Novel Therapeutic Targets to Treat Social Behavior Deficits in Autism and Related Disorders
Technical Report,30 Sep 2014,29 Sep 2015
The University of Texas Health Science Center at San Antonio San Antonio United States
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Two populations of membrane-bound transporters clear serotonin from brain extracellular fluid Uptake 1 are high-affinity sodium dependent transport proteins which include the serotonin transporter solute carrier 6 member 4, the target of Prozac. By contrast Uptake2 are low affinity, high capacity transporters that include organic cation transporters solute carrier family 22, types 1,2 and 3. Our prior behavior findings in mice suggest targeting uptake 2 transporters holds promise as a strategy for treating sociability impairments in autism.The goal of this project is to characterize the behavioral, physiological and in vitro pharmacological effects of blocking uptake 2 transporters with decynium-22 in several strains of mice, including black and tan brachury tufted BTBR mice with inherent sociability deficits and repetitive traits that parallel core autism symptoms. We dosed mice with 0.5 mgkg D-22 and collected samples to measure its concentration in blood and brains at 15-min time points from 163 mice by GCMS. The impact of D-22 on dominance and sociability preference alone and in presence of fluoxetine and risperidone continues to be assessed, but so far D-22 suppress dominance and enhances sociability. Measures of in vitro synaptosomal uptake of 3H serotonin and its blockade by D-22 and other compounds in these mice arenearly complete. A revised protocol for synaptosomal uptake of 3H histamine is being developed and 3H D-22 autoradiography is underway. Serotonin uptake blockade by D-22 seems to be the mechanism mediating the beneficial effects, but others cant be ruled out.