Antidepressant Effects Of Ketamine Research Articles

Crosstalk Between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Biomarkers for Ketamine's Antidepressant Effect.

Depression is a worldwide illness with a significant impact on both family and society. Conventional antidepressants are ineffective for more than 30% of patients. In such patients, who have what is called treatment-resistant depression (TRD), inflammatory biomarkers are expressed excessively in both the central nervous system (CNS) and the peripheral blood. Ketamine, a glutamate receptor antagonist, exerts a rapid and sustained therapeutic effect in patients with TRD. Thus, the investigation of the relations between inflammation and glutamate underlying depression has drawn great attention. Inflammation influences glutamate release, transmission, and metabolism, resulting in accumulated extracellular glutamate in the CNS. Downstream of the glutamate receptors, the mammalian target of rapamycin (mTOR) signaling pathway plays a key role in mediating ketamine's antidepressant effect by improving neurogenesis and plasticity. Based on the mechanism and clinical evidence of the inflammatory contribution to the pathogenesis of depression, extensive research has been devoted to inflammatory biomarkers of the clinical response of depression to ketamine. The inconsistent findings from the biomarker investigations are at least partially attributable to the heterogeneity of depression, limited sample size, and complex gene-environment interactions. Deep exploration of the clinical observations and the underlying mechanism of ketamine's antidepressant response can provide new insights into the selection of specific groups of depressed patients for ketamine treatment and to aid in monitoring the therapeutic effect during antidepressant medication. Further, targeting persistent inflammation in patients with TRD and the key molecules mediating ketamine's antidepressant effect may encourage the development of novel therapeutic strategies.

Ketamine promotes rapid and transient activation of AMPA receptor-mediated synaptic transmission in the dorsal raphe nucleus

Accumulating evidence indicates that the antidepressant effects of ketamine are, in part, mediated by an increase in the AMPA receptor-mediated neurotransmission in depression related areas, such as the prefrontal cortex (PFC). Therefore, activity in PFC-projecting areas related to major depression, such as the dorsal raphe nucleus (DR), may also be modulated by ketamine. We used whole-cell patch-clamp recordings and western blot experiments to determine whether ketamine promotes acute and maintained alterations in glutamatergic transmission and mTOR pathway in the DR.Bath perfusion of ketamine, but not the NMDA receptor antagonist D-AP5, increased the frequency of AMPA receptor-mediated spontaneous EPSCs (sEPSCs) in DR neurons. However, ketamine did not affect evoked EPSCs or spontaneous inhibitory currents (sIPSCs). Pre-incubation of DR slices with the mTOR inhibitor PP242 decreased the frequency of sEPSCs and prevented the effect of ketamine. The results also show that while no electrophysiological effects were detected 24 h after ketamine administration, phosphorylation levels of mTOR were significantly increased in the DR. Nevertheless, expression levels of synaptic proteins were unaffected at that time. Altogether, the present data demonstrate that ketamine transiently increases spontaneous AMPA receptor-mediated neurotransmission in the DR.

Role of Inflammatory Bone Markers in the Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model.

BackgroundA recent study demonstrated that inflammatory bone markers play a role in the antidepressant functions of (R,S)-ketamine in treatment-resistant patients with depression. We examined the effect of inflammatory bone markers in the antidepressant functions of (R)-ketamine and (S)-ketamine in a chronic social defeat stress model.MethodsBehavioral tests for antidepressant actions were performed after a single administration of (R)-ketamine or (S)-ketamine. We measured inflammatory bone marker levels in the plasma, which included osteoprotegerin, receptor activator of nuclear factor κB ligand, and osteopontin.Results(R)-ketamine’s antidepressant effects were more potent than those of (S)-ketamine in the behavioral tests. Furthermore, (R)-ketamine but not (S)-ketamine significantly attenuated increased plasma levels of receptor activator of nuclear factor κB ligand in chronic social defeat stress-susceptible mice. We found a positive correlation between sucrose preference and osteoprotegerin/receptor activator of nuclear factor κB ligand ratio.ConclusionsOur findings demonstrate that inflammatory bone markers may play a role in the antidepressant effects of (R)-ketamine.

Rapid antidepressant effect of S-ketamine in schizophrenia

Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total. Importantly, no relevant psychotic or dissociative symptoms occurred during the whole augmentation treatment period leading to a sustained remission of depressive symptoms and suicidality. Our safe and effective experience with intravenous S-ketamine might encourage researchers and clinicians to widen its administration range beyond the diagnosis of depression to enrich the current knowledge of ketamine effects in psychotic disorders.

Astrocytes activation contributes to the antidepressant-like effect of ketamine but not scopolamine

Depression is a common, debilitating mood disorder, but currently available antidepressants have several major drawbacks. Both ketamine and scopolamine attract more and more attention due to their rapid and sustained antidepressant activities. However, the molecular and cellular mechanism that underlies the therapeutic action of ketamine and scopolamine still remain to be elucidated. Considering the importance of astrocytes in the development of depression, we hypothesized that the activation of astrocyte may play a vital role in the antidepressant effects of ketamine and scopolamine. In the present study, the expression of fibrillary acidic protein (GFAP) was detected to evaluate the activation of astrocyte after single injection of ketamine and scopolamine in respective efficient doses. Behavioral tests used to assess antidepressant-like effects were forced swim test (FST) and tail suspension test (TST). Fluorocitrate, a well-established astrocyte inactivator, was adopted to inhibit the activation of astrocyte. The results demonstrated that ketamine, but not scopolamine, could increase significantly the expression of GFAP in hippocampus. In addition, inhibition of astrocyte abolished the antidepressant-like effects of ketamine, but not scopolamine in the FST and TST. It is suggested that activated astrocyte plays a vital role in the antidepressant activities of ketamine rather than scopolamine. These findings may be important for the understanding of the role of astrocyte in depression and antidepressants, especially rapid antidepressants.

Optogenetic Stimulation of <i>Drd1</i> Expressing Neurons Produces Rapid and Long-Lasting Antidepressant Effects

Depression and anxiety affect a large portion of society leading to significant social and economic costs. Numerous lines of evidence suggest that impaired function in the prefrontal cortex (PFC) is a key contributor to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by PFC activity. The PFC contains several pyramidal cell subtypes, but it is unclear whether a particular subtype is targeted to produce a rapid antidepressant response. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that targeting and activating channelrhodopsin in Drd1 expressing pyramidal cells produces rapid and long-lasting antidepressant and anxiolytic responses. Importantly, the results demonstrate that optogenetic silencing of Drd1 neurons blocks the rapid antidepressant effects of ketamine. In contrast, photostimulation of Drd2 containing pyramidal cells was ineffective across anxiety and depression measures. Pharmacological approaches also demonstrate that infusion of a D1 receptor agonist into the medial PFC produces antidepressant and anxiolytic responses, while antagonist infusion blocks the effects of ketamine. These findings aid in understanding the cellular target neurons and mechanisms of rapid-acting antidepressants and offer novel therapeutic sites that can impact antidepressant behaviors.

05-qEEG predictors of response to antidepressive treatment with ketamine

Objective Time-course of ketamine effect was assessed in depressive patients by QEEG to elucidate changes associated with treatment and to assess potential predictors of response. Methods The analysis was completed from data of two double-blind, cross-over, placebo-controlled studies, assessing the effect of ketamine infusion (0.54 mg/kg) in 51 inpatients with MDD. EEG data were analysed during the infusion (10 and 30 min) and 24hours after ketamine administration using eLORETA. Results Ketamine induced immediate decrease of parietooccipital alpha-sources and an increase of gamma-sources in all subjects. Better response to treatment was connected with higher pre-treatment alpha activity in parietooccipital region, lower theta sources in mediofrontal areas and rostral cingulate and with lower lagged-phase alpha synchronization. Responders were also characterized by increase of mediofrontal delta/theta sources immediately after ketamine infusion. The intensity of psychotomimetic symptoms were strong predictor of ketamine antidepressive effect. Conclusion Our results suggest that higher pre-treatment occipital alpha activity together with lower theta activity in anterior cingulate and mediofrontal cortex and lower alpha lagged phase synchronization could serve as moderators of treatment response to ketamine. The antidepressive effect of ketamine seems to be undoubtedly connected with patient‘s psychotomimetic experience. Supported by grant AZV MZCR 15-33250A.

The rapid-onset antidepressant effect of ketamine: More surprises?

An effective rapid-onset treatment for major depressive disorder could save lives. Extensive preclinical and clinical data demonstrate such an action of ketamine. However, the presumptive mechanism of action, inhibition of NMDA (N-methyl-D-aspartate) receptors, has recently been challenged. Elucidation of the mechanism is important clinically for drug discovery and for understanding the (patho)physiology of depression. The best-known pharmacologic property of ketamine is non-competitive inhibition of the NMDA subtype of glutamate receptor. Although other mechanisms have been postulated, this action has been assumed the major one that accounts for ketamine's antidepressant effect. However, a ketamine metabolite and a different mechanism have now been claimed to be necessary and sufficient for the effect. A metabolite has been proposed to be responsible for the antidepressant action of ketamine, via activation of non-NMDA receptors. It will be important to determine which of the competing views is correct.

Behavioral and biochemical sensitivity to low doses of ketamine: Influence of estrous cycle in C57BL/6 mice

RationaleLow-dose ketamine is a rapid-acting antidepressant, to which female rodents are more sensitive as compared to males. However, the mechanism mediating this sex difference in ketamine sensitivity remains elusive. ObjectivesWe sought to determine whether male and female mice differ in their behavioral sensitivity to low doses of ketamine, and uncover how ovarian hormones influence females’ ketamine sensitivity. We also aimed to uncover some of the molecular mechanism(s) in mood-related brain regions that mediate sex differences in ketamine antidepressant effects. MethodsMale and female mice (freely-cycling, diestrus 1 [D1], proestrus [Pro], or D1 treated with an estrogen receptor (ER) α, ERβ, or progesterone receptor (PR) agonist) received ketamine (0, 1.5, or 3 mg/kg, intraperitoneally) and were tested in the forced swim test (FST) 30 min later. Ketamine's influence over synaptic plasticity markers in the prefrontal cortex (PFC) and hippocampus (HPC) of males, D1, and Pro females was quantified by Western blot 1 h post-treatment. ResultsMales, freely cycling females, D1 and Pro females exhibited antidepressant-like responses to 3 mg/kg ketamine. Pro females were the only group where ketamine exhibited an antidepressant effect at 1.5 mg/kg. D1 females treated with an agonist for ERα or ERβ exhibited an antidepressant-like response to 1.5 mg/kg ketamine. Ketamine (3 mg/kg) increased synaptic plasticity-related proteins in the PFC and HPC of males, D1, and Pro females. Yet, Pro females exhibited an increase in p-Akt and p-CaMKIIα in response to 1.5 and 3 mg/kg ketamine. ConclusionOur results indicate that females’ enhanced sensitivity to ketamine during Pro is likely mediated through estradiol acting on ERα and ERβ, leading to greater activation of synaptic plasticity-related kinases within the PFC and HPC.

La découverte des propriétés antidépressives de la kétamine

BackgroundDepression is a frequent disease with a significant medico-economic impact. Conventional antidepressants have a delayed action and are ineffective in one third of cases. Discovery of ketamine's antidepressant effects these last years opens new perspectives for treatment-resistant depression. MethodThis article reviews the discovery of the antidepressant effect of ketamine, the current state of knowledge on its use and the mechanisms underlying these properties. ResultsMany studies now show a robust and rapid but transient antidepressant effect of a subanesthesic dose of ketamine in patients with treatment-resistant depression. To maintain the initial benefits, limited published data pinpoint the interest of repeated administrations of ketamine while relay with glutamatergic modulators seem to be inefficient as well as the combination with electroconvulsive therapy. Ketamine's mechanisms of action are strongly explored. Evidences indicate that ketamine antagonism of the NMDA receptor with a subsequent activation of AMPA receptor are mandatory for the antidepressant effect. Intracellular signalling pathways play a key role. An anti-inflammatory effect of ketamine would also be at stake. ConclusionThe demonstration of ketamine antidepressant effects is a major discovery in psychopharmacology. If studies are still required to evaluate efficacy and safety of ketamine, especially in the long-term exposure and if data remains too limited to use ketamine in routine practice, the discovery of the potent antidepressant effect of ketamine strongly stimulates research for a better understanding of the pathophysiology of depression and for new therapeutic strategies, particularly in the field of modulation of the glutamate pathway in depressive disorders.

Effects of ketamine on depression-like behaviors of male offspring rat exposed to prenatal restraint stress

Objective To investigate the effect of ketamine on depression-like behaviors at different developmental stages of offspring rat exposed to prenatal restraint stress (PRS). Methods Pregnant SD rats were randomly divided into control group (n=6) and PRS group (n=8). The dams of PRS group received three times(45 minutes/time)restraint stress every day. The anxiety-like and depression-like behaviors of the offsprings of the two groups were tested in the stage of juvenile, adolescence and early adulthood. Then the antidepressant effect of ketamine on prenatal stress rats at different developmental stages was observed. Results In the open-field test, the time in the central area of the offspring rats in PRS group at different developmental stages (juvenile(2.50±0.43)s, adolescence(9.17±1.05)s, early adulthood(8.33±0.92)s) were significantly lower than those of the control group((8.33±1.05)s, (19.17±1.06)s, (18.83±1.30 )s, all P<0.05). In the forced swimming test, the immobility time in the offspring rats of PRS group at the different developmental stages (juvenile(192.50±10.82)s, adolescence(182.75±10.12)s, early adulthood(199.88±9.20) s)were significantly higher than those of control group((76.00±19.00)s, (96.30±12.91)s, (108.30±10.98)s, all P<0.05). Ketamine could quickly and strongly reduce the immobility time of the offsprings exposed to PRS in the stage of adolescence and early adulthood (P<0.01), but the effect was weaker in the juvenile offsprings (P<0.05). Conclusion PRS leads to persistent anxiety-like and depression-like behavior in offsprings and ketamine exerts a good antidepressant effect on the offspring rats in the stage of adolescence and early adulthood. Key words: Prenatal restraint stress; Ketamine; Forced swimming test; Depression-like behavior

Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism.

The molecular mechanisms underlying major depressive disorder remain poorly understood, and current antidepressant treatments have many shortcomings. The recent discovery that a single intravenous infusion of ketamine at a subanesthetic dose had robust, rapid and sustained antidepressant effects in individuals with treatment-resistant depression inspired tremendous interest in investigating the molecular mechanisms mediating ketamine's clinical efficacy as well as increased efforts to identify new targets for antidepressant action. We review the clinical utility of ketamine and recent insights into its mechanism of action as an antidepressant, including the roles of N-methyl-D-aspartate receptor inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor upregulation, activation of downstream synaptogenic signalling pathways and the production of an active ketamine metabolite, hydroxynorketamine. Emerging knowledge of the molecular mechanisms underlying both ketamine's positive therapeutic and detrimental side effects will aid the development of a new generation of much-needed superior antidepressant agents.

Short- and long-term antidepressant effects of ketamine in a rat chronic unpredictable stress model.

ObjectiveThis research was aimed to evaluate the behaviors of short‐ or long‐term antidepressant effects of ketamine in rats exposed to chronic unpredictable stress (CUS).BackgroundKetamine, a glutamate noncompetitive NMDA receptor antagonist, regulates excitatory amino acid functions, such as anxiety disorders and major depression, and plays an important role in synaptic plasticity and learning and memory.MethodsAfter 42 days of CUS model, male rats received either a single injection of ketamine (10 mg/kg; day 43) or 15 daily injections (days 43–75). The influence of ketamine on behavioral reactivity was assessed 24 hr (short‐term) or 7 weeks after ketamine treatment (long‐term). Behavioral tests used to assess the effects of these treatments included the sucrose preference (SP), open field (OF), elevated plus maze (EPM), forced swimming (FS), and water maze (WM) to detect anxiety‐like behavior (OF and EPM), forced swimming (FS), and water maze (WM).Results: Short‐term ketamine administration resulted in increases of body weight gain, higher sensitivity to sucrose, augmented locomotor activity in the OF, more entries into the open arms of the EPM, along increased activity in the FS test; all responses indicative of reductions in depression/despair in anxiety‐eliciting situations. No significant differences in these behaviors were obtained under conditions of long‐term ketamine administration (p > .05). The CUS + Ketamine group showed significantly increased activity as compared with the CUS + Vehicle group for analysis of the long‐term effects of ketamine (*p < .05). Nor were significant differences obtained in learning and memory performance in rats receiving ketamine (p > .05).ConclusionTaken together these findings demonstrate that a short‐term administration of ketamine induced rapid antidepressant‐like effects in adult male rats exposed to CUS conditions, effects that were not observed in response to the long‐term treatment regime.

Antidepressant Actions of Ketamine Mediated by the Mechanistic Target of Rapamycin, Nitric Oxide, and Rheb.

The weeks/months it takes for traditional antidepressants to act pose an obstacle in the management of depression. Ketamine's prompt and sustained antidepressant effects constitute a major advance. Multiple studies implicate glutamatergic signaling to protein synthesis machinery and synapse formation in ketamine's antidepressant effects. Here we review evidence linking ketamine to glutamate receptor subtypes and protein homeostasis. We describe a signaling cascade wherein nitric oxide drives the formation of a ternary protein complex comprised of glyceraldehyde 3-phosphate dehydrogenase, seven in absentia homolog 1, and Ras homolog enriched in brain downstream of the glutamate N-methyl-D-aspartate receptor. Seven in absentia homolog 1 ubiquitylates and degrades Ras homolog enriched in brain leading to inhibition of mechanistic target of rapamycin. Ketamine inhibits this molecular cascade leading to activation of mechanistic target of rapamycin and, in turn, to antidepressant actions.

Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression

Introduction: Ketamine has shown rapid though short-lived antidepressant effects. The possibility of concerning neurobiological changes following repeated exposure to the drug motivates the development of strategies that obviate or minimize the need for longer-term treatment with ketamine. In this open-label trial, we investigated whether cognitive behavioral therapy (CBT) can sustain or extend ketamine's antidepressant effects. Methods: Patients who were pursuing ketamine infusion therapy for treatment-resistant depression were invited to participate in the study. If enrolled, the subjects initiated a 12-session, 10-week course of CBT concurrently with a short 4-treatment, 2-week course of intravenous ketamine (0.5 mg/kg infused over 40 min) provided under a standardized clinical protocol. Results: Sixteen participants initiated the protocol, with 8 (50%) attaining a response to the ketamine and 7 (43.8%) achieving remission during the first 2 weeks of protocol. Among ketamine responders, the relapse rate at the end of the CBT course (8 weeks following the last ketamine exposure) was 25% (2/8). On longer-term follow-up, 5 of 8 subjects eventually relapsed, the median time to relapse being 12 weeks following ketamine exposure. Among ketamine remitters, 3 of 7 retained remission until at least 4 weeks following the last ketamine exposure, with 2 retaining remission through 8 weeks following ketamine exposure. Ketamine nonresponders did not appear to benefit from CBT. Conclusions: CBT may sustain the antidepressant effects of ketamine in treatment-resistant depression. Well-powered randomized controlled trials are warranted to further investigate this treatment combination as a way to sustain ketamine's antidepressant effects.

Ketamine Alleviates Depressive-Like Behaviors &lt;i&gt;via&lt;/i&gt; Down-Regulating Inflammatory Cytokines Induced by Chronic Restraint Stress in Mice

The purpose of the present study was to investigate whether ketamine's rapid antidepressant effects were associated with its anti-inflammatory actions and to explore the underlying molecular mechanism. Depressive-like behaviors was induced in mice using chronic restraint stress (CRS) method. Anti-depressive effects of ketamine were evaluated by forced swimming tests (FST) and sucrose preference test (SPT). Subsequently, brain tissue was harvested to investigate inflammatory response in the hippocampus via investigating reactive microglia numbers, serum cytokines levels and the toll-like receptor type 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) pathway. CRS exposure caused depressive-like behaviors in mice, which was associated with increased pre-inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6) levels, reactive microglia numbers and up-regulated regulatory molecules such as TLR4/p38 and P2X7 receptor in hippocampus. Such neurobehavioral and biochemical abnormalities were normalized by ketamine treatment. CRS-induced depression-like behaviours are associated with activation of hippocampal inflammatory response, whereas down-regulation of pro-inflammatory cytokines may contribute to ketamine's antidepressant effects in mice.

Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

Clinical studies on the role of the glutamatergic system in the pathogenesis of depression found that ketamine induces an antidepressant response, but the molecular mechanisms remain unclear. The present study investigated the effects of sub-anesthetic doses of ketamine on the glutamate reuptake function in the rat hippocampus. Chronic unpredictable mild stress (CUMS) was applied to construct animal models of depression. Sixty adult male Sprague-Dawley rats were randomly assigned to 5 groups and received a different regimen of CUMS and ketamine (10, 25, and 50mg/kg) treatment. The sucrose preference test and open-field test were used to assess behavioral changes. The expression levels of excitatory amino acid transporters (EAATs) were measured by western blot. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect hippocampal glutamate concentrations. We found that the expression of EAAT2 and EAAT3 were obviously downregulated, and extracellular concentrations of glutamate were significantly increased in the hippocampi of depressive-like rats. Ketamine (10, 25, and 50mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the hippocampal concentration of extracellular glutamate, and alleviated the rats’ depressive-like behavior. The antidepressant effect of ketamine may be linked to the regulation of EAAT expression and the enhancement of glutamate uptake in the hippocampus of depressive-like rats.

Research progress in the mechanisms of the clinical effects of ketamine

Ketamine is primarily known as an effective NMDAR ( N -methyl- D -aspartic acid receptor) blocker. As one of the intravenous anesthetics, ketamine has been widely used in clinical practice for more than 50 years, exhibiting several different outcomes besides the original anesthetic effects. Recent studies provide insights into the mechanisms of the following neuropharmacological effects of ketamine: (ⅰ) Anesthesia. The anesthetic effects of ketamine are mainly due to its ability to decrease the inter-cortical communications to generate dissociative anesthesia. Besides the well-known NMDAR, another target for ketamine to show anesthetic effects has been reported to be hyperpolarization-activated cyclic nucleotide-gated channels (HCN channels). (ⅱ) Analgesia. Ketamine not only exhibits blockade on NMDAR in the central nervous system, but also reverses opioid tolerance when combined with morphine at a low dose. The affinity with sodium and potassium channels makes ketamine possible for analgesia at high doses. However, the clinical analgesic effect is currently controversial, and the algetic cases after the discontinuation of ketamine are probably caused by its metabolic product norketamine. (ⅲ) Anti-depression. Ketamine is recently regarded as a rapid antidepressant drug for its contribution to neurogenesis through several molecular processes, such as the glutamate burst by activating presynaptic NMDAR and AMPAR ( α -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor), the synaptic protein synthesis and transportation by activating mTOR (mechanistic target of rapamycin), and the synaptic maturation by releasing BDNF (brain derived neurotrophic factor). At the circuit level, ketamine widely reconstructs circuits by dual regulation on NMDAR and AMPAR, and causes loss of phenotype of the PV GABAergic neurons (parvalbumin-positive interneurons). (ⅳ) Side effects. Ketamine is strictly constrained for its psychiatric side effects resulted from the potent disruption on neural network stability, which shares similar neuro-circuit etiology with schizophrenia. Also, the potential ketamine-induced neuroapoptosis might generate risks for anesthesia during pregnancy and childhood, which is under deep investigation. Due to the potential risks of ketamine, more attention should be paid to the development of novel anesthetics keeping the anesthetic, analgesic and antidepressant effects of ketamine, however, without the potential psychiatric side effects. Thus, exceeding novel knowledge, makes ketamine a representative example for the complexity of anesthetics due to its global targets and dose-dependent properties, which provides a breakthrough point both for the mechanism researches for the working models of general anesthetics and for exploring the state of consciousness of human beings.

P.2.a.014 - Ketamine modulates catecholamine transmission in the bed nucleus of stria terminalis: a possible role of this region in the antidepressant effects of ketamine

P.2.a.014 - Ketamine modulates catecholamine transmission in the bed nucleus of stria terminalis: a possible role of this region in the antidepressant effects of ketamine

Ketamine modulates catecholamine transmission in the bed nucleus of stria terminalis: The possible role of this region in the antidepressant effects of ketamine

Since the therapeutic treatment of depression is far from being satisfactory, new therapeutic strategies ought to be pursued. In addition, further investigation on brain areas involved in the action mechanism of antidepressants can shed light on the aetiology of depression. We have previously reported that typical and atypical antidepressants strongly stimulate catecholamine transmission in the bed nucleus of stria terminalis (BNST). In this study, we have built on that work to examine the effect of ketamine, an unusual antidepressant that can produce a fast-acting and long-lasting antidepressant effect after administration of a single sub-anaesthetic dose. Ketamine is an antagonist of the ionotropic N-methyl-D-aspartate (NMDA) receptor but can also act through its metabolite (2R-6R)-hydroxynorketamine. Using the microdialysis technique in freely moving rats, we monitored the acute effect of ketamine on catecholamine release in the BNST to gain clues to its prompt antidepressant effect. Male Sprague-Dawley rats were implanted with a microdialysis probe in the BNST and 48h later, were injected with ketamine (10, 20, and 40mg/kg, i.p.). Ketamine increased norepinephrine (127%, 155%, 186%) and dopamine (114%, 156%, 176%) extracellular concentration above basal in a time and dose dependent manner, without significantly modifying motility. Since the effect of ketamine, although lower, was not substantially different from that produced by classical antidepressants, we suggest that catecholamine increase in BNST is not likely to be related to a rapid ketamine antidepressant effect, though it might be related to its performance in predictive tests of antidepressant properties.