Neuropharmacology

Biography

Biography: Georgianna G Gould

Abstract

Impaired social interaction is the most prominent and drug treatment-resistant of core autism symptoms. Clinical findings and rodent studies demonstrate serotonin transmission is often disrupted in the socially-deficient brain. For example, dietary or pharmacological depletion of the 5-HT precursor tryptophan (TRP) worsens behavioral symptoms of autism in patients and impairs social interactions in mice, while TRP supplementation improved sociability in some mouse models of autistic symptoms. Also drugs such as buspirone, pargyline and vortioxetine that mimic some postsynaptic effects of serotonin are able to enhance murine social behavior within a limited dose range or time frame. The selective serotonin reuptake inhibitor (SSRIs) Prozac (fluoxetine) enhances sociability in mice. Unfortunately, however, it only does so for limited subpopulations of patients with autism. This could be because SSRI efficacy is diminished if 5-HT transporter (SERT) function is compromised by common and rare gene polymorphisms. Aside from SERT, auxilliary transporters of 5-HT in the brain include organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT) collectively known as “uptake 2”. Uptake 2 transporters remove serotonin from extracellular fluid with greater capacity but lower affinity than SERT. Our hypothesis is that if uptake 2 is blocked, impaired social behavior may improve in a broader population of individuals with autism than presently benefit from SSRI treatments. This hypothesis was tested in two socially impaired mouse models, the BTBR T+tf/J strain and SERT knockout mice. We found that blockade of uptake 2 transporters by systemically-administered pseudoisocyanine decynium-22 promoted social behavior in these mice.