Novel Therapeutic Targets to Treat Social Behavior Deficits in Autism and Related Disorders
Annual rept. 30 Sep 2013-29 Sep 2014
TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO
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Impaired social behavior is a core symptom of autism that manifests in other psychiatric disorders and tends to be treatment-resistant. Selective serotonin reuptake inhibitors SSRIs such as Prozac enhance sociability in some patients, but their efficacy is diminished if 5-HT transporter SERT function is compromised. Thus, our goal was to characterize the effects of blocking ancillary transporters of 5-HT instead of SERT in inbred mouse strains differing in level of SERT function and sociability BTBR, 129S, C57BL6 and DBA1. These auxiliary 5-HT transporters, known as uptake 2, include organic cation OCT and plasma membrane monoamine transporters PMAT in the brain. Through synaptosomal uptake, radioligand binding and chronoamperometry we found that the pseudoisocyanine decinium-22 D-22 improves sociability otherwise impaired in mice, blocks 5-HT uptake Km92 12 nM but has negligible affinity for SERT Ki 3000 nM. Systemically administered D-22 0.1 mgkg, i.p. slows 5-HT clearance in the brain. Chronic D-22 administration via osmotic minipumps produced similar effects to acute administration in BTBR mice, both treatments increased social sniffing and dwelling near strangers. This shows that uptake 2 blockade may be an effective approach to treating sociability impairments in autism.
- Medicine and Medical Research