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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
Report Date:
2016-06-01
Pagination or Media Count:
108.0
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-22D-22 blocks 5-HT uptake Km9212 nM but has negligible affinity for the SERT Ki 3000 nM. D-22 1 mgkg, i.p. is cleared from mouse serum with a half-life 30 min, with some variability among strains. We used inbred strains BTBR, 129S1SvIMJ and SERT knock-out -- mice, exhibiting impaired social behavior relative to wild-types on C57BL6 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-220.01-0.1 mgkg, relative to vehicle-controls. Two-week D-22 0.01-0.001 mgkgd administration also improved BTBR and SERT --mouse sociability. Thus, uptake 2 blockade may be an effective strategy to ameliorate social behavior impairments.
Distribution Statement:
APPROVED FOR PUBLIC RELEASE
