Novel Therapeutic Targets to Treat Social Behavior Deficits in Autism and Related Disorders
Abstract
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, C57BL/6 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 (Km=92 12 nM) but has negligible affinity for SERT (Ki > 3000 nM). Systemically administered D-22 (0.1 mg/kg, 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA612531
Entities
People
- Georgianna G. Gould
Organizations
- University of Texas Health Science Center at San Antonio