لخّصلي

Nitric Oxide Nitric oxide (NO) has also been reported to be involved in ketamine's antidepressant effects.ACKNOWLEDGMENTS This study was supported by Young Investigator grants from the Brain & Behavior Research Foundation (to J.-W.K., 30254; to K.S., 27733), grant 21153MFDS601 from the Korean Ministry of Food and Drug Safety (to J.-W.K.), National Research Foundation of Korea (NRF) grant RS-2023-00212118 funded by the Korean government (MSIT) (to J.-W.K.), Japan Society for the Promotion of Science KAKENHI grant 22K20697 (to K.S.), and National Institutes of Health grants MH070727 and MI081060 (to L.M.M.) and MH066198 (to E.T.K.).The NMDA receptor activates neuronal nitric oxide synthase to produce NO. In a recent report, NO synthesized by NMDA activation S-nitrosylated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and stimulated the binding of the nitrosylated GAPDH to Rheb, a stimulator for mTOR signaling (91).Moreover, although selective serotonin reuptake inhibitors (SSRIs) rapidly increase serotonin levels in brain regions such as the mPFC and dorsal raphe (99, 100), the antidepressant responses appear 2 to 4 weeks after initiation of drug treatment in patients with MDD (101).In-depth endeavors are ongoing to ascertain the specific pharmacological targets) responsible for the antidepressant effects of ketamine and determine whether it is possible to separate the beneficial effects from the side effect such as abuse potential heart Problems and dissociation thesestudies will be important in contributing to improved treatment outcomes as well as sustained antidepressant action.In animal studies, ketamine restored active stress-coping behaviors in the learned helplessness test by restoring dopaminergie activity and synaptic plasticity in the mesolimbic dopaminergic circuit (94, 95).www.muarvicas.org o The dutidepresunt Action of Kecamine 137 In addition, ketamine treatment increased the activity of Drdl+ neurons in the mPFC, with chemogenetic activation of Drdl+ neurons in the mPFC relieving the helpless behavior.Similarly, depletion of serotonin by injecting p-chlorophenyl alanine, a serotonin synthesis enzyme inhibitor, abolished the antidepressant effects of ketamine, although the effect depended on the study condition (31, 96).

Nitric Oxide
Nitric oxide (NO) has also been reported to be involved in ketamine's antidepressant effects. The NMDA receptor activates neuronal nitric oxide synthase to produce NO. In a recent report, NO synthesized by NMDA activation S-nitrosylated glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and stimulated the binding of the nitrosylated GAPDH to Rheb, a stimulator for mTOR signaling (91). This complex was degraded by activating E3 ubiquitin ligase signaling through Siah 1. Ketamine has been shown to block this signaling transduction and activate mTOR signaling, an event mediated by the NO/GAPDH/Rheb pathway (91). However, other investigators found that treatment with sodium nitroprusside, a NO donor, did not alter the antidepressant effects of ketamine in mice (92). In addition, sodium nitroprusside did not alter the antidepressant effects of ketamine in patients with MIDD at 24 h postinfusion (93).
Monoaminergic System: Dopamine and Serotonin
According to the disinhibition hypothesis of ketamine, the release of neurotransmitters such as dopamine and serotonin is facilitated in the mPFC (16, 26, 29-31). By extension, the monoamin-ergic system has been suggested to be involved in ketamine's antidepressant effects. In animal studies, ketamine restored active stress-coping behaviors in the learned helplessness test by restoring dopaminergie activity and synaptic plasticity in the mesolimbic dopaminergic circuit (94, 95).
www.muarvicas.org • The dutidepresunt Action of Kecamine 137
In addition, ketamine treatment increased the activity of Drdl+ neurons in the mPFC, with chemogenetic activation of Drdl+ neurons in the mPFC relieving the helpless behavior. This suggests that activation of the ventral tegmental area projecting Drdl+ mPFC neurons is key to restoring stress-coping behaviors (95). Similarly, depletion of serotonin by injecting p-chlorophenyl alanine, a serotonin synthesis enzyme inhibitor, abolished the antidepressant effects of ketamine, although the effect depended on the study condition (31, 96). Ketamine has been shown to increase serotonin levels in the mPFC and activate serotonergic neurons projecting from the mPFC to the dorsal raphe nucleus (31, 97). While these preclinical studies suggest a role for the monoaminergic system in the antidepressant action of ketamine, there are conflicting data. For example, haloperidol pretreatment did not block ketamine-mediated mood-elevating effects in healthy subjects (98). Moreover, although selective serotonin reuptake inhibitors (SSRIs) rapidly increase serotonin levels in brain regions such as the mPFC and dorsal raphe (99, 100), the antidepressant responses appear 2 to 4 weeks after initiation of drug treatment in patients with MDD (101). Furthermore, the fact that ketamine is effective in patients who did not respond to SSRIs (also known as patients with TRD) (8, 102) suggests that its mechanism of action differs from that of conventional antidepressant drugs. In short, the monoaminergic system does not appear to be the primary target for the antidepressant effects of ketamine although it may play a role in downstream effects.
CONCLUSIONS AND FUTURE DIRECTION
Over the past several decades, the antidepressant properties of ketamine have been demonstrated in multiple clinical studies, while preclinical studies have attempted to elucidate the molecular and synaptic mechanisms. Ketamine mediates distinctive molecular and synaptic changes, depending on the brain region that engages neural circuits to produce antidepressant action. In-depth endeavors are ongoing to ascertain the specific pharmacological targets) responsible for the antidepressant effects of ketamine and determine whether it is possible to separate the beneficial effects from the side
effect such as abuse potential heart Problems and dissociation thesestudies will be important in contributing to improved treatment outcomes as well as sustained antidepressant action.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
This study was supported by Young Investigator grants from the Brain & Behavior Research Foundation (to J.-W.K., 30254; to K.S., 27733), grant 21153MFDS601 from the Korean Ministry of Food and Drug Safety (to J.-W.K.), National Research Foundation of Korea (NRF) grant RS-2023-00212118 funded by the Korean government (MSIT) (to J.-W.K.), Japan Society for the Promotion of Science KAKENHI grant 22K20697 (to K.S.), and National Institutes of Health grants MH070727 and MI081060 (to L.M.M.) and MH066198 (to E.T.K.).