Antidepressive and anxiolytic activity of selective estrogen receptor modulators in ovariectomized mice submitted to chronic unpredictable stress

Estradiol has antidepressive and anxiolytic actions. However, its therapeutic use is limited by its peripheral effects. Selective estrogen receptor modulators may represent an alternative to estradiol for the treatment of depressive symptoms. Here we report that tamoxifen and raloxifene decrease immobility time in the forced swim test and increases the time spent in open arms in the elevated plus maze in ovariectomized mice submitted to chronic unpredictable stress.     

Administration of antisense DNA for hepatocyte growth factor causes an depressive and anxiogenic response in rats

Hepatocyte growth factor (HGF) is induced in neurons during ischemia and is neuroprotective against post-ischemic delayed neuronal death in the hippocampus. HGF might play an important role in the maturation and functioning of these neurons in the hippocampus. Our aim was to determine what effect HGF antisense has on depression and anxiety in rats. HGF antisense was infused at a constant rate into cerebral lateral ventricles and its effect on anxiety in rats was monitored. In forced swimming test, rats that received antisense DNA increased the length of time that they were immobile in the water. In the elevated plus maze test, the black and white box test and conditioned fear test, HGF antisense administration caused all indicators of anxiety to increase. Number of HGF-positive cells in C1 of hippocampus was significantly decreased in the HGF antisense-infused group compared to the vehicle- and scrambled oligonucleotide-treated group. No significant effect on general locomotor activity was seen. These results indicate that inhibition of HGF induces an increase in depression and anxiety-related behaviors suggesting a depressive and anxiogenic-like effect.     

The role of CRF receptors in anxiety and depression: implications of the novel CRF1 agonist cortagine

Corticotropin-releasing factor (CRF), a 41 amino acid peptide exhibits its actions through two pharmacologically distinct CRF receptor subtypes CRF₁ and CRF₂. Regulation of the relative contribution of the two CRF receptors to central CRF activity may be essential in coordinating physiological responses to stress. To facilitate the analysis of their differential involvement, we recently developed a CRF₁-selective agonist cortagine by synthesis of chimeric peptides derived from human/rat CRF, ovine CRF, and sauvagine. Cortagine was analyzed in behavioral experiments using male wild type and CRF₂-deficient C57BL/6J mice for its action on anxiety- and depression-like behaviors. In contrast to the current hypothesis that increased CRF₁ activity facilitates the expression of anxiety- and depression-like behavior, cortagine combines anxiogenic properties with antidepressant effects. In this article, we show that antidepressant effects are partially mediated by CRF₁ of the dorsal hippocampus. Possible pathways responsible for the paradoxical antidepressant effects observed after CRF₁ activation are discussed.     

The role of CRF receptors in anxiety and depression: Implications of the novel CRF1 agonist cortagine

Corticotropin-releasing factor (CRF), a 41 amino acid peptide exhibits its actions through two pharmacologically distinct CRF receptor subtypes CRF₁ and CRF₂. Regulation of the relative contribution of the two CRF receptors to central CRF activity may be essential in coordinating physiological responses to stress. To facilitate the analysis of their differential involvement, we recently developed a CRF₁-selective agonist cortagine by synthesis of chimeric peptides derived from human/rat CRF, ovine CRF, and sauvagine. Cortagine was analyzed in behavioral experiments using male wild type and CRF₂-deficient C57BL/6J mice for its action on anxiety- and depression-like behaviors. In contrast to the current hypothesis that increased CRF₁ activity facilitates the expression of anxiety- and depression-like behavior, cortagine combines anxiogenic properties with antidepressant effects. In this article, we show that antidepressant effects are partially mediated by CRF₁ of the dorsal hippocampus. Possible pathways responsible for the paradoxical antidepressant effects observed after CRF₁ activation are discussed.     

Increased anxiety behavior in OLETF rats without cholecystokinin-A receptor

Cholecystokinin (CCK) may have a role in the mediation of human panic disorder and anxiogenic (anxiolytic)-like activity in an animal model of anxiety. Otsuka Long Evans Tokushima Fatty (OLETF) rats lacked CCK A receptors (CCKAR) because of a genetic abnormality. In order to elucidate the involvement of CCKAR in the regulation of anxiety, we investigated the exploratory behavior on elevated plus-maze test, the black and white box test, and open field test with OLETF rats in comparison with normal [Long-Evans Tokushima Otsuka (LETO)] rats. And OLETF rats increased the number of stretched attend postures and decreased open arm entry and the % time of open arm in an elevated plus-maze test. Time spent in the white box decreased significantly in OLETF rats than LETO rats. The total line crossing decreased significantly in OLETF rats compared to LETO rats. The missing CCKAR had a significant anxiogenic-like effect. These data support the involvement of the CCKAR in the neurobiological mechanism of anxiety.     

Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats

Ongoing epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and may result in increased risk for neurological co-morbidities like depressive illness. One potential mechanistic mediator linking obesity and depressive illness is the adipocyte derived hormone leptin. We previously demonstrated that lentivirus-mediated downregulation of hypothalamic insulin receptors increases body weight, adiposity and plasma leptin levels, which is consistent with features of the metabolic syndrome. Using this novel model of obesity, we examined performance in the forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM), approaches that are often used as measures of depressive-like and anxiety-like behaviors, in rats that received third ventricular injections of either an insulin receptor antisense lentivirus (hypo-IRAS) or a control lentivirus (hypo-Con). Hypo-IRAS rats exhibited significant increases in immobility time and corresponding decreases in active behaviors in the FST and exhibited anhedonia as measured by decreased sucrose intake compared to hypo-Con rats. Hypo-IRAS rats also exhibited increases in anxiety-like behaviors in the EPM. Plasma, hippocampal and amygdalar brain-derived neurotrophic factor (BDNF) levels were reduced in hypo-IRAS rats, suggesting that the obesity/hyperleptinemic phenotype may elicit this behavioral phenotype through modulation of neurotrophic factor expression. Collectively, these data support the hypothesis for an increased risk for mood disorders in obesity, which may be related to decreased expression of hippocampal and amygdalar BDNF.     

Vigabatrin has antiepileptogenic and antidepressant effects in an animal model of epilepsy and depression comorbidity

To evaluate the effects of Vigabatrin (VGB) treatment, on both absence seizure and depressive-like behaviour development in the WAG/Rij rat model of absence seizures. Early long-term treatment with VGB could alter the development of absence pathology, by significantly reducing seizure generation and synchronization in contrast to its pro-absence effects observed after acute or subchronic administration. We have demonstrated the antidepressant effects of a sub-chronic treatment with VGB in both wistar and WAG/Rij rats. In contrast, following an early long-term treatment, VGB antidepressant effects were only observable in WAG/Rij rats. In conclusion, VGB has antiepileptogenic and antidepressant properties in the WAG/Rij rat model despite its pro-absence effects suggesting that epilepsy and depression, in this animal model, are directly related and that seizure development inhibition also reduces the development of depressive behaviour.     

Analysis of the anxiolytic-like effect of TRH and the response of amygdalar TRHergic neurons in anxiety

Thyrotropin-releasing hormone (TRH) was first described for its neuroendocrine role in controlling the hypothalamus-pituitary-thyroid axis (HPT). Anatomical and pharmacological data evidence its participation as a neuromodulator in the central nervous system. Administration of TRH induces various behavioural effects including arousal, locomotion, analepsy, and in certain paradigms, it reduces fear behaviours. In this work we studied the possible involvement of TRHergic neurons in anxiety tests. We first tested whether an ICV injection of TRH had behavioural effects on anxiety in the defensive burying test (DBT). Corticosterone serum levels were quantified to evaluate the stress response and, the activity of the HPT axis to distinguish the endocrine response of TRH injection. Compared to a saline injection, TRH reduced cumulative burying, and decreased serum corticosterone levels, supporting anxiolytic-like effects of TRH administration. The response of TRH neurons was evaluated in brain regions involved in the stress circuitry of animals submitted to the DBT and to the elevated plus maze (EPM), tests that allow to correlate biochemical parameters with anxiety-like behaviour. In the DBT, the response of Wistar rats was compared with that of the stress-hypersensitive Wistar Kyoto (WKY) strain. Behavioural parameters were analysed in recorded videos. Animals were sacrificed 30 or 60min after test completion. In various limbic areas, the relative mRNA levels of TRH, its receptors TRH-R1 and -R2, and its inactivating ectoenzyme pyroglutamyl peptidase II (PPII), were determined by RT-PCR, TRH tissue content by radioimmunoassay (RIA). The extent of the stress response was evaluated by measuring the expression profile of CRH, CRH-R1 and GR mRNA in the paraventricular nucleus (PVN) of the hypothalamus and in amygdala, corticosterone levels in serum. As these tests demand increased physical activity, the response of the HPT axis was also evaluated. Both tasks increased the levels of serum corticosterone. WKY rats showed higher anxiety-like behaviour in the DBT than Wistar, as well as increased PVN mRNA levels of CRH and GR. TRH mRNA levels increased in the PVN and TSH values remained unchanged in both strains although TRH content decreased in the medial basal hypothalamus of Wistar rats only. TRH content was measured in several limbic regions but only amygdala showed specific task-related changes after DBT exposure of both strains: increased TRH content. Expression of TRH mRNA decreased in the amygdala of Wistar, suggesting inhibition of TRHergic neuronal activity in this region. The participation of amygdalar TRH neurons in anxiety was confirmed in the EPM where TRH expression and release correlated with the number of entries, and the % of time spent in open arms, supporting an anxiolytic role of these TRH-neurons. These results contribute to the understanding of the involvement of TRH during emotionally charged situations and shed light on the participation of particular circuits in related behaviours.     

Differential effects of restraint stress on hippocampal 5-HT metabolism and extracellular levels of 5-HT in streptozotocin-diabetic rats

Streptozotocin (STZ)-elicited diabetes reduces central serotonin (5-hydroxytryptamine, 5-HT) synthesis/metabolism, but whether this reduction leads to decreased release of 5-HT has only scarcely been investigated. We have thus analysed the impact of STZ diabetes on hippocampal extracellular 5-HT levels both under basal conditions and during restraint stress, a procedure known to stimulate hippocampal 5-HT synthesis/metabolism and release. The pretreatment with STZ (3 weeks beforehand) and the 1 h restraint session respectively decreased and increased hippocampal 5-HT metabolism, as assessed by tissue analysis of 5-HT and 5-hydroxyindoleacetic acid. On the other hand, hippocampal microdialysis revealed no difference in basal levels of extracellular 5-HT levels in (conscious) vehicle- and STZ-pretreated rats, but a differential effect of restraint. Thus, extracellular 5-HT levels increased throughout restraint (maximal increase: 194%) in vehicle-, but not in STZ-pretreated rats. In the latter rat group, plasma corticosterone levels were, however, increased, thus indicating a significant aversiveness to stress. Lastly, because anxiety-related behaviours may be affected by hippocampal serotonergic systems, resting and restrained vehicle- and STZ-pretreated rats were compared (immediately after stress) in an elevated plus-maze of anxiety. Pretreatment with STZ reduced the percent number of open arm entries and the number of closed arm entries, indicating increased anxiety and reduced locomotor activity, respectively. Restraint tended to increase anxiety-related behaviours in all rats, but this trend never reached significance. Our results confirm that gross analyses of 5-HT metabolism do not yield information on 5-HT release, and suggest that the prevalence of diabetes among patients suffering affective disorders could be related to the lack of hippocampal serotonergic response to aversive stimuli.     

Predictors of antidepressant response to fluvoxamine obtained using the three-factor structures of the Montgomery and Asberg Depression Rating Scale for major depressive disorders in Japanese patients

Aims:  Fluvoxamine, a selective serotonin reuptake inhibitor, is widely used to treat major depression. However, the symptomatological predictors of the response to fluvoxamine have not been studied.
Methods:  This study included 100 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Åsberg Depression Rating Scale (MADRS) was 21 or higher. Eighty-one patients were included. Patients with a pretreatment MADRS score of ≥31 were defined as 'severe' ( n  = 32) and the rest were defined as 'non-severe' ( n  = 49). The three-factor model of MADRS was used for analysis: the first factor was defined by three items, the second factor was defined by four items, and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Fluvoxamine (100–200 mg/day) was administered twice daily for 6 weeks.
Results:  In the non-severe patients, the mean factor 3 score of the non-responders at pretreatment was significantly higher than that of the responders. However, a significant difference was observed in the mean factor 3 scores from 1 week onwards between the non-severe responders and non-responders. Furthermore, the fluvoxamine response rate in the severe patients was 75% and higher than that of the non-severe patients (65.3%).
Conclusions:  This study suggested that a low factor 3 score at pretreatment was a good predictor of the response to fluvoxamine in non-severe patients. The marked efficacy of fluvoxamine in the treatment of severe patients was also confirmed.     

Effect of early life housing manipulation on baseline and drug-induced behavioural responses on neurochemistry in the male rat

Employing environmental enrichment (EE) provides continual sources of dynamic interaction for animals. Though an established discipline in behavioural science, the consequences of EE on behavioural pharmacological tests have not been extensively examined. The purpose of this study was to examine the consequences of EE (or isolation housing) on a range of behavioural pharmacological tests and brain monoamine and brain-derived neurotrophic factor (BDNF) expression in the rat. Male rats were randomly assigned to IC (isolation), SC (standard group-housed) or EE conditions. IC and SC animals were housed singly or in groups of four in standard cages, whilst the EE group were housed in groups of four in larger cages enriched with a variety of wooden, cardboard and plastic objects. After 5weeks of housing, its impact on the effects of diazepam (DZP) in the elevated plus maze (EPM); desipramine (DMI) in the forced swim test (FST) and amphetamine (AMP) effects on homecage activity were assessed. Post-mortem monoamine and BDNF levels were analysed using HPLC and ELISA. EE rats displayed reduced activity in the OFT, however no other differences were found in baseline behaviours. DMI reduced immobility time in the FST, but only for rats housed in IC, while AMP effects were somewhat greater for socially-housed animals than those in IC. There were no housing effects on monoamine or BDNF levels in discreet brain regions. The results suggest that post-weaning enrichment had no significant effect on baseline behaviours or monoamine and BDNF levels, thus it is suitable to implement as a commonplace husbandry practice, however, caution must be taken when investigating responsiveness to psychotropic drugs.     

The impact of environmental enrichment in laboratory rats--behavioural and neurochemical aspects

The provision of environmental enrichment (EE) for laboratory rats is recommended in European guidelines governing laboratory animal welfare. It is believed the EE implementation can improve animals’ well-being and EE has been used to demonstrate learning and plasticity of the brain in response to the environment. This review suggests that the definition and duration of EE varies considerably across laboratories. Notwithstanding this, some EE protocols have revealed profound effects on brain neurochemistry and resulting behaviour, suggesting that EE can have the potential to significantly modify these parameters in rats. For this review, a literature search was conducted using PubMed and the search terms “Environmental Enrichment” and “rats”. From the results of this search the most important variables for consideration in the implementation of EE are identified and summarised, and include cage size and housing density; rat age, sex and strain; duration of EE; the EE protocol and enrichment items employed; and the use of appropriate controls. The effects of EE in a number of behavioural tests and its effects on neurotransmitters, neurotrophic factors, stress hormones and neurogenesis and proliferation are outlined. The findings summarised in the present review show the range of EE protocols employed and their effects in tests of activity, learning and affect, as well neurochemical effects which mediate enhanced plasticity in the brain. EE, as is provided in many laboratories, may be of benefit to the animals, however it is important that future work aims to provide a better understanding of EE effects on research outcomes.