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Blockade of serotonin uptake by decynium‐22 enhances sociability (839.3)
Author(s) -
Smolik Corey,
Zhang Wynne,
Vitella Melissa,
Sanchez Jesus,
Javors Martin,
Koek Wouter,
Daws Lynette,
Gould Georgianna
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.839.3
Subject(s) - blockade , autism , monoamine neurotransmitter , serotonin transporter , psychology , serotonin , reuptake , fluoxetine , neuroscience , pharmacology , aggression , chemistry , medicine , psychiatry , receptor
Impaired social behavior occurs in several psychiatric disorders including autism, schizophrenia and depression. This symptom has proven difficult to treat with available pharmaceuticals. Based on clinical findings and experiments in rodents, serotonin (5‐HT) transmission is often disrupted in the socially‐impaired brain, and limbic regions and frontal cortex appear to be involved. Two drugs are commonly used to treat autism; risperidone curbs aggression but blunts social interaction, and fluoxetine improves social behavior somewhat, but its efficacy is diminished with reduced 5‐HT transporter (SERT) function. Our goal was to characterize the effects of blocking ancillary transporters of 5‐HT, with lower affinity but greater capacity than SERT to remove 5‐HT from extracellular fluid. These auxillary transporters, known as 'uptake 2' include organic cation and plasma membrane monoamine transporters. We utilized two models of impaired social behavior, inbred BTBR T+tf/J and SERT knock‐out (‐/‐) mice, to examine uptake 2 blockade effects on 5‐HT uptake and social behavior. The pseudoisocyanine decinium‐22 (D‐22) blocked 5‐HT uptake (Km = 92 +/‐ 12 nM) but had negligible affinity for SERT (Ki > 3000 nM) in hippocampal synaptosomes. In SERT ‐/‐ and BTBR mice, social behavior improved with acute D‐22 treatment at doses of 0.01 ‐ 0.1 mg/kg. This strategy may be an effective treatment for inpaired social behavior, and warrants further study. Grant Funding Source : Supported by CDMRP Autism Idea Award AR110109, NIH MH086708 and NIH GM097632.