Accession Number : AD1015166


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


Descriptive Note : Technical Report,30 Sep 2012,31 Mar 2016


Corporate Author : The University of Texas Health Science Center at San Antonio San Antonio United States


Personal Author(s) : Gould,Georgianna G


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1015166.pdf


Report Date : 01 Jun 2016


Pagination or Media Count : 108


Abstract : Impaired social behavior is a treatment-resistant core symptom of autism that also manifests in other psychiatric disorders. Selective serotonin reuptake inhibitors (SSRIs) such as Prozac (fluoxetine) are capable of enhancing sociability in some patient sub-populations, but their efficacy is greatly diminished if 5-HT transporter (SERT) function is compromised. For this reason, our goal was to characterize effects of blocking ancillary transporters of 5-HT instead of SERT. These auxiliary transporters, known as 'uptake 2', include organiccation (OCT) and plasma membrane monoamine transporters (PMAT) which exhibit lower affinity but greater capacity than SERT tore move 5-HT from extracellular fluid. Through synaptosomal uptake and radioligand binding, we found the pseudoisocyanine decinium-22(D-22) blocks 5-HT uptake (Km=9212 nM) but has negligible affinity for the SERT (Ki 3000 nM). D-22 (1 mg/kg, i.p.) is cleared from mouse serum with a half-life 30 min, with some variability among strains. We used inbred strains BTBR, 129S1/SvIMJ and SERT knock-out (-/-) mice, exhibiting impaired social behavior relative to wild-types ( / ) on C57BL/6 background or DBA1, to examine acute and chronic effects of D-22 on sociability. Social sniffing and dwelling near strangers increased in BTBR and SERT -/- mice on D-22(0.01-0.1 mg/kg), relative to vehicle-controls. Two-week D-22 (0.01-0.001 mg/kg/d) administration also improved BTBR and SERT -/-mouse sociability. Thus, uptake 2 blockade may be an effective strategy to ameliorate social behavior impairments.


Descriptors :   CORTICOSTEROID AGENTS , SEROTONIN AGENTS , behavior , human behavior , antidepressants , brain , cell membrane , therapeutics , neurosciences , biological markers , cellular structures


Distribution Statement : APPROVED FOR PUBLIC RELEASE