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Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.

Dale E, Zhang H, Leiser SC, Xiao Y, Lu D, Yang CR, Plath N, Sanchez C - J. Psychopharmacol. (Oxford) (2014)

Bottom Line: Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism.In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures.Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Lundbeck Research USA, Paramus, NJ, USA EDAL@lundbeck.com.

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Vortioxetine blocked the serotonin (5-HT)-induced increase in spontaneous inhibitory post-synaptic currents (sIPSCs).(a) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to 5-HT before (left) and after 15 min application of 20 µM vortioxetine (right). (b1), (c1) Vortioxetine blocked the 5-HT induced increase in sIPSC frequency ((b1), **p=0.0073, paired Student’s t-test) and amplitude ((c1), **p=0.0066, paired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bars represent the mean±standard error of the mean (SEM) of sIPSCs from 15 cells. (b2), (c2) Averaged cumulative probability plots of sIPSC inter-event interval (b2) and amplitude (c2) for 5-HT alone and 5-HT+vortioxetine. Data for these graphs were derived from 60 s of continuous recordings. Each data point represents the mean from 15 cells. Vortioxetine significantly increased the inter-event interval time in 14/15 cells and shifted amplitudes of sIPSCs to lower values in 13/15 cells after 5-HT application (p<0.05, Kolmogorov-Smirnov (K-S) test).
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fig2-0269881114543719: Vortioxetine blocked the serotonin (5-HT)-induced increase in spontaneous inhibitory post-synaptic currents (sIPSCs).(a) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to 5-HT before (left) and after 15 min application of 20 µM vortioxetine (right). (b1), (c1) Vortioxetine blocked the 5-HT induced increase in sIPSC frequency ((b1), **p=0.0073, paired Student’s t-test) and amplitude ((c1), **p=0.0066, paired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bars represent the mean±standard error of the mean (SEM) of sIPSCs from 15 cells. (b2), (c2) Averaged cumulative probability plots of sIPSC inter-event interval (b2) and amplitude (c2) for 5-HT alone and 5-HT+vortioxetine. Data for these graphs were derived from 60 s of continuous recordings. Each data point represents the mean from 15 cells. Vortioxetine significantly increased the inter-event interval time in 14/15 cells and shifted amplitudes of sIPSCs to lower values in 13/15 cells after 5-HT application (p<0.05, Kolmogorov-Smirnov (K-S) test).

Mentions: The effect of vortioxetine was only studied in cells that responded to 5-HT. In these cells, bath application of 20 µM vortioxetine did not affect baseline sIPSCs (n=15, data not shown), but largely suppressed the 5-HT-mediated increase in sIPSC frequency and amplitude (Figure 2, p<0.05 for both, paired Student’s t-test). Vortioxetine required at least 15 min of application to achieve its maximal effect, which lasted for >30 min. We never observed a complete wash-out of the vortioxetine response, most likely due to the fact that vortioxetine is >99% protein bound in rat brain tissue (Sanchez et al., 2014) and thus is probably difficult to wash-out. The inhibitory effect of vortioxetine on sIPSCs was observed in 14 of the 15 cells tested (Figures 2(b1) and 2(c1)). To control for a possible desensitization of 5-HT response, vortioxetine was applied after the third application of 5-HT to a subset of cells. Under these conditions, vortioxetine still fully inhibited 5-HT responses, indicating that desensitization could not explain the inhibitory effect seen with vortioxetine (n=3, data not shown).


Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.

Dale E, Zhang H, Leiser SC, Xiao Y, Lu D, Yang CR, Plath N, Sanchez C - J. Psychopharmacol. (Oxford) (2014)

Vortioxetine blocked the serotonin (5-HT)-induced increase in spontaneous inhibitory post-synaptic currents (sIPSCs).(a) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to 5-HT before (left) and after 15 min application of 20 µM vortioxetine (right). (b1), (c1) Vortioxetine blocked the 5-HT induced increase in sIPSC frequency ((b1), **p=0.0073, paired Student’s t-test) and amplitude ((c1), **p=0.0066, paired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bars represent the mean±standard error of the mean (SEM) of sIPSCs from 15 cells. (b2), (c2) Averaged cumulative probability plots of sIPSC inter-event interval (b2) and amplitude (c2) for 5-HT alone and 5-HT+vortioxetine. Data for these graphs were derived from 60 s of continuous recordings. Each data point represents the mean from 15 cells. Vortioxetine significantly increased the inter-event interval time in 14/15 cells and shifted amplitudes of sIPSCs to lower values in 13/15 cells after 5-HT application (p<0.05, Kolmogorov-Smirnov (K-S) test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4230848&req=5

fig2-0269881114543719: Vortioxetine blocked the serotonin (5-HT)-induced increase in spontaneous inhibitory post-synaptic currents (sIPSCs).(a) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to 5-HT before (left) and after 15 min application of 20 µM vortioxetine (right). (b1), (c1) Vortioxetine blocked the 5-HT induced increase in sIPSC frequency ((b1), **p=0.0073, paired Student’s t-test) and amplitude ((c1), **p=0.0066, paired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bars represent the mean±standard error of the mean (SEM) of sIPSCs from 15 cells. (b2), (c2) Averaged cumulative probability plots of sIPSC inter-event interval (b2) and amplitude (c2) for 5-HT alone and 5-HT+vortioxetine. Data for these graphs were derived from 60 s of continuous recordings. Each data point represents the mean from 15 cells. Vortioxetine significantly increased the inter-event interval time in 14/15 cells and shifted amplitudes of sIPSCs to lower values in 13/15 cells after 5-HT application (p<0.05, Kolmogorov-Smirnov (K-S) test).
Mentions: The effect of vortioxetine was only studied in cells that responded to 5-HT. In these cells, bath application of 20 µM vortioxetine did not affect baseline sIPSCs (n=15, data not shown), but largely suppressed the 5-HT-mediated increase in sIPSC frequency and amplitude (Figure 2, p<0.05 for both, paired Student’s t-test). Vortioxetine required at least 15 min of application to achieve its maximal effect, which lasted for >30 min. We never observed a complete wash-out of the vortioxetine response, most likely due to the fact that vortioxetine is >99% protein bound in rat brain tissue (Sanchez et al., 2014) and thus is probably difficult to wash-out. The inhibitory effect of vortioxetine on sIPSCs was observed in 14 of the 15 cells tested (Figures 2(b1) and 2(c1)). To control for a possible desensitization of 5-HT response, vortioxetine was applied after the third application of 5-HT to a subset of cells. Under these conditions, vortioxetine still fully inhibited 5-HT responses, indicating that desensitization could not explain the inhibitory effect seen with vortioxetine (n=3, data not shown).

Bottom Line: Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism.In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures.Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Lundbeck Research USA, Paramus, NJ, USA EDAL@lundbeck.com.

Show MeSH
Related in: MedlinePlus