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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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Related in: MedlinePlus

The serotonin (5-HT)3 receptor agonist m-chlorophenylbiguanide hydrochloride (m-CPBG) transiently increased spontaneous inhibitory post-synaptic currents (sIPSCs) and vortioxetine blocked the m-CPBG effect. (a1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to two applications of the 5-HT3 receptor agonist m-CPBG. In most of the responding cells, the effect of m-CPBG was not repeatable after various application intervals (compare right and left traces). (a2), (a3) The second application of m-CPBG did not induce the same increase in sIPSC frequency ((a2), *p=0.031, paired Student’s t-test) or amplitude ((a3), *p=0.024, paired Student’s t-test) as the first application. Bar graphs represent the mean±standard error of the mean (SEM) from 11 cells. Because of strong desensitization of m-CPBG responses, the effect of vortioxetine was tested in a separate set of cells. (b1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to m-CPBG in the presence of 20 µM vortioxetine. (b2), (b3) Pre-treatment with vortioxetine blocked the m-CPBG increase in sIPSC frequency ((b2), *p=0.034, unpaired Student’s t-test) and amplitude ((b3), *p=0.028, unpaired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bar graphs represent the mean±SEM from 11 cells for the m-CPBG only condition and from nine cells for the m-CPBG + vortioxetine condition.
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fig4-0269881114543719: The serotonin (5-HT)3 receptor agonist m-chlorophenylbiguanide hydrochloride (m-CPBG) transiently increased spontaneous inhibitory post-synaptic currents (sIPSCs) and vortioxetine blocked the m-CPBG effect. (a1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to two applications of the 5-HT3 receptor agonist m-CPBG. In most of the responding cells, the effect of m-CPBG was not repeatable after various application intervals (compare right and left traces). (a2), (a3) The second application of m-CPBG did not induce the same increase in sIPSC frequency ((a2), *p=0.031, paired Student’s t-test) or amplitude ((a3), *p=0.024, paired Student’s t-test) as the first application. Bar graphs represent the mean±standard error of the mean (SEM) from 11 cells. Because of strong desensitization of m-CPBG responses, the effect of vortioxetine was tested in a separate set of cells. (b1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to m-CPBG in the presence of 20 µM vortioxetine. (b2), (b3) Pre-treatment with vortioxetine blocked the m-CPBG increase in sIPSC frequency ((b2), *p=0.034, unpaired Student’s t-test) and amplitude ((b3), *p=0.028, unpaired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bar graphs represent the mean±SEM from 11 cells for the m-CPBG only condition and from nine cells for the m-CPBG + vortioxetine condition.

Mentions: Finally, we investigated the interaction between vortioxetine and the 5-HT3 receptor agonist m-CPBG (Figure 4). In 68% (11/16) of examined cells, local application of m-CPBG (20 µM) produced a transient increase in sIPCSs in a manner similar to that of 5-HT, suggesting that 5-HT3 receptors were involved in the 5-HT response (Figure 4(a1)). However, in most of the responding cells (9/11) the effect of m-CPBG was not repeatable after various (3–25 min) application intervals (Figure 4(a1), compare left and right panels). Even after a 25 min wash-out, there was a significant difference in response between the first and second applications of m-CPBG (Figures 4(a2) and 4(a3)). Due to this long-lasting desensitization of m-CPBG responses, the effect of vortioxetine was tested in a separate set of cells (Figures 4(b1)–4(b3), n=9). A 20–30 min pretreatment with vortioxetine (20 µM) blocked m-CPBG response in all recorded neurons. In the presence of vortioxetine, the effect of the first application of m-CPBG on both sIPSC frequency and amplitude was significantly attenuated (Figures 4(b2) and 4(b3), p<0.05 for both, unpaired Student’s t-test). Thus, vortioxetine blocked 5-HT and m-CPBG responses in a similar manner, suggesting that 5-HT3 receptor antagonism contributed to its inhibitory effect.


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)

The serotonin (5-HT)3 receptor agonist m-chlorophenylbiguanide hydrochloride (m-CPBG) transiently increased spontaneous inhibitory post-synaptic currents (sIPSCs) and vortioxetine blocked the m-CPBG effect. (a1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to two applications of the 5-HT3 receptor agonist m-CPBG. In most of the responding cells, the effect of m-CPBG was not repeatable after various application intervals (compare right and left traces). (a2), (a3) The second application of m-CPBG did not induce the same increase in sIPSC frequency ((a2), *p=0.031, paired Student’s t-test) or amplitude ((a3), *p=0.024, paired Student’s t-test) as the first application. Bar graphs represent the mean±standard error of the mean (SEM) from 11 cells. Because of strong desensitization of m-CPBG responses, the effect of vortioxetine was tested in a separate set of cells. (b1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to m-CPBG in the presence of 20 µM vortioxetine. (b2), (b3) Pre-treatment with vortioxetine blocked the m-CPBG increase in sIPSC frequency ((b2), *p=0.034, unpaired Student’s t-test) and amplitude ((b3), *p=0.028, unpaired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bar graphs represent the mean±SEM from 11 cells for the m-CPBG only condition and from nine cells for the m-CPBG + vortioxetine condition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4230848&req=5

fig4-0269881114543719: The serotonin (5-HT)3 receptor agonist m-chlorophenylbiguanide hydrochloride (m-CPBG) transiently increased spontaneous inhibitory post-synaptic currents (sIPSCs) and vortioxetine blocked the m-CPBG effect. (a1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to two applications of the 5-HT3 receptor agonist m-CPBG. In most of the responding cells, the effect of m-CPBG was not repeatable after various application intervals (compare right and left traces). (a2), (a3) The second application of m-CPBG did not induce the same increase in sIPSC frequency ((a2), *p=0.031, paired Student’s t-test) or amplitude ((a3), *p=0.024, paired Student’s t-test) as the first application. Bar graphs represent the mean±standard error of the mean (SEM) from 11 cells. Because of strong desensitization of m-CPBG responses, the effect of vortioxetine was tested in a separate set of cells. (b1) Representative sIPSCs recorded from a CA1 pyramidal neuron in response to m-CPBG in the presence of 20 µM vortioxetine. (b2), (b3) Pre-treatment with vortioxetine blocked the m-CPBG increase in sIPSC frequency ((b2), *p=0.034, unpaired Student’s t-test) and amplitude ((b3), *p=0.028, unpaired Student’s t-test). Frequency and amplitude were normalized to the mean value during the 30 s of recordings prior to 5-HT application. Bar graphs represent the mean±SEM from 11 cells for the m-CPBG only condition and from nine cells for the m-CPBG + vortioxetine condition.
Mentions: Finally, we investigated the interaction between vortioxetine and the 5-HT3 receptor agonist m-CPBG (Figure 4). In 68% (11/16) of examined cells, local application of m-CPBG (20 µM) produced a transient increase in sIPCSs in a manner similar to that of 5-HT, suggesting that 5-HT3 receptors were involved in the 5-HT response (Figure 4(a1)). However, in most of the responding cells (9/11) the effect of m-CPBG was not repeatable after various (3–25 min) application intervals (Figure 4(a1), compare left and right panels). Even after a 25 min wash-out, there was a significant difference in response between the first and second applications of m-CPBG (Figures 4(a2) and 4(a3)). Due to this long-lasting desensitization of m-CPBG responses, the effect of vortioxetine was tested in a separate set of cells (Figures 4(b1)–4(b3), n=9). A 20–30 min pretreatment with vortioxetine (20 µM) blocked m-CPBG response in all recorded neurons. In the presence of vortioxetine, the effect of the first application of m-CPBG on both sIPSC frequency and amplitude was significantly attenuated (Figures 4(b2) and 4(b3), p<0.05 for both, unpaired Student’s t-test). Thus, vortioxetine blocked 5-HT and m-CPBG responses in a similar manner, suggesting that 5-HT3 receptor antagonism contributed to its inhibitory effect.

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