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Rapid Antidepressant‐like Effects of the “Uptake‐2” Blocker, Decynium 22 in the Flinders Sensitive Line Rat Model of Depression
Author(s) -
FraserSpears Rheaclare,
Owens W. Anthony,
Mitchell Nathan C,
Overstreet David,
Koek Wouter,
Daws Lynette C
Publication year - 2016
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.30.1_supplement.929.7
Subject(s) - antidepressant , pharmacology , fluoxetine , serotonin transporter , behavioural despair test , serotonin , fluvoxamine , reuptake inhibitor , transporter , monoamine neurotransmitter , medicine , chemistry , hippocampus , receptor , biochemistry , gene
Background Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat major depression and mood disorders, however, many patients report low to no symptom relief with SSRI treatment. We found that activity of low‐affinity, high‐capacity (uptake 2) transporters for biogenic amines, in particular organic cation transporter 3 (OCT3), may limit therapeutic efficacy of SSRIs. Moreover, in C56BL/6 mice we found that decynium‐22 (D22), which blocks OCT1, OCT2, OCT3 and the plasma membrane monoamine transporter (PMAT), produced antidepressant‐like effects when the serotonin transporter was either pharmacologically or genetically compromised. These studies point to D22 sensitive transporters, putatively OCT3, as a promising target for development of new therapeutics for depression. Here, we expand these studies to examine the antidepressant utility of D22 in a genetically based animal model of depression, the Flinders Sensitive Line (FSL) rat. Importantly, like humans, FSL rats show reduced depressive behaviors after repeated but not acute antidepressant administration. Thus, the FSL rat model can be used to identify novel drugs, or drug combinations, that may have faster acting antidepressant‐like activity and improved therapeutic efficacy. Methods Antidepressant‐like behaviors were assessed in adult, male Sprague Dawley (SD) and FSL rats using the forced swim test (FST). Rats were tested 30 min after single saline, fluvoxamine or D22 injections given intraperitoneally. Uptake 2 transporter expression was measured by western blotting techniques and radioligand binding of [ 3 H]D22 in rat hippocampal preparations. Results As expected, FSL rats displayed higher baseline levels of immobility in the FST indicating a higher level of depressive behavior compared with SD control rats. Also, as expected, acute injection of the SSRI fluvoxamine (10 mg/kg) reduced immobility time in SD but not FSL rats. Conversely, acute D22 (0.1 mg/kg) administration significantly lowered immobility time in FSL rats, but was not effective in control SD rats. FSL rats also appeared to have elevated expression of hippocampal OCT3 and PMAT total protein measured by western blotting. Measurements of uptake 2 transporter levels via D22 binding are currently in progress. Conclusions The reduction in immobility time observed after acute, low dose D22 in FSL rats suggests that OCTs and/or PMAT may be targets for rapidly acting antidepressant drugs, and underscores the utility of animal models for depression. Studies are underway to compare chronic D22 treatment with and without an SSRI in the FSL rat model of depression, with the goal to examine OCT3 and PMAT as targets to develop more efficacious and rapidly acting antidepressants. Support or Funding Information NIH MH093320 and NRSA T32DA031115.