Evaluation of reward processes in an animal model of depression

Rationale Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Objective Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. Materials and methods The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Results Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Conclusions Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence.     

Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine

Rationale The role of pharmacotherapy in the treatment of major depressive disorder (MDD) in youth has received much attention in recent years due to concerns of efficacy and safety of the antidepressants for the treatment of MDD in youth. Objectives This review describes the existing published and unpublished literature regarding the efficacy and short-term safety of the antidepressants and decision-making process required for the use of these medications for youth with MDD. In addition, current continuation and maintenance treatments are discussed. Results In general, nine depressed youth must be treated with an antidepressant to obtain one clinical response above that achieved with placebo. To date, fluoxetine has showed the most consistent positive treatment effects. Depressed youth had also acutely responded to other antidepressants, but the response to placebo has also been high. Overall, the antidepressants are well tolerated, but 1–3 children and adolescents of 100 taking antidepressants showed onset or worsening of suicidal ideation and, more rarely, suicide attempts. Conclusions There is a positive risk–benefit ratio for the use of antidepressants in the acute treatment of depressed youth. First-line antidepressant treatment with—or without—specific types of psychotherapy is indicated for youth with MDD of at least moderate severity. All youth taking antidepressants must be closely monitored for suicidality and medication side effects. Many youth will likely require psychotherapy or additional medication treatments to address comorbid disorders. Treatments to prevent relapses and recurrences require further study.     

Activation of the mGlu7 receptor elicits antidepressant-like effects in mice

Rationale Broad evidence indicates that modulation of the glutamatergic system could be an efficient way to achieve antidepressant activity. Metabotropic glutamate receptor (mGlu receptor) ligands seem to be promising agents to treat several central nervous system disorders, including psychiatric ones. Objectives The aim of our study was to investigate potential antidepressant-like activity of the first, selective, and bio-available mGlu7 receptor agonist, AMN082 (N,N′-dibenzyhydryl-ethane-1,2-diamine dihydrochloride), in wild-type (WT) and mGlu7 receptor knock-out (KO) mice. Materials and methods The forced swim test (FST) and the tail suspension test (TST) in mice were used to assess antidepressant-like activity of AMN082. Results We found that AMN082, administered IP, induced a dose-dependent decrease in the immobility time of WT animals in the FST and TST, suggesting antidepressant-like potency of an mGlu7 receptor agonist. Moreover, AMN082 did not change the behaviour of mGlu7 receptor KO mice compared to WT littermates in the TST, while imipramine, used as a reference control, significantly reduced their immobility, indicating an mGlu7 receptor-dependent mechanism of the antidepressant-like activity of AMN082. However, at high doses, AMN082 significantly decreased spontaneous locomotor activity of both mGlu7 receptor KO mice and WT control animals, suggesting off-target activity of AMN082 resulting in hypo-locomotion. Conclusions These results strongly suggest that activation of the mGlu7 receptor elicits antidepressant-like effects.     

Maprotiline block of the human ether-a-go-go-related gene (HERG) K<Superscript>+</Superscript> channel

Maprotiline, an atypical antidepressant, can induce prolonged QT and torsades de pointes. We studied the effects of maprotiline on human ether-a-go-go-related gene (HERG) channels expressed in Xenopus oocytes and HEK293 cells. Maprotiline induced a concentration-dependent decrease in current amplitudes at the end of the voltage steps and tail currents of HERG. The V1/2 values in the absence and presence of 1-20 microM maprotiline were not significantly different, while the values decreased according to the concentrations of the drug at 50-300 microM. The IC50 for a maprotiline block of HERG current in Xenopus oocytes did not change according to depolarization; 39.5 +/- 3.2 microM at -40 mV and 43.6 +/- 2.8 microM at +40 mV. The block of HERG by maprotiline was examined after treatment of trinitrobenzene sulfonic acid (TNBS), an amino-group reagent that neutralizes the positively charged amino-groups of peptide N-terminal and lysine residues. TNBS inhibited the change of V1/2 values induced by 50-300 mM maprotiline, and aggravated the drug-induced gmax decrease. The IC50 for the maprotiline-induced blockade of HERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Our findings suggest that the arrhythmogenic side effects of maprotiline are caused by a blockade of HERG and possibly by a blockade of delayed rectifier K+ channel.     

越鞠升降汤对轻中度抑郁症患者躯体症状的改善作用

目的观察越鞠升降汤对轻中度抑郁症患者躯体症状的改善作用。方法将58例轻中度抑郁症患者随机分为2组,治疗组30例予越鞠升降汤治疗,对照组28例予盐酸氟西汀胶囊治疗．2组均6周为1个疗程,治疗2个疗程。比较2组疗效,观察2组治疗前后汉密尔顿抑郁量表（HAMD）评分、躯体症状评分变化。结果2组总有效比较差异有统计学意义（P〈0．05）,治疗组疗效优于对照组。2组治疗后HAMD评分、躯体症状评分均较本组治疗前降低（P〈0．01）,且治疗组降低更明显（P〈0．01）。结论越鞠升降汤治疗轻中度抑郁症安全有效,可显著改善患者的躯体症状。     

Antidepressant-like effect of genipin in mice

The present study aimed to investigate the antidepressant potential of genipin and its possible mechanisms. Mouse models of depression including the forced swimming test (FST) and the tail suspension test (TST) were used to evaluate the effects of genipin. A possible mechanism was explored in the test of antagonism of reserpine-induced ptosis and hypothermia in mice. The contents of monoamine neurotransmitters and their metabolites including epinephrine (NE), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in mice hippocampi were determined by HPLC–ECD. The results showed that intra-gastric administration of genipin at 50, 100, 200 mg/kg or fluoxetine at 7.5 mg/kg for 7 days significantly reduced the duration of immobility in FST and TST, while it did not affect the locomotor activity in the open field test (OFT). However, the effect was not dose-dependent. When the mice were treated with genipin or fluoxetine for 7 days, both of them could antagonize reserpine-induced ptosis and hypothermia. The 5-HT and NE contents in mice hippocampi were decreased after the peritoneal injection of reserpine at 2.0 mg/kg. The pre-treatment with genipin at 50, 100, 200 mg/kg or fluoxetine at 7.5 mg/kg for 7 days could elevate the contents of NE and 5-HT in mice hippocampi significantly. The results suggest that compared with fluoxetine, genipin exerts antidepressant-like effects significantly. A possible mechanism, at least in part, is the regulation of the 5-HT and NE levels in the hippocampus.     

SA4503, a sigma-1 receptor agonist,prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression

Many studies suggest that antidepressants act as neuroprotective agents in the central nervous system (CNS), though the underlying mechanism has not been fully elucidated. In the present study, we examined the effect of SA4503, which is a sigma-1 receptor agonist and a novel antidepressant candidate, on oxidative stress-induced cell death in cultured cortical neurons. Exposure of the neurons to H₂O₂ induced cell death, while pretreatment with SA4503 inhibited neuronal cell death. The SA4503-dependent survival effect was reversed by co-application with BD1047 (an antagonist of sigma-1/2 receptors). Previously we found that H₂O₂ triggers a series of events including over-activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and intracellular Ca²⁺ accumulation via voltage-gated Ca²⁺ channels and ionotropic glutamate receptors, resulting in neuronal cell death (Numakawa et al. (2007) [20]). Importantly, we found in this study that SA4503 reduced the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1. Taking these findings together, it is possible that SA4503 blocks neuronal cell death via repressing activation of the MAPK/ERK pathway and, consequently, expression levels of glutamate receptors.     

Synthesis, antidepressant and antifungal evaluation of novel 2-chloro-8-methylquinoline amine derivatives

A new series of N-[(2-chloro-8-methylquinolin-3-yl)methyl]-(substituted)-aniline/butylamine/cyclohexylamine/benzylamine derivatives (4a-p) was synthesized by nucleophilic substitution reaction of 2-chloro-3-(chloromethyl)-8-methylquinoline 3 with various aliphatic and aromatic amines in absolute ethanol in the presence of triethylamine (TEA). The newly synthesized secondary amines were characterized by the combined use of IR, ¹H NMR, ¹³C NMR, mass spectral data and microanalyses. The antidepressant activity of the synthesized compounds (4a-p) was evaluated by Forced swim test in rats and their neurotoxicity was evaluated by the rotarod test. Test compounds and clomipramine were administered intraperitoneally at dose of 100 mg/kg and 20 mg/kg respectively. Preliminary antidepressant screening of compounds (4a-p) revealed that compounds 4b, 4c, 4d, 4e, 4i and 4o significantly (P < 0.01) reduces the duration of immobility time. These compounds were also tested in-vitro for MAO inhibitory effect. All the compounds were also screened for antifungal activity against Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus purpureus MTCC 369 and Penicillium citrinum NCIM 768 strains.     

Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists

Growing evidence has indicated that the blockade of group II metabotropic glutamate (mGlu2/3) receptor exerts antidepressant-like effects in several animal models of depression. However, the molecular mechanisms underlying the action of mGlu2/3 receptor antagonists are not well understood. Here, we investigated the involvement of mammalian target of rapamycin (mTOR) signaling in the acute and sustained antidepressant-like effects of mGlu2/3 receptor antagonists such as (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495).Mice were subjected to a tail suspension test (TST) to assess the acute and sustained antidepressant-like effects. We evaluated the effect of rapamycin, an mTOR antagonist, on the acute and sustained antidepressant-like effects of mGlu2/3 receptor antagonists.Both MGS0039 and LY341495 exerted antidepressant-like effects, as evaluated using the TST; these effects were sustained for 24 h. Pretreatment with rapamycin blocked the sustained, but not the acute, antidepressant-like effects of mGlu2/3 receptor antagonists, as observed in ketamine.The present result suggests that the blockade of the mGlu2/3 receptor may activate mTOR signaling, and that the activation of mTOR signaling may contribute to the sustained antidepressant-like effects of mGlu2/3 receptor antagonists.     

Fluoxetine prevents 8-OH-DPAT-induced hyperphagia in Fischer inbred rats

Ovariectomized, Fischer rats were hormonally primed with 10 μg estradiol benzoate and 50 μg progesterone or were treated with the sesame seed oil vehicle. Food intake was measured 2 h and 24 h after treatment with 0.25 mg/kg of the 5-HT_1A receptor agonist, (±)-8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT), 5 mg/kg of the selective serotonin reuptake inhibitor, fluoxetine, or their combination. Consistent with prior studies, two hour food intake of rats given fluoxetine and 8-OH-DPAT did not differ from vehicle controls. 8-OH-DPAT-induced hyperphagia, evident at 2 h, was blocked by co-treatment with fluoxetine. However, in contrast to prior studies, 5 mg/kg fluoxetine, alone, had only modest effects on food intake. Differences in our experimental protocols and/or the strain of rat may account for the lower anorectic response to fluoxetine. Nevertheless, the absence of a significant response to fluoxetine, alone, coupled with the drug's attenuation of the hyperphagic effect of 8-OH-DPAT, leads to the suggestion that the behavioral response to the combined treatment is more complex than that of simple additivity. Consistent with this suggestion, 24 h food intake of rats given 8-OH-DPAT and fluoxetine was lower than that of vehicle or 8-OH-DPAT-treated rats.