Chronic Restraint Stress Inhibits the Response to a Second Hit in Adult Male Rats: A Role for BDNF Signaling.

Depression is a recurrent disorder, with about 50% of patients experiencing relapse. Exposure to stressful events may have an adverse impact on the long-term course of the disorder and may alter the response to a subsequent stressor. Indeed, not all the systems impaired by stress may normalize during symptoms remission, facilitating the relapse to the pathology. Hence, we investigated the long-lasting effects of chronic restraint stress (CRS) and its influence on the modifications induced by the exposure to a second hit on brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC). We exposed adult male Sprague Dawley rats to 4 weeks of CRS, we left them undisturbed for the subsequent 3 weeks, and then we exposed animals to one hour of acute restraint stress (ARS). We found that CRS influenced the release of corticosterone induced by ARS and inhibited the ability of ARS to activate mature BDNF, its receptor Tropomyosin receptor kinase B (TRKB), and their associated intracellular cascades: the TRKB-PI3K-AKT), the MEK-MAPK/ERK, and the Phospholipase C γ (PLCγ) pathways, positively modulated by ARS in non-stressed animals. These results suggest that CRS induces protracted and detrimental consequences that interfere with the ability of PFC to cope with a challenging situation.

Chronic vortioxetine treatment improves the responsiveness to an acute stress acting through the ventral hippocampus in a glucocorticoid-dependent way.

Vortioxetine is a novel multimodal antidepressant approved in 2013 by the Food and Drug Administration and the European Medicines Agency for the treatment of major depressive disorder (MDD). It combines the modulation of serotonin receptors activity with the inhibition of serotonin transporter (SERT). In this study, we aim at establishing the effect of chronic vortioxetine treatment (5 mg/kg twice/daily) in modulating neuroplastic mechanisms as well as hypothalamic pituitary adrenal axis (HPA) activity under basal condition and in response to an acute challenge. We found that prolonged vortioxetine administration significantly increased total Bdnf expression in the dorsal and ventral hippocampus of adult male rats and affected the stress-induced modulation of the immediate early genes Arc and Zif268, mainly in the ventral sub-region. Moreover, we also found that, within this brain area, chronic drug treatment was able to modulate glucocorticoid responsiveness at genomic level by enhancing the translocation of the glucocorticoid receptor (GR) in the nuclear compartment in response to the acute stress. Interestingly, this effect was mirrored by the up-regulation of different GR responsive-genes. Taken together, our data suggest that repeated exposure to vortioxetine specifically targets the ventral hippocampus by improving the ability to cope with stressful conditions. Moreover, its ability to facilitate HPA axis function might provide an indication to use this drug in patients characterized by glucocorticoid resistance.

Persistent marked cerebrospinal fluid eosinophilia in a dog with primary central nervous system histiocytic sarcoma.

A 6-year-old female spayed Jack Russell Terrier was evaluated for episodic seizure-like activity and intermittent obtundation over the previous 3 weeks. Magnetic resonance imaging (MRI) of the brain revealed mild generalized dilation of the ventricular system with periventricular edema. A focal area of mildly increased lepto- and pachymeningeal contrast uptake in the region of the right parietal and occipital lobes was observed. Analysis of cerebrospinal fluid (CSF) revealed marked mixed pleocytosis with 20% eosinophils and no atypical cells or microorganisms. The dog transiently improved with prednisolone for suspected eosinophilic meningoencephalitis/meningoencephalomyelitis of unknown origin (MUO) but worsened over the following 5 months. Brain MRI and CSF sampling were repeated. Additional multifocal lesions were evident in the brainstem and cerebellum. On CSF analysis, the eosinophilic pleocytosis and increased total protein persisted. The clinical signs progressed despite treatment, and the patient was euthanized 6 weeks later. A post-mortem examination was performed. Histopathology and immunohistochemistry revealed a multifocal neoplastic proliferation of cells in the brain, diffusely and strongly positive for ionized calcium-binding adapter molecule (Iba-1) and negative for AE1/AE3 pan-cytokeratin and glial-fibrillar-acid-protein (GFAP) immunostaining, consistent with a diagnosis of histiocytic sarcoma (HS). No other organic lesions were found; therefore, the neoplasm was considered a primary HS of the central nervous system (CNS). This case report stresses the importance of considering primary CNS HS in the differential diagnosis of dogs with marked CSF eosinophilia, even in the absence of atypical cells on cytologic examination.

Prevalence and clinical characteristics of phenobarbitone-associated adverse effects in epileptic cats.

OBJECTIVES: The study objective was to investigate the prevalence and clinical characteristics of phenobarbitone-associated adverse effects in epileptic cats. METHODS: The medical records of two veterinary referral clinics from 2007 to 2017 were searched for cats fulfilling the inclusion criteria of a diagnosis of epilepsy, treatment with phenobarbitone and available follow-up information on the occurrence of adverse effects. Follow-up information was obtained from the medical records of the primary veterinarian and referral institutions and a questionnaire completed by the cats' owners. RESULTS: Seventy-seven cats met the inclusion criteria. Fifty-eight were affected by idiopathic epilepsy and 19 by structural epilepsy. One or more of the following adverse effects were reported in 47% of the cats: sedation (89%); ataxia (53%); polyphagia (22%); polydipsia (6%); polyuria (6%); and anorexia (6%). Logistic regression analyses revealed significant associations between adverse effect occurrence and both phenobarbitone starting dosage and administration of a second antiepileptic drug (AED). For each 1 mg/kg q12h increment of phenobarbitone, the likelihood of adverse effects increased 3.1 times. When a second AED was used, the likelihood of adverse effects increased 3.2 times. No association was identified between epilepsy aetiology and adverse effect occurrence. An idiosyncratic adverse effect, characterised by severe neutropenia and granulocytic hypoplasia, was diagnosed in one cat. This resolved following phenobarbitone discontinuation. CONCLUSIONS AND RELEVANCE: The prevalence of phenobarbitone-associated adverse effects was 47%. Sedation and ataxia were most common. These are type A adverse effects and are predictable from phenobarbitone's known pharmacological properties. In the majority of cases, adverse effects occurred within the first month of treatment and were transient. Idiosyncratic (type B) adverse effects, which were not anticipated given the known properties of the drug, occurred in one cat. Increased phenobarbitone starting dosage and the addition of a second AED were significantly associated with the occurrence of adverse effects.

Diurnal Body Temperature and Rate of Passage of Loggers in Lions.

The documentation of diurnal patterns in body temperature in lions could be important because disruption of circadian patterns can be a useful measure of distress. This study quantified changes in body temperature of seven African lions (Panthera leo) at 5 min intervals during cold conditions from noon until the ingested body temperature loggers were expelled the next day. Thirteen loggers were fed to 11 lions during their daily noon feeding, while ambient temperatures were also recorded using six data loggers. The lions had continuous access to their dens and exercise pens during the day but were restricted to their heavily bedded dens that also contained a heat lamp from 23:00 until 08:00 the next day. Body temperatures averaged 37.95 ± 0.42 °C at 15:50, and 36.81 ± 0.17 °C at 06:50 the next day, 30 min before the first loggers passed from a lion, and were significantly different (t-test, t = 8.09, df = 6, p < 0.0003). The mean duration for the time of passage was 22 ± 2.69 (h ± SD), so future studies using the noninvasive feeding of temperature loggers need to consider that time frame.