Standardised ginseng extract G115® potentiates the antidepressant-like properties of fluoxetine in the forced swim test.

OBJECTIVE: Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. METHODS: Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot. RESULTS: One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression. CONCLUSIONS: We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.

Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways.

Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine-phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.

Sex differences in the stress response in SD rats.

Sex differences play an important role in depression, the basis of which is an excessive stress response. We aimed at revealing the neurobiological sex differences in the same study in acute- and chronically-stressed rats. Female Sprague-Dawley (SD) rats were randomly divided into 6 groups: chronic unpredictable mild stress (CUMS), acute foot shock (FS) and controls, animals in all 3 groups were sacrificed in proestrus or diestrus. Male SD rats were randomly divided into 3 groups: CUMS, FS and controls. Comparisons were made of behavioral changes in CUMS and control rats, plasma levels of corticosterone (CORT), testosterone (T) and estradiol (E2), and of the hypothalamic mRNA-expression of stress-related molecules, i.e. estrogen receptor α and ß, androgen receptor, aromatase, mineralocorticoid receptor, glucocorticoid receptor, corticotropin-releasing hormone, arginine vasopressin and oxytocin. CUMS resulted in disordered estrus cycles, more behavioral and hypothalamic stress-related molecules changes and a stronger CORT response in female rats compared with male rats. Female rats also showed decreased E2 and T levels after FS and CUMS, while male FS rats showed increased E2 and male CUMS rats showed decreased T levels. Stress affects the behavioral, endocrine and the molecular response of the stress systems in the hypothalamus of SD rats in a clear sexual dimorphic way, which has parallels in human data on stress and depression.

Melatonin reduces anxiety induced by lipopolysaccharide in the rat.

In male Sprague-Dawley rats intraperitoneal (i.p.) injection of Escherichia coli lipopolysaccharide (0.25, 0.50 and 1 mg/kg) increased anxiety levels. This effect was reversed by a prior, concomitant, and subsequent i.p. treatment with melatonin (4 and 6 mg/kg). As the effects of melatonin upon the actions induced by lipopolysaccharide were reversed by the melatonin receptor antagonist luzindole (30 and 60 mg/kg, i.p.), we argued that they are, but not only, melatonin receptor mediated. These findings, in accordance with our previous works, suggest that melatonin could be useful in the treatment of sickness behaviour associated with systemic infection diseases or as adjuvant in the anti-anxiety therapy.

Measurement of startle response, prepulse inhibition, and habituation.

The startle response is comprised of a constellation of reflexes elicited by sudden, relatively intense stimuli. The startle reflex is useful for studying fundamental properties of nervous function ranging from neurophysiological and anatomical relationships within the pons and reticular formation to forebrain regulation of complex behavioral states and cognitive processes. This unit presents protocols for measurement of the startle response in rats to acoustic stimuli, along with modifications encompassing an experimental manipulation such as drug treatment and measures of habituation of startle; a method for measuring prepulse inhibition (PPI) of startle; and specialized rat handling and calming techniques that supplement the startle protocols.

Contextual control of long-term habituation in rats.

This study examined contextual control of long-term habituation and whether such effects are dependent on the habituating response system. Habituation of the acoustic startle response transferred from the home cage to the testing context, whereas habituation of lick suppression was context specific (Experiments 1 and 2). Contextual control of habituation was demonstrated between 2 experimental contexts for lick suppression to a tone (Experiment 3) and bar-press suppression to a light (Experiment 4). Experiment 5 extinguished habituation of lick suppression and the orienting response to a tone with 27 exposures to the habituation context. Context specificity of both responses also was found. Previous failures to demonstrate contextual control of habituation may be due to the choice of response system and to less sensitive procedures to detect response recovery. The habituation mechanism for startle is independent from the process or processes that underlie habituation in other response systems, but the nature of these mechanisms is not yet known.

Odor preferences in neonatal and weanling rats.

In order to establish odors which can be used in appetitive and aversive conditioning paradigms, naive rat pups, postnatal day 7 (i.e., PND 7) and weanlings (PND 25), were placed in a rectangular open field with an odorant at one or both ends. Time spent over each odor was measured for 3 min. At both ages subjects avoided peppermint, orange, and lemon odors in favor of fresh home-cage bedding. Comparing any of these three odorants with each other resulted in no significant differences in preferences. In experiments using banana odorant, equal time was spent between banana and no odorant. However, in a two-odorant choice between banana and peppermint, weanlings preferred banana whereas pups showed no preference. The results of this study indicate that in an appetitive learning paradigm, peppermint, orange, or lemon odors may be used, while in aversive learning paradigms banana odor may be more appropriate for weanlings.

Eurycoma longifolia Jack enhances libido in sexually experienced male rats.

The effects of Eurycoma longifolia Jack were studied on the libido of sexually experienced male rats after dosing them with 200, 400 and 800 mg/kg body weight twice daily of different fractions of E. longifolia Jack for 10 days. Results showed that E. longifolia Jack produced a dose-dependent increase in mounting frequency of the treated animals with 400 mg/kg of chloroform, methanol, water and butanol fractions resulting in mounting frequencies of 5.3 +/- 1.2, 4.9 +/- 0.7, 4.8 +/- 0.7 and 5.2 +/- 0.1, and 800 mg/kg further increased them to 5.4 +/- 0.8, 5.4 +/- 0.8, 5.2 +/- 0.6 and 5.3 +/- 0.2 respectively but there were no erections, intromissions, ejaculations or seminal emissions during the 20-min observation period which allowed for the measurement of sexual arousal reflected by mounting frequency uninfluenced by other behavioural components. This study provides evidence that E. longifolia Jack is a potent stimulator of sexual arousal in sexually vigorous male rats in the absence of feedback from genital sensation.