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Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Rodent models of depression are useful for the investigation of cellular and neuronal mechanisms of antidepressant drugs and for the discovery of potential new targets. In this study, we examined the antidepressant-like effect of scopolamine, a non-selective muscarinic antagonist, in a genetic mouse model of depression obtained through a selective breeding strategy and called H/Rouen. In this model, we observed that scopolamine was active both in males and females at a lower dose (0.03 mg/kg) in the tail suspension test, 30 min following its administration, than observed in CD-1 mice. In addition, we showed this antidepressant-like effect was partly inhibited by an injection of 10 mg/kg of the AMPA receptor antagonist NBQX in both males and females, suggesting the antidepressant-like effect of scopolamine was mainly driven by AMPA receptors in the H/Rouen mouse line. Altogether, our results showed the high sensitivity of the H/Rouen mouse model of depression to study the antidepressant-like effects of pharmacological compounds., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Background: Verbal and non-verbal communication, as well as empathy are central to patient-doctor interactions and have been associated with patients' satisfaction. Non-verbal communication tends to override verbal messages. The aim of this study was to analyze how medical students use verbal and non-verbal communication using two different educational approaches, student role play (SRP) and actor simulated patient (ASP), and whether the non-verbal behaviour is different in the two different poses., Methods: Three raters evaluated 20 students playing the doctor role, 10 in the SRP group and 10 in the ASP group. The videos were analyzed with the Calgary-Cambridge Referenced Observation Guide (CCG) and, for a more accurate evaluation of non-verbal communication, we also evaluated signs of nervousness, and posture. Empathy was rated with the CARE questionnaire. Independent Mann Whitney U tests and Qhi square tests were performed for statistical analysis., Results: From the 6 main tasks of the CCG score, we obtained higher scores in the ASP group for the task 'Gathering information' (p = 0.0008). Concerning the 17 descriptors of the CCG, the ASP group obtained significantly better scores for 'Exploration of the patients' problems to discover the biomedical perspective' (p = 0.007), 'Exploration of the patients' problems to discover background information and context' (p = 0.0004) and for 'Closing the session - Forward planning' (p = 0.02). With respect to non-verbal behaviour items, nervousness was significantly higher in the ASP group compared to the SRP group (p < 0.0001). Concerning empathy, no differences were found between the SRP and ASP groups., Conclusions: Medical students displayed differentiated verbal and non-verbal communication behaviour during the two communication skills training methodologies. These results show that both methodologies have certain advantages and that more explicit non-verbal communication training might be necessary in order to raise students' awareness for this type of communication and increase doctor-patient interaction effectiveness.

Study Objectives: Paradoxical sleep (PS) has been shown to play an important role in memory, in particular in emotional memory processes. However, the involvement of this particular sleep stage in the systemic consolidation of remote (30 days old) memory has never been tested. We examined whether post-learning PS could play a role in the consolidation of remote fearful memory and in the brain network reorganization that depends on it., Methods: Mice were PS-deprived during 6 hours after contextual fear conditioning using an automated method, and their memory was tested either 1 day or 30 days after learning. Brain activity during retrieval was assessed using the immediate early gene Egr1 (Zif 268) as a neuronal marker of activity., Results: We found that PS deprivation impaired the recall of remote (30 days)-but not recent (1 day)-memory. We also showed that the superficial layers of the anterior cingulate cortex were significantly less activated during the retrieval of remote memory after PS deprivation. In contrast, after such deprivation, retrieval of remote memory significantly activated several areas involved in emotional processing such as the CA1 area of the ventral hippocampus, the basolateral amygdala and the superficial layers of the ventral orbitofrontal cortex. By performing graph-theoretical analyses, our result also suggests that post-learning PS deprivation could impact the reorganization of the functional connections between limbic areas in order to reduce the level of global activity in this network., Conclusions: These findings suggest an important role for PS in the systemic consolidation of remote memory.

Caffeine prophylactically prevents mood and memory impairments through adenosine A 2A receptor (A 2A R) antagonism. A 2A R antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 ± 7 %) and GABAergic (vGAT; -23 ± 8 %) markers in the hippocampus. HM displayed higher A 2A R density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A 2A R agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the A 2A R antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A 2A R controlling synaptic glutamatergic function.

Background: Major depression has multiple comorbidities, in particular drug use disorders, which often lead to more severe and difficult-to-treat illnesses. However, the mechanisms linking these comorbidities remain largely unknown., Methods: We investigated how a depressive-like phenotype modulates cocaine-related behaviors using a genetic model of depression: the Helpless H/Rouen (H) mouse. We selected the H mouse line for its long immobility duration in the tail suspension test when compared to non-helpless (NH) and intermediate (I) mice. Since numerous studies revealed important sex differences in drug addiction and depression, we conducted behavioral experiments in both sexes., Results: All mice, regardless of phenotype or sex, developed a similar behavioral sensitization after 5 daily cocaine injections (10 mg/kg). Male H and NH mice exhibited similar cocaine-induced conditioned place preference scores that were only slightly higher than in I mice, whereas female H mice strikingly accrued much higher preferences for the cocaine-associated context than those of I and NH mice. Moreover, female H mice acquired cocaine-associated context learning much faster than I and NH mice, a facilitating effect that was associated to a rapid increase in striatal and accumbal brain-derived neurotrophic factor levels (BDNF; up to 35% 24 h after cocaine conditioning). Finally, when re-exposed to the previously cocaine-associated context, female H mice displayed greater Fos activation in the cingulate cortex, nucleus accumbens, and basolateral amygdala., Conclusions: Our data indicate that neurobiological mechanisms such as alterations in associative learning, striato-accumbal BDNF expression, and limbic-cortico-striatal circuit reactivity could mediate enhanced cocaine vulnerability in female depressive-like mice., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.

Cardinal symptoms of depression include helplessness and anhedonia. In addition, depression and anxiety are often comorbid disorders. H/Rouen mice, a genetic mouse model of depression, display helpless behavior in the tail suspension test, whereas non-helpless NH/Rouen mice show the opposite behavior. It is unknown whether H/Rouen mice display an anxious behavior as compared to NH/Rouen mice, and is unclear whether they display anhedonia. Time spent in the periphery of an open-field, an index of anxiety, was found to be higher in male and female H/Rouen mice as compared to NH/Rouen mice. In the elevated plus-maze, a decrease in the number of entries and in the time spent in the open arms was observed in both male and female H/Rouen. In the light/dark box, the number of entries and the time spent in the anxiogenic bright compartment was significantly reduced in male and female H/Rouen mice. In addition, the preference of consumption of a 2% sucrose solution was significantly reduced in male and female H/Rouen mice as compared to NH/Rouen and I/Rouen mice in a two-bottle choice paradigm but was restored by a chronic (3 weeks) fluoxetine treatment. H/Rouen mice thus display both anxiety and anhedonia making them a potent animal model in the treatment of forms depression comorbidly expressed with anxiety., (Copyright © 2013. Published by Elsevier B.V.)

The neurotransmitter glutamate is increasingly being implicated as playing a role in the molecular pathology underlying depression. The group III family of metabotropic glutamate (mGlu) receptors (mGlu(4,) mGlu(7) and mGlu(8) receptors) remains the most poorly investigated of all glutamate receptors in this regard, despite early research efforts showing that they may be major players in stress-induced pathology, genetic vulnerability to the onset of depression and in the action of pharmacotherapies. To redress this deficit, we investigated whether the mRNA levels of the group III mGlu receptors display sensitivity to the preclinical stress models' chronic immobilisation stress (CIS) in BALB/c mice and chronic social defeat in BALB/c and C57BL/6j mice. We also investigated the potential of the mood stabiliser lithium to reverse any stress-induced alterations to expression levels of the group III mGlu receptors. Furthermore, we investigated if changes to hippocampal group III mGlu receptors are involved in the augmentation strategy of administering lithium in conjunction with the tricyclic antidepressant desipramine using BALB/c mice. Finally, we investigated whether differences in hippocampal group III mGlu receptors exist between the non-helpless NH/Rouen mouse line and the helpless H/Rouen line. We found no changes to hippocampal group III mGlu receptor expression in any of the stress models investigated, the H/Rouen mouse genetic model of depression or due to pharmacological treatment. This indicates that these receptors may not be involved in the manifestation of behavioural and physiological changes observed in these models and furthermore, may not contribute to the therapeutic mechanisms of the above mentioned pharmacotherapies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Genetic factors are believed to be involved in the aetiology of unipolar depressive disorders. We have previously described a model built up by selective breeding of mice with different responses in the tail suspension test, a screening test for potential antidepressants. In this model, helpless H/Rouen mice are essentially immobile in this test, as well as in the Porsolt forced-swim test, whereas non-helpless NH/Rouen mice show the opposite behaviour, i.e. very low immobility. However, it is unclear whether or not the other phenotypic differences (forced swim test, locomotor activity, sucrose test, sleep patterns, effect of fluoxetine) observed between H/Rouen and the NH/Rouen mice may be attributed to a genetic drift phenomenon during the selection step, rather than being related to the trait of selection. In this study we used reciprocal crossbreeding between H/Rouen and NH/Rouen mice and obtained a segregating F2 population in order to determine whether phenotypic differences between the two lines co-segregate with the trait of selection. In the segregating F2 population, we found significant and strong genetic correlations between helplessness in the tail suspension test and some phenotypical features associated with depressive disorders such as 'alterations of sleep patterns', behavioural response to fluoxetine, immobility duration in the forced swim test, and anhedonia. Our results converge with clinical observations in depressed humans. These results strengthen the validity of the H/Rouen mouse as a model of depression, notably for preclinical studies with antidepressants. In addition, this model should open the way to identifying genes related to depression-like behaviours.

The novel antidepressant agomelatine behaves as an agonist at melatonergic MT(1) and MT(2) receptors and as an antagonist at serotonin 5-HT(2C) receptors. This study investigated the effects of agomelatine and fluoxetine in a genetic model of depression called H/Rouen mice Male and female H/Rouen (helpless line) and NH/Rouen (nonhelpless line) mice, received once daily for 3 weeks agomelatine (10 and 50 mg/kgi.p.), fluoxetine (10 mg/kgi.p.) or vehicle. Immobility duration in the tail suspension test (TST) was assessed on day 1 (D1), day 8 (D8), day 15 (D15) and day 22 (D22). Locomotor activity in a novel environment was assessed on day 18 (D18) and anhedonia (2-bottle sucrose preference test) was considered after the end of chronic treatment, from days 22 to 25. Agomelatine (50 mg/kg) significantly reduced immobility at D15 (p<0.01), and D22 (p<0.001) in treated H/Rouen mice whereas agomelatine at 10 mg/kg did not induce a statistically significant change. Fluoxetine reduced immobility at D8 (p<0.01), D15 (p<0.001) and D22 (p<0.001). Locomotor activity was unchanged in all treated groups as compared to vehicle groups. In the sucrose test, there was a significant decrease in sucrose preference in H/Rouen mice compared with NH/Rouen mice receiving vehicle. Both agomelatine doses (10 mg/kg (p=0.05) and 50 mg/kg (p<0.001) as well as fluoxetine (p<0.001) significantly increased the sucrose preference in H/Rouen mice as compared with H/Rouen mice that had received vehicle. These data indicate that the novel antidepressant agomelatine has antidepressant-like properties in H/Rouen mice, a genetic model of depression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

There is growing evidence suggesting that antagonists of group II metabotropic glutamate receptors (mGluR2/3) exhibit antidepressant-like properties in several preclinical models of depression. However, all those studies have been performed using competitive group II non-selective orthosteric antagonists. In this study we extensively characterized a group II selective negative allosteric modulator (4-[3-(2,6-Dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one, namely RO4491533, Woltering et al., 2010) in several in vitro biochemical assays and in vivo models of depression. In vitro, RO4491533 completely blocked the glutamate-induced Ca(2+) mobilization and the glutamate-induced accumulation in [(35)S]GTP(γS) binding in cells expressing recombinant human or rat mGluR2 and in native tissues. Results from Schild plot experiments and reversibility test at the target on both cellular and membrane-based assays confirmed the negative allosteric modulator properties of the compound. RO4491533 was equipotent on mGluR2 and mGluR3 receptors but not active on any other mGluRs. RO4491533 has acceptable PK properties in mice and rats, is bioavailable following oral gavage (F = 30%) and brain-penetrant (CSF conc/total plasma conc ratio = 0.8%). RO4491533 appeared to engage the central mGluR2 and mGluR3 receptors since the compound reversed the hypolocomotor effect of an mGluR2/3 orthosteric agonist LY379268 in a target-specific manner, as did the group II orthosteric mGluR2/3 antagonist LY341495. RO4491533 and LY341495 dose-dependently reduced immobility time of C57Bl6/J mice in the forced swim test. Also, RO4491533 and LY341495 were active in the tail suspension test in a line of Helpless (H) mice, a putative genetic model of depression. These data suggest that mGluR2/3 receptors are viable targets for development of novel pharmacotherapies for depression.

Rationale: H/Rouen (displaying a helpless phenotype in the tail suspension test) mice exhibiting features of depressive disorders and NH/Rouen (displaying non-helpless phenotype) mice were previously created through behavioural screening and selective breeding. Learned helplessness (LH), in which footshock stress induces a coping deficit, models some aspects of depression in rodents, but so far, fewer LH studies have been performed in mice than in rats., Objectives: To study H/Rouen and NH/Rouen in the LH paradigm., Results: When CD1 mice were submitted to footshock with various training durations and shock intensities, the most suitable parameters to induce a behavioural deficit were 0.3 mA and four training sessions. A significantly longer latency to escape shocks was found in male H/Rouen mice compared to male NH/Rouen mice. On the other hand, once shocked, NH/Rouen mice showed more severe coping deficits than H/Rouen mice. In addition, a sub-chronic treatment with fluoxetine lacked efficacy in NH/Rouen mice, whereas it improved performances in H/Rouen mice. We also found that a shock reminder at day 8, subsequent to inescapable shocks, maintained helplessness for 20 days. Finally, female H/Rouen mice responded to chronic fluoxetine administration after 10 days of treatment, while a 20-day treatment was necessary to improve the behavioural deficit in H/Rouen male mice., Conclusion: H/Rouen and NH/Rouen lines displayed different despair-related behaviour in the LH paradigm. Fluoxetine had beneficial effects after sub-chronic or chronic but not acute treatment of H/Rouen mice, thus providing a pharmacological validation of the protocols.

Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression., Competing Interests: The authors have declared that no competing interests exist.

The neuromodulator adenosine, acting through activation of four defined metabotropic receptors called A(1), A(2A), A(2B) and A(3,) has been proposed as an endogenous anticonvulsant. Here, the consequences of deleting the adenosine A(2A) receptor have been examined in different experimental models of epilepsy. A(2A)R KO mice were not protected against seizures originating from brainstem structures, namely electroshock-induced seizures. The intensities of seizures induced by pentylenetetrazol or pilocarpine, as well as the percentages of convulsing mice, were significantly reduced in A(2A) receptor knockout (A(2A)R KO) animals. A(2A)R KO mice exhibited reduced pentylenetetrazol-induced kindled seizures, demonstrating an important role of the A(2A) receptor in the acquisition of kindling. These data suggest that adenosine stimulating A(2A) receptors modulates excitatory neurotransmission and exacerbates limbic seizures. It is therefore suggested that adenosine A(2A) receptor antagonists might offer protection from some epileptic syndromes.

Although numerous studies investigated the mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity, little is known about its long-term functional consequences on 5-HT neurotransmission in mice. This led us to evaluate the delayed effects of MDMA exposure on the 5-HT system, using in-vitro and in-vivo approaches in both 5-HTT wild-type and knock-out mice. Acute MDMA in-vitro application on slices of the dorsal raphe nucleus (DRN) induced concentration-dependent 5-HT release and 5-HT cell firing inhibition. Four weeks after MDMA administration (20 mg/kg b.i.d for 4 d), a 2-fold increase in the potency of the 5-HT1A receptor agonist ipsapirone to inhibit the discharge of DRN 5-HT neurons and a larger hypothermic response to 8-OH-DPAT were observed in MDMA- compared to saline-treated mice. This adaptive 5-HT1A autoreceptor supersensitivity was associated with decreases in 5-HT levels but no changes of [3H]citalopram binding in brain. Long-term MDMA treatment also induced a 30% decrease in BrdU labelling of proliferating hippocampal cells and an increased immobility duration in the forced swim test suggesting a depressive-like behaviour induced by MDMA treatment. All these effects were abolished in 5-HTT-/- knock-out mice. These data indicated that, in mice, MDMA administration induced a delayed adaptive supersensitivity of 5-HT1A autoreceptors in the DRN, a deficit in hippocampal cell proliferation and a depressive-like behaviour. These 5-HTT-dependent effects, opposite to those of antidepressants, might contribute to MDMA-induced mood disorders.

Long-term caffeine intake has been reported to decrease the susceptibility to convulsants in mice. Occurrence of seizures following long-term oral administration of caffeine (0.3g/l) was investigated using adenosine A(2A) receptor knockout (A(2A)R KO) and control (A(2A)R WT) mice. Clonic seizures induced by acute pentylenetetrazol (PTZ, 50mg/kg i.p.) were significantly attenuated in adenosine A(2A)R KO mice drinking only water and reduced by a 14-day caffeine treatment in adenosine A(2A)R WT mice. In addition we showed a protecting effect of a 21-day caffeine treatment in A(2A)R WT mice against kindled seizures induced by PTZ in an increasing dose schedule. Summing up, these protective effects against PTZ-induced seizures occurring when adenosine A(2A)R is absent or chronically blocked by a relevant dose of caffeine may be related to a decreased neuronal excitability.

Are there appropriate rodent models for human depressive disorders? A model that targets a core aspect of depression can become a helpful tool in the analysis of the causes, genetic or environmental, that result in symptoms homologous to those of depressed patients. Rodent models can also allow the study of the pathophysiology of specific behaviors, and can help in predicting therapeutic responses to pharmacological agents. A rodent model of depression should satisfy as many of the three main criteria as possible: similar etiology, similar pathophysiology, and similar treatment to the human condition. A wide range of rodent models of depression has been developed so far, including genetic models.

Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1-deficient (Kcnk2-/-) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.