Several studies also demonstrated that ketamine produced antidepressant-like behaviour in animals exposed to various distinct stressors [127,144]. to the dissociative anaesthetic feature of Proglumide ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed. rapid acting antidepressant effect rapid acting antidepressant effect rapid acting antidepressant effect[4,125] br / [4] br / [4] br / [124] br / br / sucrose consumption (anhedonia test) (after chronic moderate stress)Ketamineno antidepressant effects antidepressant/antianhedonic effect antidepressant effect[4] br / [127] br / [4,127] br / novelty-suppressed feeding (after chronic moderate stress)Ketamineno antidepressant effects antidepressant effect[4] br / [4]fear conditioningketamineNo effect[4]passive avoidance testsketaminenot impair fear memory retention.[124]maternal deprivationketamineantidepressant effect[128,129,130]TrkB knockout forced swimming novelty-suppressed feedingKetamine, MK801 ketamineno antidepressant effects no antidepressant effects[4] br / [4]BDNF knockout Forced swimming Ketamine MK801no antidepressant effects no antidepressant effects[125] br / [4] Arketamine/Esketamine Arketamine Esketamine learned helplessnessrapid acting antidepressant effectno antidepressant effect[131]forced swimmingrapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132]tail suspension rapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132]social defeat stressrapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[131]repeated corticosteronerapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132] Open in a separate window Behavioural screening tests have provided important validation in the development of antidepressants [133]. Therefore, a novel screening framework is required for the development of novel effective antidepressants against conventional monoaminergic antidepressant-resistant depressive disorder. Paradoxically, utilizing animal models that do not respond to conventional monoaminergic antidepressants but are responsive to target agents that have shown efficacy in monoaminergic antidepressant-resistant patients with depressive disorder in the clinic can provide an improved framework to develop novel pharmacological screening for monoaminergic antidepressant-resistant depressive disorder (Table 2) [133]. Ideally, several animal models of monoaminergic antidepressant-resistant depressive disorder must be validated by demonstration that populations resistant to conventional monoaminergic antidepressants respond to medication that is effective in patients with depressive disorder [134]. Currently, some studies have focused on the understanding of which antidepressant responsiveness and resistance mechanisms are present in animal models [135]. According to these concepts, three basic approaches for the animal models of monoaminergic antidepressant-resistant depression have been proposed. (1) Separation of rodents into bimodal subpopulations that respond or are resistant to traditional antidepressant treatments, which are often used following a behavioural stressor such as chronic mild stress [136] or chronic social defeat (Table 2) [137]. (2) Treatments that render rodents resistant to antidepressants (e.g., adrenocorticotropic hormone) [138] or inflammation [139] (Table 2). (3) Genetic models that show resistance to conventional monoaminergic antidepressant treatments (e.g., use of genetically modified mice) (Table 2) [4,125]. Behavioural studies have demonstrated that non-competitive NMDAR antagonists exhibit antidepressant-like effects in forced swimming and tail suspension tests, in learned helplessness paradigms, and in animals exposed to chronic stressors [4,140,141,142,143]. Several studies reported that ketamine displayed rapid-acting antidepressant-like features in mice exposed to a learned helplessness paradigm and forced swimming test (Table 2) [4,124,125]. Several studies also demonstrated that ketamine produced antidepressant-like behaviour in animals exposed to various distinct stressors Proglumide [127,144]. Furthermore, in the maternal deprivation protocol, ketamine could produce antidepressant-like effects in the forced swimming test (Table 2) [128,129,130]. The approval of esketamine has come with serious restrictions, since the doses of Rabbit polyclonal to ADRA1B esketamine required for depression may cause dissociation and delirium, which probably presents shortly after onset of the drug but rapidly disappears just before the antidepressant response [8]. To overcome the adverse side effects, other NMDAR antagonism alternatives have been pursued. Selective antagonists to both GluN2A (NVP-AAM077) and GluN2B (Ro25C6981) have shown antidepressant-like effects without psychotomimetic-like activities preclinically [124,133,145]; however, combination administration of these two agents was sufficient to generate schizophrenia-like stereotypical behaviour [145]. Behavioural studies indicated that NMDAR inhibition probably contributed to the rapid-acting antidepressant effect but could not be involved in the long-lasting antidepressant effect..Inhibition of NMDAR in the ventral tegmental area (VTA), LC and dorsal raphe nucleus (DRN) also increased respective dopamine, norepinephrine and 5-HT releases in the frontal cortex [32,33,34,35,36,39,40,166,167] (Figure 1). consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed. rapid acting antidepressant effect rapid acting antidepressant effect rapid acting antidepressant effect[4,125] br / [4] br / [4] br / [124] br / br / sucrose consumption (anhedonia test) (after chronic mild stress)Ketamineno antidepressant effects antidepressant/antianhedonic effect antidepressant effect[4] br / [127] br / [4,127] br / novelty-suppressed feeding (after chronic mild stress)Ketamineno antidepressant effects antidepressant effect[4] br / [4]fear conditioningketamineNo effect[4]passive avoidance testsketaminenot impair fear memory retention.[124]maternal deprivationketamineantidepressant effect[128,129,130]TrkB knockout forced swimming novelty-suppressed feedingKetamine, MK801 ketamineno antidepressant effects no antidepressant effects[4] br / [4]BDNF knockout Forced swimming Ketamine MK801no antidepressant effects no antidepressant effects[125] br / [4] Arketamine/Esketamine Arketamine Esketamine learned helplessnessrapid acting antidepressant effectno antidepressant effect[131]forced swimmingrapid acting antidepressant effect longer-lasting Proglumide antidepressant effect than esketaminerapid acting antidepressant effect[132]tail suspension rapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132]social defeat stressrapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[131]repeated corticosteronerapid acting antidepressant effect longer-lasting antidepressant effect than esketaminerapid acting antidepressant effect[132] Open in a separate window Behavioural screening tests have provided important validation in the development of antidepressants [133]. Therefore, a novel screening framework is required for the development of novel effective antidepressants against conventional monoaminergic antidepressant-resistant depression. Paradoxically, utilizing animal models that do not respond to conventional monoaminergic antidepressants but are responsive to target agents that have shown effectiveness in monoaminergic antidepressant-resistant individuals with major depression in the medical center can provide an improved framework to develop novel pharmacological screening for monoaminergic antidepressant-resistant major depression (Table 2) [133]. Ideally, several animal models of monoaminergic antidepressant-resistant major depression must be validated by demonstration that populations resistant to standard monoaminergic antidepressants respond to medication that is effective in individuals with major depression [134]. Currently, some studies possess focused on the understanding of which antidepressant responsiveness and resistance mechanisms are present in animal models [135]. Relating to these ideas, three basic methods for the animal models of monoaminergic antidepressant-resistant major depression have been proposed. (1) Separation of rodents into bimodal subpopulations that respond or are resistant to traditional antidepressant treatments, which are often used following a behavioural stressor such as chronic mild stress [136] or chronic interpersonal defeat (Table 2) [137]. (2) Treatments that render rodents resistant to antidepressants (e.g., adrenocorticotropic hormone) [138] or swelling [139] (Table 2). (3) Genetic models that display resistance Proglumide to standard monoaminergic antidepressant treatments (e.g., use of genetically altered mice) (Table 2) [4,125]. Behavioural studies have shown that non-competitive NMDAR antagonists show antidepressant-like effects in forced swimming and tail suspension tests, in learned helplessness paradigms, and in animals exposed to chronic stressors [4,140,141,142,143]. Several studies Proglumide reported that ketamine displayed rapid-acting antidepressant-like features in mice exposed to a learned helplessness paradigm and pressured swimming test (Table 2) [4,124,125]. Several studies also shown that ketamine produced antidepressant-like behaviour in animals exposed to numerous unique stressors [127,144]. Furthermore, in the maternal deprivation protocol, ketamine could create antidepressant-like effects in the pressured swimming test (Table 2) [128,129,130]. The authorization of esketamine offers come with severe restrictions, since the doses of esketamine required for major depression may cause dissociation and delirium, which probably presents shortly after onset of the drug but.