Depression and related disorders are a major public health problem, compounded by the fact that at least half of patients are not effectively treated by currently available medications. Among the most commonly prescribed is the class of selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act to inhibit 5-HT transporter (SERT) mediated 5-HT uptake. The increase in extracellular 5-HT that follows is thought to be critical for initiation of the cascade of downstream events needed for therapeutic effects. Although SERT is the major player regulating high-affinity 5-HT uptake, there is emerging evidence for an important role of organic cation transporter-3 (OCT3) and possibly the plasma membrane monoamine transporter (PMAT) in taking up 5-HT in brain. This raises the possibility that lack of therapeutic response following SERT blockade could be due to significant 5-HT uptake by OCT3 (and/or PMAT). Our studies using decynium-22 (D-22), a blocker of both OCT3 and PMAT, lend support to this idea. For example, D-22 augments the effect of an SSRI, fluvoxamine, to inhibit 5-HT uptake and to produce antidepressant-like effects in wildtype mice. Moreover, D-22 produces these effects also when given alone in mice that lack, or have reduced SERT expression. Thus, the antidepressant-like effect of D-22 appears to be most pronounced when SERT is either pharmacologically or genetically inactivated. We also found that OCT3 expression (but not PMAT) is increased in mice with a constitutive reduction of SERT, suggesting a compensatory role for OCT3. One important aspect of the proposed studies will be to examine the possibility that this also occurs after chronic treatment with SSRIs, which is known to reduce SERT expression. In addition to 5-HT, OCT3 (and PMAT) can transport norepinephrine (NE) and dopamine (DA), neurotransmitters also linked to the therapeutic action of current antidepressants. Taken together, the goals of the proposed studies are to (1) validate OCT3 (and/or PMAT) as the site where D-22 produces its antidepressant-like effect;(2) determine the relative importance of inhibition of 5-HT, NE and DA uptake in producing the antidepressant-like effect of D-22, and (3) examine the therapeutic potential of D-22 by studying its effect on biogenic amine uptake and antidepressant-like activity after its chronic administration. The results of these studies will help to establish OCT3 (and/or PMAT) as a novel target for the discovery of drugs with improved therapeutic potential, as well as provide a mechanism that can, at least in part, account for poor therapeutic response to current antidepressant drugs.

Public Health Relevance

Although reports vary, it is estimated that major depression is unsuccessfully treated in more than half the patient population, underlining the urgent need to identify new targets for antidepressant medications. OCT3 is emerging as one such target. By validating this target, the experiments proposed here will lay the foundation for the discovery of novel antidepressants with marked therapeutic potential, especially in treatment resistant patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH093320-01A1
Application #
8262100
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Nadler, Laurie S
Project Start
2012-03-01
Project End
2016-11-30
Budget Start
2012-03-01
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$530,267
Indirect Cost
$172,904
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
Mayer, Felix P; Schmid, Diethart; Owens, W Anthony et al. (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408-2417
Mitchell, N C; Gilman, T L; Daws, L C et al. (2018) High salt intake enhances swim stress-induced PVN vasopressin cell activation and active stress coping. Psychoneuroendocrinology 93:29-38
Garbarino, Valentina R; Gilman, T Lee; Daws, Lynette C et al. (2018) Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder. Pharmacol Res :
Koek, Wouter; Mitchell, Nathan C; Daws, Lynette C (2018) Biphasic effects of selective serotonin reuptake inhibitors on anxiety: rapid reversal of escitalopram's anxiogenic effects in the novelty-induced hypophagia test in mice? Behav Pharmacol 29:365-369
Gilman, T Lee; George, Christina M; Vitela, Melissa et al. (2018) Constitutive plasma membrane monoamine transporter (PMAT, Slc29a4) deficiency subtly affects anxiety-like and coping behaviours. Eur J Neurosci :
Koek, Wouter; Sandoval, Thomas L; Daws, Lynette C (2018) Effects of the antidepressants desipramine and fluvoxamine on latency to immobility and duration of immobility in the forced swim test in adult male C57BL/6J mice. Behav Pharmacol 29:453-456
Gasser, Paul J; Daws, Lynette C (2017) Extending the family: Roles for uptake2 transporters in regulation of monoaminergic signaling. J Chem Neuroanat 83-84:107-108
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
Gasser, Paul J; Daws, Lynette C (2017) Editorial for the special issue: Monoamine transporters in health and disease. J Chem Neuroanat 83-84:1-2
Krause-Heuer, Anwen M; Fraser-Spears, Rheaclare; Dobrowolski, Jeremy C et al. (2017) Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22. Eur J Med Chem 137:476-487

Showing the most recent 10 out of 22 publications