SUMMARY Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some but not all behavioral paradigms, suggesting both neurogenesis-dependent and independent mechanisms of antidepressant actions. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, β-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that β-arrestin signaling is necessary for the antidepressant effects of fluoxetine.

Nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic (DA) neurons have long been considered as potential therapeutic targets for the treatment of several neuropsychiatric diseases, including nicotine and cocaine addiction or Parkinson's disease. However, DA neurons express mRNAs coding for most, if not all, neuronal nAChR subunits, and the subunit composition of functional nAChRs has been difficult to establish. Immunoprecipitation experiments performed on mouse striatal extracts allowed us to identify three main types of heteromeric nAChRs (alpha4beta2*, alpha6beta2*, and alpha4alpha6beta2*) in DA terminal fields. The functional relevance of these subtypes was then examined by studying nicotine-induced DA release in striatal synaptosomes and recording ACh-elicited currents in DA neurons fromalpha4, alpha6, alpha4alpha6, and beta2 knock-out mice. Our results establish that alpha6beta2* nAChRs are functional and sensitive to alpha-conotoxin MII inhibition. These receptors are mainly located on DA terminals and consistently do not contribute to DA release induced by systemic nicotine administration, as evidenced by in vivo microdialysis. In contrast, (nonalpha6)alpha4beta2* nAChRs represent the majority of functional heteromeric nAChRs on DA neuronal soma. Thus, whereas a combination of alpha6beta2* and alpha4beta2* nAChRs may mediate the endogenous cholinergic modulation of DA release at the terminal level, somato-dendritic (nonalpha6)alpha4beta2* nAChRs most likely contribute to nicotine reinforcement.

Background Stress exposure is one of the greatest risk factors for psychiatric illnesses like Major Depressive Disorder (MDD) and Post-Traumatic Stress Disorder (PTSD). However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress-induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. Methods Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine (K) could protect against depressive-like behavior. Mice were administered a single dose of saline (Sal) or ketamine and then one week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. Results SD robustly and reliably induced depressive-like behavior in control (Ctrl) mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test (FST) and in the dominant interaction (DI) test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training—and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the FST, novelty suppressed feeding (NSF) paradigm, and the sucrose splash test (ST). Conclusions These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders.

Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT 4 receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT 4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT 4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety-and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT 4 receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT 4 receptor activation is necessary for these effects of SSRIs. 5-HT 4 receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.

Our study showed that drug sensitivity is genotype dependent. FST results have shown that Swiss mice are the most sensitive strain to detect 5-HT and/or NA treatment. The use of DBA/2 inbred mice may be limited, as an absence of antidepressant-like response was observed in the FST. The lack of sensitivity to antidepressant treatment in DBA/2 strains could be due to high DA, NA and 5-HT whole brain concentrations.

Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel object recognition test, NORT), associative (one-trial contextual fear conditioning, CFC), and visuo-spatial (Morris water maze, MWM; Barnes maze, BM) learning/memory. Altered emotional phenotype after chronic corticosterone treatment was confirmed in mice using tests predictive of anxiety or depression-related behaviors. In the NORT, CORT-treated mice showed a decrease in time exploring the novel object during the test session and a lower discrimination index compared to control mice, characteristic of recognition memory impairment. Associative memory was also impaired, as observed with a decrease in freezing duration in CORT-treated mice in the CFC, thus pointing out the cognitive alterations in this model. In the MWM and in the BM, spatial learning performance but also short-term spatial memory were altered in CORT-treated mice. In the MWM, unlike control animals, CORT-treated animals failed to learn a new location during the reversal phase, suggesting a loss of cognitive flexibility. Finally, in the BM, the lack of preference for the target quadrant during the recall probe trial in animals receiving corticosterone regimen demonstrates that long-term retention was also affected in this paradigm. Taken together, our results highlight that CORT-induced anxio-depressive-like phenotype is associated with a cognitive deficit affecting all aspects of memory tested.

Vortioxetine (Lu AA21004) is an investigational novel antidepressant with multimodal activity that functions as a 5-HT3, 5-HT7 and 5-HT(1D) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and inhibitor of the 5-HT transporter in vitro. Here we explore its anxiolytic and antidepressant potential in adult mice. Vortioxetine was assessed in BalB/cJ@RJ mice using the open-field and forced-swim tests (acute: p.o. 1 h, repeated: daily p.o. 21 days), and in 129S6/SvEvTac mice using the novelty suppressed feeding paradigm (acute: p.o. 1 h, sustained: daily p.o. 14 or 21 days). Fluoxetine and diazepam were controls. Acute and repeated dosing of vortioxetine produced more pronounced anxiolytic- and antidepressant-like activities than fluoxetine. Vortioxetine significantly increased cell proliferation and cell survival and stimulated maturation of immature granule cells in the subgranular zone of the dentate gyrus of the hippocampus after 21 days of treatment. After 14 days, a high dose of vortioxetine increased dendritic length and the number of dendrite intersections, suggesting that vortioxetine accelerates the maturation of immature neurons. Vortioxetine displays an antidepressant and anxiolytic profile following repeated administration associated with increased neurogenesis at several stages. Vortioxetine effects were observed at low levels of 5-HT transporter occupancy, suggesting an alternative mechanism of action to 5-HT reuptake inhibition.

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