Accession Number : ADA612531


Title :   Novel Therapeutic Targets to Treat Social Behavior Deficits in Autism and Related Disorders


Descriptive Note : Annual rept. 30 Sep 2013-29 Sep 2014


Corporate Author : TEXAS UNIV HEALTH SCIENCE CENTER AT SAN ANTONIO


Personal Author(s) : Gould, Georgianna G


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a612531.pdf


Report Date : Oct 2014


Pagination or Media Count : 70


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.


Descriptors :   *DRUGS , *SOCIAL PSYCHOLOGY , MICE , SEROTONIN


Subject Categories : Psychology
      Medicine and Medical Research
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE