The potential and limitations of DOV 216,303 as a triple reuptake inhibitor for the treatment of major depression: A microdialyis study in olfactory bulbectomized rats

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2011-01, Vol.97 (3), p.444-452
• Main Authors: Prins, J., Westphal, K.G.C., Korte-Bouws, G.A.H., Quinton, M.S., Schreiber, R., Olivier, B., Korte, S.M.
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Anhedonia; Biological and medical sciences; Depression; Dopamine; DOV 216,303; In vivo microdialysis; Medical sciences; Monoamine; Mood disorders; Olfactory bulbectomy; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2010.10.001

DOV 216,303 belongs to a new class of antidepressants, the triple reuptake inhibitors (TRIs), that blocks serotonin, norepinephrine and dopamine transporters and thereby increases extracellular brain monoamine concentrations. The aim of the present study was to measure extracellular monoamine concentrations both in the prefrontal cortex (PFC) and dorsal hippocampus (DH) after chronic administration of DOV 216,303 in the OBX animal model of depression and to compare the effects with acute drug treatment. OBX animals showed lower dopamine levels in PFC upon acute administration of DOV 216,303 than sham animals for up to five weeks after surgery. No such changes were observed in the DH. Unexpectedly, a DOV 216,303 challenge in chronic DOV 216,303 treated sham animals resulted in a blunted dopamine response in the PFC compared to the same challenge in vehicle treated animals. This blunted response probably reflects pharmacokinetic adaptations and/or pharmacodynamic changes, since brain and plasma concentrations of DOV 216,303 were significantly lower after chronic administration compared to acute administration. Surprisingly, and in contrast what we have reported earlier, chronic DOV 216,303 treatment was unable to normalize the hyperactivity of the OBX animals. Interestingly, by measuring the drug plasma and brain levels, it was demonstrated that at the time of behavioral testing (24h after last drug treatment) DOV 216,303 was not present anymore in either plasma or brain. This seems to indicate that this putative antidepressant drug has no lasting antidepressant-like behavioral effects in the absence of the drug in the brain. ► DOV 216,303 increased monoamine release in PFC and DH even five weeks after OBX. ► Extracellular DA levels in PFC lower in OBX than shams after acute DOV 216,303. ► DOV 216,303-challenge leads to blunted DA response in chronic DOV-treated shams. ► Brain and plasma levels of DOV lower after chronic compared to acute treatment.