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DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats.

Kato T, Matsumoto Y, Yamamoto M, Matsumoto K, Baba S, Nakamichi K, Matsuda H, Nishimuta H, Yabuuchi K - Pharmacol Res Perspect (2015)

Bottom Line: In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time.In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects.Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes.

View Article: PubMed Central - PubMed

Affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.

ABSTRACT
Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the K i values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg(-1), dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.

No MeSH data available.


Related in: MedlinePlus

Effects of DSP-1053 on 5-HT and dopamine levels in rat frontal cortex. (A and C) Time-course changes in 5-HT and dopamine (DA) levels in the rat frontal cortex after DSP-1053 p.o. administration. Each point with a vertical bar represents the mean ± SEM of percentage baseline value. (B and D) Effects of DSP-1053 on extracellular 5-HT and DA levels in the rat frontal cortex. Each column with vertical bar represents the mean ± SEM of AUC of 5-HT or DA percent over 3 h. **P < 0.01, compared to the vehicle-treated group using parametric Dunnett’s multiple comparison test. Vehicle group, n = 6; DSP-1053 1 and 3 mg kg−1 groups, n = 4; and DSP-1053 10 mg kg−1, n = 3.
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fig03: Effects of DSP-1053 on 5-HT and dopamine levels in rat frontal cortex. (A and C) Time-course changes in 5-HT and dopamine (DA) levels in the rat frontal cortex after DSP-1053 p.o. administration. Each point with a vertical bar represents the mean ± SEM of percentage baseline value. (B and D) Effects of DSP-1053 on extracellular 5-HT and DA levels in the rat frontal cortex. Each column with vertical bar represents the mean ± SEM of AUC of 5-HT or DA percent over 3 h. **P < 0.01, compared to the vehicle-treated group using parametric Dunnett’s multiple comparison test. Vehicle group, n = 6; DSP-1053 1 and 3 mg kg−1 groups, n = 4; and DSP-1053 10 mg kg−1, n = 3.

Mentions: Basal microdialysate levels of 5-HT and DA in the rat frontal cortex were 0.355 ± 0.025 and 0.305 ± 0.019 pg/10 μL (n = 17), respectively. DSP-1053 increased 5-HT extracellular levels in the rat frontal cortex. This increase reached a maximum of 180 ± 25.9% and 264 ± 58.0% (mean ± SEM) of baseline value 100 min after DSP-1053 administration at 3 and 10 mg kg−1, respectively (Fig.3A). In addition, DSP-1053 (3 and 10 mg kg−1) significantly increased cortical 5-HT cumulative value over 3 h after administration, F(3, 13) = 30.90, P < 0.05 (Fig.3B). On the other hand, DSP-1053 did not affect dopamine extracellular levels in the rat frontal cortex at any dose, F(3, 13) = 0.13, P > 0.05 (Fig.3C and D).


DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant effect with minimal undesirable effects in juvenile rats.

Kato T, Matsumoto Y, Yamamoto M, Matsumoto K, Baba S, Nakamichi K, Matsuda H, Nishimuta H, Yabuuchi K - Pharmacol Res Perspect (2015)

Effects of DSP-1053 on 5-HT and dopamine levels in rat frontal cortex. (A and C) Time-course changes in 5-HT and dopamine (DA) levels in the rat frontal cortex after DSP-1053 p.o. administration. Each point with a vertical bar represents the mean ± SEM of percentage baseline value. (B and D) Effects of DSP-1053 on extracellular 5-HT and DA levels in the rat frontal cortex. Each column with vertical bar represents the mean ± SEM of AUC of 5-HT or DA percent over 3 h. **P < 0.01, compared to the vehicle-treated group using parametric Dunnett’s multiple comparison test. Vehicle group, n = 6; DSP-1053 1 and 3 mg kg−1 groups, n = 4; and DSP-1053 10 mg kg−1, n = 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492758&req=5

fig03: Effects of DSP-1053 on 5-HT and dopamine levels in rat frontal cortex. (A and C) Time-course changes in 5-HT and dopamine (DA) levels in the rat frontal cortex after DSP-1053 p.o. administration. Each point with a vertical bar represents the mean ± SEM of percentage baseline value. (B and D) Effects of DSP-1053 on extracellular 5-HT and DA levels in the rat frontal cortex. Each column with vertical bar represents the mean ± SEM of AUC of 5-HT or DA percent over 3 h. **P < 0.01, compared to the vehicle-treated group using parametric Dunnett’s multiple comparison test. Vehicle group, n = 6; DSP-1053 1 and 3 mg kg−1 groups, n = 4; and DSP-1053 10 mg kg−1, n = 3.
Mentions: Basal microdialysate levels of 5-HT and DA in the rat frontal cortex were 0.355 ± 0.025 and 0.305 ± 0.019 pg/10 μL (n = 17), respectively. DSP-1053 increased 5-HT extracellular levels in the rat frontal cortex. This increase reached a maximum of 180 ± 25.9% and 264 ± 58.0% (mean ± SEM) of baseline value 100 min after DSP-1053 administration at 3 and 10 mg kg−1, respectively (Fig.3A). In addition, DSP-1053 (3 and 10 mg kg−1) significantly increased cortical 5-HT cumulative value over 3 h after administration, F(3, 13) = 30.90, P < 0.05 (Fig.3B). On the other hand, DSP-1053 did not affect dopamine extracellular levels in the rat frontal cortex at any dose, F(3, 13) = 0.13, P > 0.05 (Fig.3C and D).

Bottom Line: In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time.In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects.Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes.

View Article: PubMed Central - PubMed

Affiliation: Drug Development Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd. Osaka, Japan.

ABSTRACT
Enhancement of serotonergic neurotransmission has been the main stream of treatment for patients with depression. However, delayed therapeutic onset and undesirable side effects are major drawbacks for conventional serotonin reuptake inhibitors. Here, we show that DSP-1053, a novel serotonin reuptake inhibitor with 5-HT1A partial agonistic activity, displays fast antidepressant efficacy with minimal undesirable effects, especially nausea and emesis in animal models. DSP-1053 bound human serotonin transporter and 5-HT1A receptor with the K i values of 1.02 ± 0.06 and 5.05 ± 1.07 nmol/L, respectively. This compound inhibited the serotonin transporter with an IC50 value of 2.74 ± 0.41 nmol/L and had an intrinsic activity for 5-HT1A receptors of 70.0 ± 6.3%. In rat microdialysis, DSP-1053, given once at 3 and 10 mg kg(-1), dose-dependently increased extracellular 5-HT levels. In the rat forced swimming test, 2-week administration of DSR-1053 (1 mg kg(-1)) significantly reduced rats immobility time after treatment, whereas paroxetine (3 and 10 mg kg(-1)) required 3-week administration to reduce rats immobility time. In olfactory bulbectomy model, 1- and 2-week administration of DSP-1053 reduced both of emotional scores and activity in the open field, whereas paroxetine required 2 weeks to show similar beneficial effects. Although single administration of DSP-1053-induced emesis and vomiting in the rat and Suncus murinus, multiple treatment with this compound, but not with paroxetine, decreased the number of vomiting episodes. These results highlight the important role of 5-HT1A receptors in both the efficacy and tolerability of DSP-1053 as a new therapeutic option for the treatment of depression.

No MeSH data available.


Related in: MedlinePlus