Organic Cation Transporter Blocker Decynium 22 and Substrates Metformin and Berberine Enhance Social Interaction Preference in Adult Male Mice, Perhaps by Modulating Corticosterone Release
Authors: Gould Georgianna G. , Lalani Kiran , Pham Timothy , Sanchez Alicia , Smolik Corey M. , Daws Lynette C. 
Published: April 2020

Social withdrawal in psychiatric disorders such as schizophrenia, depression and dementia resemble impaired preference for social interaction, which is a treatment‐resistant core symptom of autism. Deficient serotonin (5‐HT) signaling is strongly implicated as a contributing factor common to these psychiatric and neurodegenerative disorders. The relative lack of clinical efficacy of selective 5‐HT reuptake inhibitors (SSRIs) to improve social behavior deficits in these conditions has brought into question their therapeutic utility for this debilitating symptom. Given the limitations associated with treating sociability deficits by targeting the 5‐HT transporter (SERT), our initial goal was to characterize the effects of blocking auxiliary ‘uptake 2’ transporters of 5‐HT on social behaviors in mice. Organic cation transporters (OCTs) are among the ancillary 5‐HT transporters found in brain, and they are blocked endogenously by steroid hormones such as corticosterone. Male BTBR T+Itpr3tf/J (BTBR) mice have elevated serum corticosterone, particularly in adolescence, and they exhibit inherent deficits in preference for social interaction. In three‐chamber sociability preference tests the OCT blocker decynium‐22 (D‐22) enhanced social interactions in otherwise socially‐deficient BTBR mice, and was without adverse effect on the social behaviors of C57BL/6J (B6) mice (p < 0.05, N= 8–9). Furthermore, D‐22, and OCT substrates, berberine and metformin, all similarly attenuated the social dominance of BTBR mice in tube tests. However in the course of our studies we also found that the alkaloid antibiotic berberine and the anti‐diabetic drug metformin also had sociability enhancing properties similar to D‐22 in BTBR mice. Yet as compared to D‐22 these substrates are poor blockers of synaptosomal 5‐HT uptake. For example, a lower concentration of D‐22 is required to inhibit cortical [3H] 5‐HT uptake, with a Michaelis constant (Km) ≈ 0.5 μM, while 500x more berberine is required to equivalently inhibit it (Km ≈ 240 μM), and metformin is an even less potent 5‐HT uptake inhibitor (Km > 1000 μM, N = 3). However we and others have observed that D‐22, berberine and metformin can attenuate circulating corticosterone levels. Our findings confirm that systemic OCT blockade by D‐22 may be a promising strategy for improving social behavior, but the mechanism of action of berberine and metformin to similarly do so remain unclear. This warrants further investigation into how these compounds modulate corticosterone release, and how serum corticosterone relates to sociability impairments.Support or Funding InformationAutism Idea Award (AR110109), Department of Defense ‐ Congressionally Directed Medical Research Programs; South Texas Advanced Research Training: Undergraduate Program (R25GM097632), National Institutes of HealthD‐22 is a more potent 5‐HT uptake blocker than berberine.Figure 1