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Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.

ABSTRACT: Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in major depressive disorder (MDD) patients. (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a metabolite of ketamine, is reported to produce rapid antidepressant effects in rodent models without the side effects of ketamine. Importantly, (2R,6R)-HNK does not block NMDA receptors like ketamine, and the molecular signaling mechanisms for (2R,6R)-HNK remain unknown. Here, we examined the involvement of BDNF/TrkB/mechanistic target of rapamycin complex 1 (mTORC1) signaling in the antidepressant actions of (2R,6R)-HNK. Intramedial prefrontal cortex (intra-mPFC) infusion or systemic (2R,6R)-HNK administration induces rapid and long-lasting antidepressant effects in behavioral tests, identifying the mPFC as a key region for the actions of (2R,6R)-HNK. The antidepressant actions of (2R,6R)-HNK are blocked in mice with a knockin of the BDNF Val66Met allele (which blocks the processing and activity-dependent release of BDNF) or by intra-mPFC microinjection of an anti-BDNF neutralizing antibody. Blockade of L-type voltage-dependent Ca2+ channels (VDCCs), required for activity-dependent BDNF release, also blocks the actions of (2R,6R)-HNK. Intra-mPFC infusion of pharmacological inhibitors of TrkB or mTORC1 signaling, which are downstream of BDNF, also block the actions of (2R,6R)-HNK. Moreover, (2R,6R)-HNK increases synaptic function in the mPFC. These findings indicate that activity-dependent BDNF release and downstream TrkB and mTORC1 signaling, which increase synaptic function in the mPFC, are required for the rapid and long-lasting antidepressant effects of (2R,6R)-HNK, supporting the potential use of this metabolite for the treatment of MDD.

SUBMITTER: Fukumoto K

PROVIDER: S-EPMC6320534 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.

Fukumoto Kenichi K Fogaça Manoela V MV Liu Rong-Jian RJ Duman Catharine C Kato Taro T Li Xiao-Yuan XY Duman Ronald S RS

Proceedings of the National Academy of Sciences of the United States of America 20181217 1

Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces rapid and long-lasting antidepressant effects in major depressive disorder (MDD) patients. (2R,6R)-Hydroxynorketamine [(2R,6R)-HNK], a metabolite of ketamine, is reported to produce rapid antidepressant effects in rodent models without the side effects of ketamine. Importantly, (2R,6R)-HNK does not block NMDA receptors like ketamine, and the molecular signaling me ...[more]

PMID: 30559184

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Project description:(R,S)-Ketamine has rapid and sustained antidepressant effects in depressed patients. Although the metabolism of (R,S)-ketamine to (2 R,6 R)-hydroxynorketamine (HNK), a metabolite of (R)-ketamine, has been reported to be essential for its antidepressant effects, recent evidence suggests otherwise. The present study investigated the role of the metabolism of (R)-ketamine to (2 R,6 R)-HNK in the antidepressant actions of (R)-ketamine. Antidepressant effects were evaluated using the forced swimming test in the lipopolysaccharide (LPS)-induced inflammation model of mice and the tail suspension test in naive mice. To prevent the metabolism of (R)-ketamine to (2 R,6 R)-HNK, mice were pretreated with cytochrome P450 (CYP) inhibitors. The concentrations of (R)-ketamine, (R)-norketamine, and (2 R,6 R)-HNK in plasma, brain, and cerebrospinal fluid (CSF) samples were determined using enantioselective liquid chromatography-tandem mass spectrometry. The concentrations of (R)-norketamine and (2 R,6 R)-HNK in plasma, brain, and CSF samples after administration of (R)-norketamine (10 mg/kg) and (2 R,6 R)-HNK (10 mg/kg), respectively, were higher than those generated after administration of (R)-ketamine (10 mg/kg). Nonetheless, while (R)-ketamine attenuated, neither (R)-norketamine nor (2 R,6 R)-HNK significantly altered immobility times of LPS-treated mice. Treatment with CYP inhibitors prior to administration of (R)-ketamine increased the plasma levels of (R)-ketamine, while generation of (2 R,6 R)-HNK was almost completely blocked. (R)-Ketamine exerted the antidepressant effects at a lower dose in the presence of CYP inhibitors than in their absence, which is consistent with exposure levels of (R)-ketamine but not (2 R,6 R)-HNK. These results indicate that metabolism to (2 R,6 R)-HNK is not necessary for the antidepressant effects of (R)-ketamine and that unmetabolized (R)-ketamine itself may be responsible for its antidepressant actions.

Project description:Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice.

Project description:Background and purpose(R)-Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)-ketamine has lower potency than (R,S)-ketamine to inhibit NMDA receptors in vitro, the extent to which (R)-ketamine shares the NMDA receptor-mediated adverse effects of (R,S)-ketamine in vivo has not been fully characterised. Furthermore, (R)-ketamine is metabolised to (2R,6R)-hydroxynorketamine (HNK), which may contribute to its antidepressant-relevant actions.Experimental approachUsing mice, we compared (R)-ketamine with a deuterated form of the drug (6,6-dideutero-(R)-ketamine, (R)-d2 -ketamine), which hinders its metabolism to (2R,6R)-HNK, in behavioural tests predicting antidepressant responses. We also examined the actions of intracerebroventricularly infused (2R,6R)-HNK. Further, we quantified putative NMDA receptor inhibition-mediated adverse effects of (R)-ketamine.Key results(R)-d2 -Ketamine was identical to (R)-ketamine in binding to and functionally inhibiting NMDA receptors but hindered (R)-ketamine's metabolism to (2R,6R)-HNK. (R)-Ketamine exerted greater potency than (R)-d2 -ketamine in several antidepressant-sensitive behavioural measures, consistent with a role of (2R,6R)-HNK in the actions of (R)-ketamine. There were dose-dependent sustained antidepressant-relevant actions of (2R,6R)-HNK following intracerebroventricular administration. (R)-Ketamine exerted NMDA receptor inhibition-mediated behaviours similar to (R,S)-ketamine, including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination, with approximately half the potency of the racemic drug.Conclusions and implicationsMetabolism of (R)-ketamine to (2R,6R)-HNK increases the potency of (R)-ketamine to exert antidepressant-relevant actions in mice. Adverse effects of (R)-ketamine require higher doses than those necessary for antidepressant-sensitive behavioural changes in mice. However, our data revealing that (R)-ketamine's adverse effects are elicited at sub-anaesthetic doses indicate a potential risk for sensory dissociation and abuse liability.

Project description:BACKGROUND:Brain-derived neurotrophic factor (BDNF) plays a key role in the pathophysiology and treatment of depression. Recent clinical studies demonstrate that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, produces rapid antidepressant effects in patients with depression. Rodent studies demonstrate that scopolamine increases glutamate transmission and synaptogenesis in the medial prefrontal cortex (mPFC). Here we tested the hypothesis that activity-dependent BDNF release within the mPFC is necessary for the antidepressant actions of scopolamine. METHODS:Behavioral effects of scopolamine were assessed in BDNF Val/Met knock-in mice, in which BDNF processing and release are impaired. In addition, intra-mPFC infusion of a BDNF-neutralizing antibody was performed to test the necessity of BDNF release in driving scopolamine-induced behavioral responses. Further in vivo and in vitro experiments were performed to delineate BDNF-dependent mechanisms underlying the effects of scopolamine. RESULTS:We found that BDNF Met/Met mice have attenuated responses to scopolamine and that anti-BDNF antibody infusions into the mPFC prevented the antidepressant-like behavioral effects of scopolamine. In vitro experiments show that scopolamine rapidly stimulates BDNF release and tropomyosin receptor kinase B-extracellular signal-regulated kinase signaling. Moreover, these effects require alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor activation and are blocked by neuronal silencing. Importantly, pretreatment with verapamil prevented scopolamine-induced behavioral responses and BDNF-tropomyosin receptor kinase B signaling, suggesting that these effects are dependent on activation of voltage-dependent calcium channels. CONCLUSIONS:The results identify an essential role for activity-dependent BDNF release in the rapid antidepressant effects of scopolamine. Attenuation of responses in BDNF Met mice indicates that patients with the Met allele may be less responsive to scopolamine.

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Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine.

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Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2<i>R</i>,6<i>R</i>)-hydroxynorketamine.

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