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Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex.

Tsutsui-Kimura I, Yoshida T, Ohmura Y, Izumi T, Yoshioka M - Int. J. Neuropsychopharmacol. (2014)

Bottom Line: We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats.Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug.Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura).

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The effects of lesions of the ventromedial prefrontal cortex (vmPFC) and repeated milnacipran administration on excitatory postsynaptic currents (EPSCs) in the layer V pyramidal neurons in the vmPFC. Electrophysiological characterization of pyramidal neurons in the vmPFC using whole-cell patch-clamp recording. (A) vmPFC position and representative photographs of a coronal slice submerged in our recording chamber depicting the position of an electrode for the recording of EPSCs when stimulating (B) apical (239±33 μm from soma) and (C) basal (77±9 μm from soma) dendrites. (D) Only vmPFC neurons that satisfied the criteria (see supplementary Methods) were used for this study. Examples of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (E) apical and (F) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average AMPA EPSC amplitude in (G) apical and (H) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. Examples of N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (I) apical and (J) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average NMDA EPSC amplitude in (K) apical and (L) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. The peak amplitude was measured on the basis of the averaged waveform of evoked EPSCs (5 consecutive trials) #P<.05, a main effect of the lesion with a 2-factor ANOVA. *P<.05, with a 1-factor ANOVA. DW, distilled water; MIL, milnacipran.
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Figure 6: The effects of lesions of the ventromedial prefrontal cortex (vmPFC) and repeated milnacipran administration on excitatory postsynaptic currents (EPSCs) in the layer V pyramidal neurons in the vmPFC. Electrophysiological characterization of pyramidal neurons in the vmPFC using whole-cell patch-clamp recording. (A) vmPFC position and representative photographs of a coronal slice submerged in our recording chamber depicting the position of an electrode for the recording of EPSCs when stimulating (B) apical (239±33 μm from soma) and (C) basal (77±9 μm from soma) dendrites. (D) Only vmPFC neurons that satisfied the criteria (see supplementary Methods) were used for this study. Examples of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (E) apical and (F) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average AMPA EPSC amplitude in (G) apical and (H) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. Examples of N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (I) apical and (J) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average NMDA EPSC amplitude in (K) apical and (L) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. The peak amplitude was measured on the basis of the averaged waveform of evoked EPSCs (5 consecutive trials) #P<.05, a main effect of the lesion with a 2-factor ANOVA. *P<.05, with a 1-factor ANOVA. DW, distilled water; MIL, milnacipran.

Mentions: Considering that the majority of excitatory synapses in the brain occur on dendritic spines, we hypothesized that repeated milnacipran treatment ameliorates reduced excitatory currents in the vmPFC of vmPFC-lesioned rats. Therefore, we analyzed EPSCs mediated by AMPA and NMDA receptors in the layer V pyramidal neurons of the vmPFC when stimulating apical and basal dendrites (Figure 6A-D). A 3-factor ANOVA revealed a significant stimulation intensity×lesion×drug interaction in the AMPA EPSCs when stimulating apical (F10, 610=3.56, P<.05; Figure 6E and G) and basal (F10, 360=9.44, P<.05; Figure 6F and H) dendrites. However, a subsequent 2-factor ANOVA did not find any significant main effect of the lesion (F1, 40=0.09, NS) or drug (F1, 40=0.35, NS) or a lesion×drug interaction (F1, 40=0.63, NS) in AMPA EPSCs when stimulating apical dendrites (Figure 6G). In contrast, there was a significant main effect of lesion (F1, 40=5.37, P<.05) and lesion×drug interaction (F1, 40=4.16, P<.05), but not main effect of drug, in AMPA EPSCs when stimulating basal dendrites, and a 1-factor ANOVA revealed significant differences in AMPA EPSCs between the Nonlesioned-DW and Lesioned-DW groups (F1, 21=7.01, P<.05) and between the lesioned-DW and lesioned-MIL groups (F1, 20=6.25, P<.05) (Figure 6H).


Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex.

Tsutsui-Kimura I, Yoshida T, Ohmura Y, Izumi T, Yoshioka M - Int. J. Neuropsychopharmacol. (2014)

The effects of lesions of the ventromedial prefrontal cortex (vmPFC) and repeated milnacipran administration on excitatory postsynaptic currents (EPSCs) in the layer V pyramidal neurons in the vmPFC. Electrophysiological characterization of pyramidal neurons in the vmPFC using whole-cell patch-clamp recording. (A) vmPFC position and representative photographs of a coronal slice submerged in our recording chamber depicting the position of an electrode for the recording of EPSCs when stimulating (B) apical (239±33 μm from soma) and (C) basal (77±9 μm from soma) dendrites. (D) Only vmPFC neurons that satisfied the criteria (see supplementary Methods) were used for this study. Examples of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (E) apical and (F) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average AMPA EPSC amplitude in (G) apical and (H) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. Examples of N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (I) apical and (J) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average NMDA EPSC amplitude in (K) apical and (L) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. The peak amplitude was measured on the basis of the averaged waveform of evoked EPSCs (5 consecutive trials) #P<.05, a main effect of the lesion with a 2-factor ANOVA. *P<.05, with a 1-factor ANOVA. DW, distilled water; MIL, milnacipran.
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Figure 6: The effects of lesions of the ventromedial prefrontal cortex (vmPFC) and repeated milnacipran administration on excitatory postsynaptic currents (EPSCs) in the layer V pyramidal neurons in the vmPFC. Electrophysiological characterization of pyramidal neurons in the vmPFC using whole-cell patch-clamp recording. (A) vmPFC position and representative photographs of a coronal slice submerged in our recording chamber depicting the position of an electrode for the recording of EPSCs when stimulating (B) apical (239±33 μm from soma) and (C) basal (77±9 μm from soma) dendrites. (D) Only vmPFC neurons that satisfied the criteria (see supplementary Methods) were used for this study. Examples of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (E) apical and (F) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average AMPA EPSC amplitude in (G) apical and (H) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. Examples of N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs evoked by 1-, 5-, and 10-μA stimulation of (I) apical and (J) basal dendrites of layer V pyramidal neurons of the 4 groups of rats. Average NMDA EPSC amplitude in (K) apical and (L) basal dendrites of layer V pyramidal neurons of rats from the 4 groups. The peak amplitude was measured on the basis of the averaged waveform of evoked EPSCs (5 consecutive trials) #P<.05, a main effect of the lesion with a 2-factor ANOVA. *P<.05, with a 1-factor ANOVA. DW, distilled water; MIL, milnacipran.
Mentions: Considering that the majority of excitatory synapses in the brain occur on dendritic spines, we hypothesized that repeated milnacipran treatment ameliorates reduced excitatory currents in the vmPFC of vmPFC-lesioned rats. Therefore, we analyzed EPSCs mediated by AMPA and NMDA receptors in the layer V pyramidal neurons of the vmPFC when stimulating apical and basal dendrites (Figure 6A-D). A 3-factor ANOVA revealed a significant stimulation intensity×lesion×drug interaction in the AMPA EPSCs when stimulating apical (F10, 610=3.56, P<.05; Figure 6E and G) and basal (F10, 360=9.44, P<.05; Figure 6F and H) dendrites. However, a subsequent 2-factor ANOVA did not find any significant main effect of the lesion (F1, 40=0.09, NS) or drug (F1, 40=0.35, NS) or a lesion×drug interaction (F1, 40=0.63, NS) in AMPA EPSCs when stimulating apical dendrites (Figure 6G). In contrast, there was a significant main effect of lesion (F1, 40=5.37, P<.05) and lesion×drug interaction (F1, 40=4.16, P<.05), but not main effect of drug, in AMPA EPSCs when stimulating basal dendrites, and a 1-factor ANOVA revealed significant differences in AMPA EPSCs between the Nonlesioned-DW and Lesioned-DW groups (F1, 21=7.01, P<.05) and between the lesioned-DW and lesioned-MIL groups (F1, 20=6.25, P<.05) (Figure 6H).

Bottom Line: We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats.Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug.Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Drs Tsutsui-Kimura, Yoshida, Ohmura, Izumi, and Yoshioka); Japan Society for the Promotion of Science, Tokyo, Japan (Dr Tsutsui-Kimura); Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan (Dr Tsutsui-Kimura).

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Related in: MedlinePlus