[Resolvin E1 as a potential lead for the treatment of depression].

Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

Role of medial prefrontal cortex voltage-dependent potassium 4.3 channels in nicotine-induced enhancement of object recognition memory in male mice.

Nicotine has been shown to enhance object recognition memory in the novel object recognition (NOR) test by activating excitatory neurons in the medial prefrontal cortex (mPFC). However, the exact neuronal mechanisms underlying the nicotine-induced activation of mPFC neurons and the resultant memory enhancement remain poorly understood. To address this issue, we performed brain-slice electrophysiology and the NOR test in male C57BL/6J mice. Whole-cell patch-clamp recordings from layer V pyramidal neurons in the mPFC revealed that nicotine augments the summation of evoked excitatory postsynaptic potentials (eEPSPs) and that this effect was suppressed by N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2,4-dibromo-6-(2H-tetrazol-5-yl)phenyl]urea (NS5806), a voltage-dependent potassium (Kv) 4.3 channel activator. In line with these findings, intra-mPFC infusion of NS5806 suppressed systemically administered nicotine-induced memory enhancement in the NOR test. Additionally, miRNA-mediated knockdown of Kv4.3 channels in mPFC pyramidal neurons enhanced object recognition memory. Furthermore, inhibition of A-type Kv channels by intra-mPFC infusion of 4-aminopyridine was found to enhance object recognition memory, while this effect was abrogated by prior intra-mPFC NS5806 infusion. These results suggest that nicotine augments the summation of eEPSPs via the inhibition of Kv4.3 channels in mPFC layer V pyramidal neurons, resulting in the enhancement of object recognition memory.

Neuron-specific deletion of VEGF or its receptor Flk-1 occludes the antidepressant-like effects of desipramine and fluoxetine in mice.

Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant-like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron-specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk-1) in the forebrain, we examined the effects of forebrain excitatory neuron-specific deletion of VEGF or Flk-1 on the antidepressant-like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron-specific VEGF or Flk-1 deletion. Although chronic treatment with FLX (18 mg/kg/day, i.p.) did not impact immobility in control mice 1 day after the 22nd injection, immobility was significantly reduced 1 day after the preswim and the 23rd FLX injection. However, in mice with neuron-specific Flk-1 deletion, chronic FLX treatment significantly increased immobility in the preswim and failed to produce antidepressant-like effects. Collectively, these findings indicate that neuronal VEGF-Flk-1 signaling contributes to the antidepressant-like actions of conventional antidepressants.

Antidepressant-like effects of tomatidine and tomatine, steroidal alkaloids from unripe tomatoes, via activation of mTORC1 in the medial prefrontal cortex in lipopolysaccharide-induced depression model mice.

ABSTRACTKetamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant effects in patients with treatment-resistant depression. However, owing to the undesirable adverse effects of ketamine, there is an urgent need for developing safer and more effective prophylactic and therapeutic interventions for depression. Preclinical studies have demonstrated that activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant effects of ketamine. The steroidal alkaloid tomatidine and its glycoside α-tomatine (tomatine) can activate mTORC1 signaling in peripheral tissues/cells. We examined whether tomatidine and tomatine exerted prophylactic and therapeutic antidepressant-like actions via mPFC mTORC1 activation using a mouse model of lipopolysaccharide (LPS)-induced depression. Male mice were intraperitoneally (i.p.) administered tomatidine/tomatine before and after the LPS challenge to test their prophylactic and therapeutic effects, respectively. LPS-induced depression-like behaviors in the tail suspension test (TST) and forced swim test (FST) were significantly reversed by prophylactic and therapeutic tomatidine/tomatine administration. LPS-induced anhedonia in the female urine sniffing test was reversed by prophylactic, but not therapeutic, injection of tomatidine, and by prophylactic and therapeutic administration of tomatine. Intra-mPFC infusion of rapamycin, an mTORC1 inhibitor, blocked the prophylactic and therapeutic antidepressant-like effects of tomatidine/tomatine in TST and FST. Moreover, both tomatidine and tomatine produced antidepressant-like effects in ovariectomized female mice, a model of menopause-associated depression. These results indicate that tomatidine and tomatine exert prophylactic and therapeutic antidepressant-like effects via mTORC1 activation in the mPFC and suggest these compounds as promising candidates for novel prophylactic and therapeutic agents for depression.

[Elucidation of the Mechanisms Underlying the Rapid Antidepressant Actions of Ketamine and Search for Possible Candidates for Novel Rapid-acting Antidepressants].

Ketamine, an N-methyl-D-aspartate receptor antagonist, elicits swift antidepressant effects even in subjects with treatment-resistant depression. Nonetheless, owing to the serious adverse effects associated with ketamine, including psychotomimetic effects, the development of safer rapid-acting antidepressants is imperative. The elucidation of the mechanisms underlying the antidepressant effects of ketamine will facilitate the advancement of these alternative treatments. Previous preclinical studies have indicated that the antidepressant properties of ketamine are mediated by the activity-dependent release of brain-derived neurotrophic factor (BDNF) and the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC). Our research has demonstrated that ketamine exerts antidepressant-like effects by inducing the release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in the mPFC. Furthermore, our recent findings have revealed that resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), which are bioactive lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, exhibit antidepressant-like effects in rodent models. Notably, the antidepressant-like effects of RvD1, RvD2, and RvE1 require mTORC1 activation. Moreover, the intranasal administration of RvE1 elicits rapid antidepressant-like effects through the release of BDNF and VEGF in the mPFC and hippocampal dentate gyrus (DG), as well as mTORC1 activation in the mPFC, albeit not in the DG. These findings strongly suggest that resolvins, particularly RvD1, RvD2, and RvE1, hold promise as prospective candidates for novel, safer, and rapid-acting antidepressants.

Varenicline enhances recognition memory via α7 nicotinic acetylcholine receptors in the medial prefrontal cortex in male mice.

Previous studies postulated that chronic administration of varenicline, a partial and full agonist at α4ß2 and α7 nicotinic acetylcholine receptors (nAChRs), respectively, enhances recognition memory. However, whether its acute administration is effective, on which brain region(s) it acts, and in what signaling it is involved, remain unknown. To address these issues, we conducted a novel object recognition test using male C57BL/6J mice, focusing on the medial prefrontal cortex (mPFC), a brain region associated with nicotine-induced enhancement of recognition memory. Systemic administration of varenicline before the training dose-dependently enhanced recognition memory. Intra-mPFC varenicline infusion also enhanced recognition memory, and this enhancement was blocked by intra-mPFC co-infusion of a selective α7, but not α4ß2, nAChR antagonist. Consistent with this, intra-mPFC infusion of a selective α7 nAChR agonist augmented object recognition memory. Furthermore, intra-mPFC co-infusion of U-73122, a phospholipase C (PLC) inhibitor, or 2-aminoethoxydiphenylborane (2-APB), an inositol trisphosphate (IP3) receptor inhibitor, suppressed the varenicline-induced memory enhancement, suggesting that α7 nAChRs may also act as Gq-coupled metabotropic receptors. Additionally, whole-cell recordings from mPFC layer V pyramidal neurons in vitro revealed that varenicline significantly increased the summation of evoked excitatory postsynaptic potentials, and this effect was suppressed by U-73122 or 2-APB. These findings suggest that varenicline might acutely enhance recognition memory via mPFC α7 nAChR stimulation, followed by mPFC neuronal excitation, which is mediated by the activation of PLC and IP3 receptor signaling. Our study provides evidence supporting the potential repositioning of varenicline as a treatment for cognitive impairment.

Noradrenergic stimulation of α1 adrenoceptors in the medial prefrontal cortex mediates acute stress-induced facilitation of seizures in mice.

Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α1 adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α1 adrenoceptors.

Role of 5-HT1A receptors in the basolateral amygdala on 3,4-methylenedioxymethamphetamine-induced prosocial effects in mice.

3,4-methylenedioxymethamphetamine (MDMA), a recreational drug, induces euphoric sensations and psychosocial effects, such as increased sociability and empathy. Serotonin, also called 5-hydroxytryptamine (5-HT), is a neurotransmitter that has been associated with MDMA-induced prosocial effects. However, the detailed neural mechanisms remain elusive. In the present study, we investigated whether 5-HT neurotransmission in the medial prefrontal cortex (mPFC) and the basolateral nucleus of amygdala (BLA) is involved in MDMA-induced prosocial effects using the social approach test in male ICR mice. Systemic administration of (S)-citalopram, a selective 5-HT transporter inhibitor, before administration of MDMA failed to suppress MDMA-induced prosocial effects. On the other hand, systemic administration of the 5-HT1A receptor antagonist WAY100635, but not 5-HT1B, 5-HT2A, 5-HT2C, or 5-HT4 receptor antagonist, significantly suppressed MDMA-induced prosocial effects. Furthermore, local administration of WAY100635 into the BLA but not into the mPFC suppressed MDMA-induced prosocial effects. Consistent with this finding, intra-BLA MDMA administration significantly increased sociability. Together, these results suggest that MDMA induces prosocial effects through the stimulation of 5-HT1A receptors in the BLA.

Intranasal Administration of Resolvin E1 Produces Antidepressant-Like Effects via BDNF/VEGF-mTORC1 Signaling in the Medial Prefrontal Cortex.

Intracerebroventricular infusion of resolvin E1 (RvE1), a bioactive metabolite derived from eicosapentaenoic acid, exerts antidepressant-like effects in a mouse model of lipopolysaccharide (LPS)-induced depression; these effects are blocked by systemic injection of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor. Additionally, local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) produces antidepressant-like effects. To evaluate the potential of RvE1 for clinical use, the present study examined whether treatment with RvE1 via intranasal (i.n.) route, a non-invasive route for effective drug delivery to the brain, produces antidepressant-like effects in LPS-challenged mice using tail suspension and forced swim tests. Intranasal administration of RvE1 significantly attenuated LPS-induced immobility, and these antidepressant-like effects were completely blocked by an AMPA receptor antagonist or L-type voltage-dependent Ca2+ channel blocker. The antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 were blocked by intra-mPFC infusion of a neutralizing antibody (nAb) for brain-derived neurotrophic factor (BDNF) or vascular endothelial growth factor (VEGF). Intra-mPFC infusion of rapamycin completely blocked the antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 as well as those of intra-mPFC infusion of BDNF and VEGF. Moreover, i.n. RvE1 produced antidepressant-like effects via mTORC1 activation in the mPFC of a mouse model of repeated prednisolone-induced depression. Intra-dorsal DG infusion of BDNF and VEGF nAbs, but not rapamycin, blocked the antidepressant-like effects of i.n. RvE1. These findings suggest that i.n. administration of RvE1 produces antidepressant-like effects through activity-dependent BDNF/VEGF release in the mPFC and dorsal DG, and mTORC1 activation in the mPFC, but not in the dorsal DG. Thus, RvE1 can be a promising candidate for a novel rapid-acting antidepressant.

Role of neurotrophic and growth factors in the rapid and sustained antidepressant actions of ketamine.

The neurotrophic hypothesis of depression proposes that reduced levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) contribute to neuronal atrophy or loss in the prefrontal cortex (PFC) and hippocampus and impaired hippocampal adult neurogenesis, which are associated with depressive symptoms. Chronic, but acute, treatment with typical monoaminergic antidepressants can at least partially reverse these deficits, in part via induction of BDNF and/or VEGF expression, consistent with their delayed onset of action. Ketamine, an N-methyl-d-aspartate receptor antagonist, exerts rapid and sustained antidepressant effects. Rodent studies have revealed that ketamine rapidly increases BDNF and VEGF release and/or expression in the PFC and hippocampus, which in turn increases the number and function of spine synapses in the PFC and hippocampal neurogenesis. Ketamine also induces the persistent release of insulin-like growth factor 1 (IGF-1) in the PFC of male mice. These neurotrophic effects of ketamine are associated with its rapid and sustained antidepressant effects. In this review, we first provide an overview of the neurotrophic hypothesis of depression and then discuss the role of BDNF, VEGF, IGF-1, and other growth factors (IGF-2 and transforming growth factor-ß1) in the antidepressant effects of ketamine and its enantiomers. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Resolution of depression: antidepressant actions of resolvins.

Major depressive disorder, one of the most widespread mental illnesses, brings about enormous individual and socioeconomic consequences. Conventional monoaminergic antidepressants require weeks to months to produce a therapeutic response, and approximately one-third of the patients fail to respond to these drugs and are considered treatment-resistant. Although recent studies have demonstrated that ketamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant effects in treatment-resistant patients, it also has undesirable side effects. Hence, rapid-acting antidepressants that have fewer adverse effects than ketamine are urgently required. D-series (RvD1-RvD6) and E-series (RvE1-RvE4) resolvins are endogenous lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, respectively. These mediators reportedly play a pivotal role in the resolution of acute inflammation. In this review, we reveal that intracranial infusions of RvD1, RvD2, RvE1, RvE2, and RvE3 produce antidepressant-like effects in various rodent models of depression. Moreover, the behavioral effects of RvD1, RvD2, and RvE1 are mediated by the activation of the mechanistic target of rapamycin complex 1, which is essential for the antidepressant-like actions of ketamine. Finally, we briefly provide our perspective on the possible role of endogenous resolvins in stress resilience.

A spatiotemporal increase of neuronal activity accompanies the motivational effect of wheel running in mice.

Spatiotemporal patterns of neuronal activity underlying the motivational effect of rotating running wheels (RWs) in rodents remain largely undetermined. Here, we investigated changes of neuronal activity among brain regions associated with motivation across different intensities of motivation for RWs in mice. Daily exposure to RWs gradually increased rotation number, then became stable after approximately 3 weeks. Immunohistochemical analyses revealed that the number of c-Fos (a neuronal activity marker)-positive cells increased in the medial prefrontal cortex (mPFC), core and shell of the nucleus accumbens (NAc), dorsal striatum (Str), and lateral septum (LS) at day 1, day 9, and days 20-24, in a time-dependent manner. Additionally, despite exposure to locked RWs for over 7 days after establishing stable rotation with 3-week RW access, increased c-Fos expression was still observed in most of these brain areas. Furthermore, daily overnight RW access developed stable rotation by day 6, with high and low rotation numbers at the start and end of the overnight session, respectively. The number of c-Fos-positive cells at the start of RW rotation was significantly higher than at the end of RW rotation in most brain regions. Furthermore, after establishing stable rotation, the number of c-Fos-positive cells increased in the mPFC and shell of the NAc of mice that only observed RWs. These findings suggest that the subareas of the mPFC and NAc may be critically involved in the motivational effects of RW rotations.

IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine.

Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine. However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine. In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively). The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation. These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.

The antidepressant-like effect of resolvin E1 in repeated prednisolone-induced depression model mice.

Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from eicosapentaenoic acid. We previously demonstrated that intracerebroventricular (i.c.v.) and intra-medial prefrontal cortex (mPFC) infusions of RvE1 produce antidepressant-like effects in a lipopolysaccharide-induced depression mouse model. To further confirm the antidepressant-like effect of RvE1, the present study examined whether RvE1 ameliorated depression-like behavior induced by repeated injections of prednisolone (PSL), a synthetic glucocorticoid, in male ICR mice. We first ascertained whether repeated subcutaneous treatment with PSL (50 mg/kg, once a day) affected locomotor activity and anxiety-like behavior in the open field test (OFT; after a 5-day PSL treatment) and induced depression-like behavior in the tail suspension test (TST; after a 6-day PSL treatment) and forced swim test (FST; after a 7-day PSL treatment). Repeated PSL injections significantly increased immobility in the FST, which was not ameliorated by acute desipramine treatment (30 mg/kg, i.p.), but not in the TST, without affecting locomotor activity and anxiety-like behavior in the OFT. Subsequently, we investigated the therapeutic effects of i.c.v. (1 ng) and intra-mPFC (50 pg/side) infusions of RvE1 in the repeated PSL-induced depression mouse model using the OFT and FST after 5- and 6-day PSL treatments, respectively. The repeated PSL-induced increase in immobility in the FST was significantly attenuated by both i.c.v. and intra-mPFC infusions of RvE1 without affecting the locomotor activity and anxiety-like behavior. In addition, a single i.c.v. infusion of RvE1 immediately before the first or fourth injection of PSL also attenuated PSL-induced depression-like behavior in the FST, suggesting the preventive effect of RvE1. These results indicate that RvE1 produces antidepressant-like effects in a mouse model of repeated PSL-induced depression.

Resolvin E1 Attenuates Chronic Pain-Induced Depression-Like Behavior in Mice: Possible Involvement of Chemerin Receptor ChemR23.

The antidepressant effect of eicosapentaenoic acid-derived bioactive lipid, resolvin E1 (RvE1), was examined in a murine model of chronic pain-induced depression using a tail suspension test. Because RvE1 reportedly possesses agonistic activity on a chemerin receptor ChemR23, we also examined the antidepressant effect of chemerin. Two weeks after surgery for unilateral spared nerve injury to prepare neuropathic pain model mice, immobility time was measured in a tail suspension test. Chronic pain significantly increased immobility time, and this depression-like behavior was attenuated by intracerebroventricular injection of RvE1 (1 ng) or chemerin (500 ng). These results demonstrate that RvE1 exerts an antidepressant effect in a murine model of chronic pain-induced depression, which is likely to be via ChemR23. RvE1 and its receptor may be promising targets to develop novel antidepressants.

Resolvins as potential candidates for the treatment of major depressive disorder.

In contrast with the delayed onset of therapeutic responses and relatively low efficacy of currently available monoamine-based antidepressants, a single subanesthetic dose of ketamine, an N-methyl-D-aspartate receptor antagonist, produces rapid and sustained antidepressant actions even in patients with treatment-resistant depression. However, since the clinical use of ketamine as an antidepressant is limited owing to its adverse effects, such as psychotomimetic/dissociative effects and abuse potential, there is an unmet need for novel rapid-acting antidepressants with fewer side effects. Preclinical studies have revealed that the antidepressant actions of ketamine are mediated via the release of brain-derived neurotrophic factor and vascular endothelial growth factor, with the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex. Recently, we demonstrated that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), endogenous lipid mediators generated from n-3 polyunsaturated fatty acids (docosahexaenoic and eicosapentaenoic acids), exert antidepressant effects in a rodent model of depression, and that the antidepressant effects of RvD1, RvD2, and RvE1 necessitate mTORC1 activation. In this review, we first provide an overview of the mechanisms underlying the antidepressant effects of ketamine and other rapid-acting agents. We then discuss the possibility of using resolvins as novel therapeutic candidates for depression.

Nicotine enhances object recognition memory through inhibition of voltage-dependent potassium 7 channels in the medial prefrontal cortex of mice.

Nicotine administration enhances object recognition memory. However, target brain regions and cellular mechanisms underlying the nicotine effects remain unclear. In mice, the novel object recognition test revealed that systemic nicotine administration before training enhanced object recognition memory. Moreover, this effect was inhibited by infusion of retigabine, a selective voltage-dependent potassium 7 (Kv7) channel opener, into the medial prefrontal cortex (mPFC) before nicotine administration. Additionally, infusion of XE-991, a selective Kv7 channel blocker, into the mPFC before training enhanced object recognition memory. Therefore, Kv7 channels in the mPFC may be at least partly involved in nicotine-induced enhancement of object recognition memory.

Resolvin D2 attenuates chronic pain-induced depression-like behavior in mice.

AIM: We previously demonstrated that intracerebroventricular injection of resolvin D2 (RvD2), a bioactive lipid mediator derived from docosahexaenoic acid, ameliorated depression-like behavior in lipopolysaccharide-induced and chronic mild stress-induced mouse models of depression. In the present study, we examined the antidepressant effect of RvD2 on chronic pain-induced depression-like behavior. METHODS: To prepare the neuropathic pain model, mice were subjected to surgery for unilateral spared nerve injury. Two weeks after surgery, the antidepressant effect of RvD2 was examined using the tail suspension test. RESULTS: Chronic pain significantly increased immobility time, and this depression-like behavior was attenuated by intracerebroventricular injection of RvD2 (10 ng). No effect of RvD2 on the locomotor activity was observed. CONCLUSION: RvD2 produces an antidepressant effect in a murine model of chronic pain-induced depression and may be a promising lead for the development of novel antidepressants.

Nicotine Enhances Object Recognition Memory via Stimulating α4ß2 and α7 Nicotinic Acetylcholine Receptors in the Medial Prefrontal Cortex of Mice.

Nicotine has been known to enhance recognition memory in various species. However, the brain region where nicotine acts and exerts its effect remains unclear. Since the medial prefrontal cortex (mPFC) is associated with memory, we examined the role of the mPFC in nicotine-induced enhancement of recognition memory using the novel object recognition test in male C57BL/6J mice. Systemic nicotine administration 10 min before training session significantly enhanced object recognition memory in test session that was performed 24 h after the training. Intra-mPFC infusion of mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist, 5 min before nicotine administration blocked the effect of nicotine. Additionally, intra-mPFC infusion of dihydro-ß-erythroidine, a selective α4ß2 nAChR antagonist, or methyllycaconitine, a selective α7 nAChR antagonist, significantly suppressed the nicotine-induced object recognition memory enhancement. Finally, intra-mPFC infusion of nicotine 1 min before the training session augmented object recognition memory in a dose-dependent manner. These findings suggest that mPFC α4ß2 and α7 nAChRs mediate the nicotine-induced object recognition memory enhancement.

Nicotine Enhances Firing Activity of Layer 5 Pyramidal Neurons in the Medial Prefrontal Cortex through Inhibition of Kv7 Channels.

Nicotine enhances attention, working memory and recognition. One of the brain regions associated with these effects of nicotine is the medial prefrontal cortex (mPFC). However, cellular mechanisms that induce the enhancing effects of nicotine remain unclear. To address this issue, we performed whole-cell patch-clamp recordings from mPFC layer 5 pyramidal neurons in slices of C57BL/6J mice. Shortly (approx. 2 min) after bath application of nicotine, the number of action potentials, which were elicited by depolarizing current injection, was increased, and this increase persisted for over 5 min. The effect of nicotine was blocked by the α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-ß-erythroidine, α7 nAChR antagonist methyllycaconitine, or intracellular perfusion with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Additionally, the voltage-dependent potassium 7 (Kv7) channel blocker, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991), as well as nicotine, shortened the spike threshold latency and increased the spike numbers. By contrast, the Kv7 channel opener, retigabine reduced the number of firings, and the addition of nicotine did not increase the spike numbers. These results indicate that nicotine induces long-lasting enhancement of firing activity in mPFC layer 5 pyramidal neurons, which is mediated by the stimulation of the α4ß2 and α7 nAChRs and subsequent increase in intracellular Ca2+ levels followed by the suppression of the Kv7 channels. The novel effect of nicotine might underlie the nicotine-induced enhancement of attention, working memory and recognition.