Autism spectrum disorders (ASD), depression and schizophrenia are complex psychiatric conditions involving serotonin (5-HT) dysfunction with a range of symptoms which prominently include impaired social behavior. Drug interventions for these disorders, such as risperidone (Risperdal) and fluoxetine (Prozac), commonly enhance 5-HT neurotransmission or mimic its downstream effects, but these interventions often do not improve social behavior, particularly in patients with gene polymorphisms impairing 5-HT transporter (SERT) function. SERT tightly controls the strength and duration of 5-HT neurotransmission by high affinity uptake of 5-HT from extracellular fluid in brain, but a role for organic cation transporter 3 (OCT3) in 5-HT uptake is emerging as an important mechanism contributing to regulation of extracellular levels of 5-HT in brain. These new findings suggest OCT3 might be a novel target for therapeutic intervention to improve social behavior. Consistent with this idea, we found that acute OCT3 blockade increased social behavior in socially-impaired BTBR mice. The studies we propose here will build on these new findings using SERT knock-out (-/-) mice, which like BTBR mice, are less social than their wild-type (SERT +/+) counterpart. Importantly, SERT-/- mice have increased OCT3 expression and function relative to +/+ mice, making them a unique and useful tool for exploring the effects of OCT3 blockade on 5-HT neurotransmission and social behavior. We hypothesize that the OCT3 blocker, 1,12-diethyl-2,22-cyanine iodide (decynium-22 (D-22)), will improve social behavior in SERT-/- mice more effectively than risperidone, while fluoxetine, which blocks SERT, will have no effect in SERT -/- mice. We expect, however, that D-22 administered in combination with risperidone will produce the greatest increase in social behavior in SERT -/- mice. D-22's effects on SERT +/+ mice, which express both SERT and OCT3 and are highly sociable relative to other strains, will be of interest for use of OCT3 blockade to other ends in broader patient populations. Behavioral data will be correlated with D-22 inhibition of [3H] 5-HT uptake into synaptosomes prepared from hippocampus. Serotonin is a substrate for several biogenic amine transporters, so measuring its uptake in SERT -/- mice, along with selective blockade and control experiments to account for contributions from other transporters expressed in hippocampus, will provide important new information about the relative roles of SERT, OCT3 and other monoamine transporters in 5-HT uptake. Finally, to confirm that D- 22 is exerting its effects centrally, we will measure brain concentration of behaviorally active doses of D-22. Extremely little is known about the role of OCT3 in brain and even less about the effects of systemically administered D-22. Therefore, these fundamental experiments are an essential first step in establishing the potential of OCT3 as a novel target for therapeutic intervention in the treatment of social dysfunction prominent in many psychiatric disorders.

Public Health Relevance

Dysfunction of the serotonin neurotransmitter system has been strongly implicated in the etiology of autism, schizophrenia and depression, and may also underlie impaired social interaction common to these disorders. The proposed studies examine a novel target for pharmaceutical intervention to regulate 5-HT neurotransmission and improve sociability, the organic cation transporter 3 (OCT3), which like the serotonin transporter (SERT, the target of Prozac), removes serotonin from extracellular fluid in the brain to stop neurotransmission. Blockade of OCT3 may prove to be a more uniformly useful mechanism to enhance 5-HT transmission, particularly in patients with SERT gene polymorphisms that make drugs like Prozac less effective.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
1R03MH086708-01A2
Application #
8048331
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Nadler, Laurie S
Project Start
2011-06-15
Project End
2013-05-31
Budget Start
2011-06-15
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$74,250
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Physiology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Mitchell, Nathan C; Bowman, Melodi A; Gould, Georgianna G et al. (2017) Ontogeny of Norepinephrine Transporter Expression and Antidepressant-Like Response to Desipramine in Wild-Type and Serotonin Transporter Mutant Mice. J Pharmacol Exp Ther 360:84-94
Mitchell, Nathan C; Gould, Georgianna G; Koek, Wouter et al. (2016) Ontogeny of SERT Expression and Antidepressant-like Response to Escitalopram in Wild-Type and SERT Mutant Mice. J Pharmacol Exp Ther 358:271-81
Zhang, Wynne Q; Smolik, Corey M; Barba-Escobedo, Priscilla A et al. (2015) Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains. Neuropharmacology 90:1-8
Gould, Georgianna G; Burke, Teresa F; Osorio, Miguel D et al. (2014) Enhanced novelty-induced corticosterone spike and upregulated serotonin 5-HT1A and cannabinoid CB1 receptors in adolescent BTBR mice. Psychoneuroendocrinology 39:158-69
Connors, Kristin A; Valenti, Theodore W; Lawless, Kelly et al. (2014) Similar anxiolytic effects of agonists targeting serotonin 5-HT1A or cannabinoid CB receptors on zebrafish behavior in novel environments. Aquat Toxicol 151:105-13
Mitchell, Nathan C; Gould, Georgianna G; Smolik, Corey M et al. (2013) Antidepressant-like drug effects in juvenile and adolescent mice in the tail suspension test: Relationship with hippocampal serotonin and norepinephrine transporter expression and function. Front Pharmacol 4:131
Bai, Xiang; Fermandez, Elizabeth; Gould, Georgianna et al. (2013) Homozygous Deletion of Glutathione Peroxidase 1 and Aldehyde Dehydrogenase 1a1 Genes Is Not Associated with Schizophrenia-Like Behavior in Mice. J Biochem Pharmacol Res 1:228-235
Horton, Rebecca E; Apple, Deana M; Owens, W Anthony et al. (2013) Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. J Neurosci 33:10534-43
Barba-Escobedo, P A; Gould, G G (2012) Visual social preferences of lone zebrafish in a novel environment: strain and anxiolytic effects. Genes Brain Behav 11:366-73
Gould, Georgianna G; Seillier, Alexandre; Weiss, Gabriela et al. (2012) Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice. Prog Neuropsychopharmacol Biol Psychiatry 38:260-9

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