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BDNF release is required for the behavioral actions of ketamine.

Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS - Int. J. Neuropsychopharmacol. (2014)

Bottom Line: Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF).Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF.They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.

View Article: PubMed Central - PubMed

Affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).

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L-type channel antagonists block the antidepressant behavioral effects of ketamine in the FST. Rats were injected i.p. with either nifedipine (10 mg/kg) or verapamil (10 mg/kg) 30 min prior to a systemic ketamine injection (10 mg/kg). 24 hours after the ketamine injection, immobility was measured in the FST. (A) Ketamine produced a significant decrease in immobility time over the entire 10 min test that was completely blocked by pretreatment with nifedipine (n = 6; drug × drug interaction, F1,20 = 7.023, *p < 0.05). (D) Verapamil pretreatment also completely blocked the effects of ketamine over the entire 10 min test (n = 8; ANOVA, F3,28 = 3.936, *p < 0.05). Fisher’s PLSD post hoc tests revealed a significant difference between vehicle-treated and ketamine-treated rats, pretreatment with verapamil and ketamine (p < 0.05), and verapamil and ketamine alone (p < 0.01). (B, C, E, and F) Immobility was also examined during the first (0–5 min) and second (6–10 min) time blocks of the 10 min test. Ketamine significantly decreased immobility time compared to controls in the first and second epochs, and these effects was blocked by nifedipine (B and C) or verapamil (E and F) in the second epoch: (B) ANOVA, F3,20 = 5.581, *p < 0.05; (C) ANOVA, F3,20 = 10.067, *p < 0.05; (E) ANOVA, F3,28 = 4.857, *p < 0.05; and (F) ANOVA, F3,28 = 3.130, *p < 0.05. All values are the means ± SEM.
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Figure 2: L-type channel antagonists block the antidepressant behavioral effects of ketamine in the FST. Rats were injected i.p. with either nifedipine (10 mg/kg) or verapamil (10 mg/kg) 30 min prior to a systemic ketamine injection (10 mg/kg). 24 hours after the ketamine injection, immobility was measured in the FST. (A) Ketamine produced a significant decrease in immobility time over the entire 10 min test that was completely blocked by pretreatment with nifedipine (n = 6; drug × drug interaction, F1,20 = 7.023, *p < 0.05). (D) Verapamil pretreatment also completely blocked the effects of ketamine over the entire 10 min test (n = 8; ANOVA, F3,28 = 3.936, *p < 0.05). Fisher’s PLSD post hoc tests revealed a significant difference between vehicle-treated and ketamine-treated rats, pretreatment with verapamil and ketamine (p < 0.05), and verapamil and ketamine alone (p < 0.01). (B, C, E, and F) Immobility was also examined during the first (0–5 min) and second (6–10 min) time blocks of the 10 min test. Ketamine significantly decreased immobility time compared to controls in the first and second epochs, and these effects was blocked by nifedipine (B and C) or verapamil (E and F) in the second epoch: (B) ANOVA, F3,20 = 5.581, *p < 0.05; (C) ANOVA, F3,20 = 10.067, *p < 0.05; (E) ANOVA, F3,28 = 4.857, *p < 0.05; and (F) ANOVA, F3,28 = 3.130, *p < 0.05. All values are the means ± SEM.

Mentions: The antidepressant actions of ketamine are blocked by pre-treatment with a glutamate-AMPA receptor antagonist (Maeng et al., 2008; Li et al., 2010). Furthermore, an in vitro study demonstrated that activation of the mTORC1 pathway by stimulation of AMPA receptors is dependent on activation of L-type VDCC (Jourdi et al., 2009). We hypothesized that this cellular mechanism would also be required for the antidepressant effects of ketamine. To test this hypothesis, rats were pretreated with nifedipine (10 mg/kg) or verapamil (10 mg/kg), two structurally different VDCC blockers, 30 min prior to a ketamine injection; the following day (24 hr after ketamine), rats were examined in the FST. Doses for L-type VDCC blockers were chosen based on previous studies of these antagonists in learning and memory (Woodside et al., 2004; Seoane et al., 2009). Rats injected with ketamine had reduced mobility in the FST compared to vehicle-treated rats, and pretreatment with nifedipine completely blocked the antidepressant effect of ketamine, but had no effect alone (two-way ANOVA, F1,20 = 7.023, p < 0.05; Figure 2A–C). Pretreatment with verapamil also completely blocked the effects of ketamine in the FST and had no effect alone (ANOVA, F3,28 = 3.936, p < 0.05; Figure 2D–F). These effects were observed over the total 10 min of the FST, as well as in the first (0–5 min) and second (5–10 min) time blocks for both nifedipine and verapamil. Previous studies have shown that both nifedipine (24 hour following injection) and verapamil (30 and 60 min following injection) do not have an effect on locomotor activity, indicating the effects seen in the FST were not due to a generalized decrease in ambulation for the groups receiving a channel blocker (Borroni et al., 2000; Cain et al., 2002).


BDNF release is required for the behavioral actions of ketamine.

Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS - Int. J. Neuropsychopharmacol. (2014)

L-type channel antagonists block the antidepressant behavioral effects of ketamine in the FST. Rats were injected i.p. with either nifedipine (10 mg/kg) or verapamil (10 mg/kg) 30 min prior to a systemic ketamine injection (10 mg/kg). 24 hours after the ketamine injection, immobility was measured in the FST. (A) Ketamine produced a significant decrease in immobility time over the entire 10 min test that was completely blocked by pretreatment with nifedipine (n = 6; drug × drug interaction, F1,20 = 7.023, *p < 0.05). (D) Verapamil pretreatment also completely blocked the effects of ketamine over the entire 10 min test (n = 8; ANOVA, F3,28 = 3.936, *p < 0.05). Fisher’s PLSD post hoc tests revealed a significant difference between vehicle-treated and ketamine-treated rats, pretreatment with verapamil and ketamine (p < 0.05), and verapamil and ketamine alone (p < 0.01). (B, C, E, and F) Immobility was also examined during the first (0–5 min) and second (6–10 min) time blocks of the 10 min test. Ketamine significantly decreased immobility time compared to controls in the first and second epochs, and these effects was blocked by nifedipine (B and C) or verapamil (E and F) in the second epoch: (B) ANOVA, F3,20 = 5.581, *p < 0.05; (C) ANOVA, F3,20 = 10.067, *p < 0.05; (E) ANOVA, F3,28 = 4.857, *p < 0.05; and (F) ANOVA, F3,28 = 3.130, *p < 0.05. All values are the means ± SEM.
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Figure 2: L-type channel antagonists block the antidepressant behavioral effects of ketamine in the FST. Rats were injected i.p. with either nifedipine (10 mg/kg) or verapamil (10 mg/kg) 30 min prior to a systemic ketamine injection (10 mg/kg). 24 hours after the ketamine injection, immobility was measured in the FST. (A) Ketamine produced a significant decrease in immobility time over the entire 10 min test that was completely blocked by pretreatment with nifedipine (n = 6; drug × drug interaction, F1,20 = 7.023, *p < 0.05). (D) Verapamil pretreatment also completely blocked the effects of ketamine over the entire 10 min test (n = 8; ANOVA, F3,28 = 3.936, *p < 0.05). Fisher’s PLSD post hoc tests revealed a significant difference between vehicle-treated and ketamine-treated rats, pretreatment with verapamil and ketamine (p < 0.05), and verapamil and ketamine alone (p < 0.01). (B, C, E, and F) Immobility was also examined during the first (0–5 min) and second (6–10 min) time blocks of the 10 min test. Ketamine significantly decreased immobility time compared to controls in the first and second epochs, and these effects was blocked by nifedipine (B and C) or verapamil (E and F) in the second epoch: (B) ANOVA, F3,20 = 5.581, *p < 0.05; (C) ANOVA, F3,20 = 10.067, *p < 0.05; (E) ANOVA, F3,28 = 4.857, *p < 0.05; and (F) ANOVA, F3,28 = 3.130, *p < 0.05. All values are the means ± SEM.
Mentions: The antidepressant actions of ketamine are blocked by pre-treatment with a glutamate-AMPA receptor antagonist (Maeng et al., 2008; Li et al., 2010). Furthermore, an in vitro study demonstrated that activation of the mTORC1 pathway by stimulation of AMPA receptors is dependent on activation of L-type VDCC (Jourdi et al., 2009). We hypothesized that this cellular mechanism would also be required for the antidepressant effects of ketamine. To test this hypothesis, rats were pretreated with nifedipine (10 mg/kg) or verapamil (10 mg/kg), two structurally different VDCC blockers, 30 min prior to a ketamine injection; the following day (24 hr after ketamine), rats were examined in the FST. Doses for L-type VDCC blockers were chosen based on previous studies of these antagonists in learning and memory (Woodside et al., 2004; Seoane et al., 2009). Rats injected with ketamine had reduced mobility in the FST compared to vehicle-treated rats, and pretreatment with nifedipine completely blocked the antidepressant effect of ketamine, but had no effect alone (two-way ANOVA, F1,20 = 7.023, p < 0.05; Figure 2A–C). Pretreatment with verapamil also completely blocked the effects of ketamine in the FST and had no effect alone (ANOVA, F3,28 = 3.936, p < 0.05; Figure 2D–F). These effects were observed over the total 10 min of the FST, as well as in the first (0–5 min) and second (5–10 min) time blocks for both nifedipine and verapamil. Previous studies have shown that both nifedipine (24 hour following injection) and verapamil (30 and 60 min following injection) do not have an effect on locomotor activity, indicating the effects seen in the FST were not due to a generalized decrease in ambulation for the groups receiving a channel blocker (Borroni et al., 2000; Cain et al., 2002).

Bottom Line: Recent studies demonstrate that the rapid antidepressant ketamine increases spine number and function in the medial prefrontal cortex (mPFC), and that these effects are dependent on activation of glutamate α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and brain-derived neurotrophic factor (BDNF).Taken together, these results indicate that the antidepressant effects of ketamine are mediated by activation of L-type VDCCs and the release of BDNF.They further elucidate the cellular mechanisms underlying this novel rapid-acting antidepressant.

View Article: PubMed Central - PubMed

Affiliation: Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, CT (Drs Lepack, Fuchikami, Dwyer, Banasr, and Duman).

Show MeSH
Related in: MedlinePlus