,69).…”