Intracerebroventricularly administered oxytocin attenuated cortisol secretion, but not behavioral responses, during isolation in Holstein steers.

In rodents, intracerebroventricular oxytocin administration attenuated hypothalamo-pituitary-adrenal (HPA) responses and anxiety behavior during stress. We examined the effects of intracerebroventricular injection of oxytocin on isolation-induced stress responses in cattle. In a methodological test, we determined the dosage of oxytocin applied in a main test which did not induce an increase in plasma cortisol concentration or stereotyped behaviors. In a main test, 5 steers aged from 199 to 250 days were assigned to the following three treatments randomly: T1, no isolation after injection of 200 microl of artificial cerebrospinal fluid (aCSF); T2, isolation after aCSF injection; and T3, isolation after 0.5 microg of oxytocin in 200 microl aCSF injection. The isolation was conducted by leaving the experimental steer alone in its stall for one hour while its peers were taken outside. In T2, the isolation induced a rapid increase in plasma cortisol concentration. The maximum %-changes from the pre-isolation value were significantly attenuated by oxytocin injection (T2 vs. T3, p<0.05). The isolation also induced an increase in the frequency (number of occurrences/1 hr isolation) of vocalizations and body orientation changes, and a decrease in the percentage of time spent lying and ruminating. The effect of oxytocin on these behavioral responses to isolation was not apparent. These results indicate that intracerebroventricularly injected oxytocin at low dose attenuated the cortisol response to isolation in steers while the effect on behavior was very small in this experimental condition.

[Effects of sedative agents on metabolic demand]. / Effets des agents sédatifs sur la demande métabolique.

Literature about the effects of sedative drugs on the metabolic demand of critically ill patients is relatively old and of relatively poor quality. Most are experimental or observational studies. Level of evidence is therefore relatively low corresponding to "expert opinion". The effects of analgesics and hypnotics on tissue metabolic demand associated remain difficult to be adequately quantified. They are essentially related to a decreased neuro-humoral response to stress. This response involves principally the sympathetic system, which could be effectively blocked by most of the anesthetic agents. Other factors could participate to the observed reduction in tissue metabolic demand, as a decrease in spontaneous muscular activity, a reduction in work of breathing and/or a decrease in body temperature. The relative contribution of these different factors will depend on the clinical situation of the patient. Proper effects of anesthetic agents on cellular metabolism are limited as they can only decrease the functional component of this metabolism especially at the level of the heart and to some extent, at the level of the brain. Although the control of the sympathetic activity may be beneficial in critically ill patient, complete sympathetic blockade could be detrimental. Indeed, when oxygen transport to the tissues is acutely reduced, the sympathetic system plays an important role in the redistribution of blood flow according of local metabolic demand. The complete blunting of the neuro-humoral response to stress and therefore of the sympathetic system alters this physiological mechanism and results in a decrease in tissue oxygen extraction capabilities. An imbalance between tissue oxygen demand and delivery could appear with the development of cellular hypoxia. The institution of sedation in a critically ill patient requires careful evaluation of the sedation level using an appropriate scale. In patients in whom a reduction in metabolic demand is specifically requested, but also in patients with limited oxygen transport, the effects of sedative agents on the oxygen consumption-oxygen delivery relationship must also be monitored. The choice of the different agents to be administered will depend on the predefined objectives. As far as intravenous agents are concerned, there is no evidence than one association is more efficient in reducing patient's metabolic demand.

[Sedation an acute respiratory distress syndrome]. / Sédation du patient présentant un syndrome de détresse respiratoire aiguë.

AIM: To assess the role of sedation and myorelaxant agents in acute respiratory distress syndrome (ARDS) and to propose an updated management according to recent literature. EXTRACTION OF DATA: From Medline and Cochrane database of English and French language articles. Keywords were: acute respiratory distress syndrome, acute lung injury, general anaesthetics, inhalation, intravenous anaesthetics and intensive care. Selection of original articles, reviews and expert reports. Case reports have been included. TOPIC: ARDS is a clinical picture in which respiratory constraints are major because of hypoxemia. To insure correct haematosis, mechanical ventilation has to be considered. It constitutes, then, the most frequent indication of sedation in the intensive care unit. The objectives are to help the ventilation of lungs and to improve gas exchange, by controlling agitation, fight against ventilation and to reduce mechanical ventilation associated injuries. In this situation, use of myorelaxant agents is aimed at facilitating synchronization of the patient with his/her ventilator and serves to improve oxygenation during the early inflammatory phase of ARDS. Several mechanisms may enflame this improvement of oxygenation. One of the most probable effect on optimization is the possibility of optimize protective ventilation at the cares phase of ARDS and to reduce mechanical ventilation-associated injuries. CONCLUSION: With regard to benefits and inconvenient, sedation is considered as a treatment of ARDS. Its goals are the well being of patient and his/her adaptation to ventilator, but also the prevention on mechanical ventilation associated injuries. Hence, most authors suggest using a deep sedation at the early phase of ARDS. In this contact, use of myorelaxant agent is an intersecting adjuvant if sedation is not enough. The benefit is terms of survival and outcome remains to show.

Effect of pioglitazone treatment on endoplasmic reticulum stress response in human adipose and in palmitate-induced stress in human liver and adipose cell lines.

Obesity and elevated cytokine secretion result in a chronic inflammatory state and may cause the insulin resistance observed in type 2 diabetes. Recent studies suggest a key role for endoplasmic reticulum stress in hepatocytes and adipocytes from obese mice, resulting in reduced insulin sensitivity. To address the hypothesis that thiazolidinediones, which improve peripheral insulin sensitivity, act in part by reducing the endoplasmic reticulum stress response, we tested subcutaneous adipose tissue from 20 obese volunteers treated with pioglitazone for 10 wk. We also experimentally induced endoplasmic reticulum stress using palmitate, tunicamycin, and thapsigargin in the human HepG2 liver cell line with or without pioglitazone pretreatment. We quantified endoplasmic reticulum stress response by measuring both gene expression and phosphorylation. Pioglitazone significantly improved insulin sensitivity in human volunteers (P = 0.002) but did not alter markers of endoplasmic reticulum stress. Differences in pre- and posttreatment endoplasmic reticulum stress levels were not correlated with changes in insulin sensitivity or body mass index. In vitro, palmitate, thapsigargin, and tunicamycin but not oleate induced endoplasmic reticulum stress in HepG2 cells, including increased transcripts CHOP, ERN1, GADD34, and PERK, and increased XBP1 splicing along with phosphorylation of eukaryotic initiation factor eIF2alpha, JNK1, and c-jun. Although patterns of endoplasmic reticulum stress response differed among palmitate, tunicamycin, and thapsigargin, pioglitazone pretreatment had no significant effect on any measure of endoplasmic reticulum stress, regardless of the inducer. Together, our data suggest that improved insulin sensitivity with pioglitazone is not mediated by a reduction in endoplasmic reticulum stress.

Effect of potassium chloride supplementation in drinking water on broiler performance under heat stress conditions.

The effect of water supplementation of KCl on performance of heat-stressed Hubbard broilers was evaluated in the present experiment. The 3 experimental treatments (i.e., control, 0.3 and 0.6% KCl) were allocated to 3 replicates of 15 birds each. The control group was kept on dugout tap water, whereas the other 2 groups were supplied water supplemented with 0.3 and 0.6% KCl (wt/vol) by supplementing 3 and 6 g of KCl, respectively, per liter of drinking water. Broilers were provided ad libitum access to feed and water for the experimental period of 7 to 42 d of age and kept in open-sided house. The birds were reared under continuous thermostress (minimum 28.2 +/- 1.02 and maximum 37.5 +/- 0.78 degrees C) environment. Supplementing drinking water with 0.6% KCl reduced panting-phase blood pH to 7.31 and significantly increased live BW gain by 14.5 (P = 0.036) and 7.9% (P = 0.029) at 28 and 42 d of age, respectively, relative to control. An improved (P = 0.04) feed:gain and lowered body temperature were noted in groups supplemented with 0.6% KCl as compared with control and 0.3% KCl. Enhanced physiological adaptation with 0.6% KCl was evidenced by a more favorable pH during the panting phase in the present study. These findings demonstrated a possibility of better broiler live performance through KCl supplementation under conditions of severe heat stress (35 to 38 degrees C).

Quercetin reduces susceptibility to influenza infection following stressful exercise.

Exercise stress is associated with increased risk for upper respiratory tract infection. We have shown that exercise stress can increase susceptibility to infection. Quercetin, a flavonoid present in a wide variety of fruits and vegetables, has been reported to inhibit infectivity and replication of a broad spectrum of viruses and may offset the increase in susceptibility to infection associated with stressful exercise. This study examined the effects of quercetin feedings on susceptibility to the influenza virus A/Puerto Rico/8/34 (H1N1) following stressful exercise. Mice were randomly assigned to one of four treatment groups: exercise-placebo, exercise-quercetin, control-placebo, or control-quercetin. Exercise consisted of a run to fatigue (approximately 140 min) on a treadmill for 3 consecutive days. Quercetin (12.5 mg/kg) was administered via gavage for 7 days before viral challenge. At 30 min after the last bout of exercise or rest, mice (n=23-30) were intranasally inoculated with a standardized dose of influenza virus (0.04 hemagglutinating units). Mice were monitored daily for morbidity (time to sickness), symptom severity, and mortality (time to death) for 21 days. Exercise stress was associated with an increased susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)]; quercetin offset the increase in susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P<0.05)] that was associated with stressful exercise. These data suggest that short-term quercetin feedings may prove to be an effective strategy to lessen the impact of stressful exercise on susceptibility to respiratory infection.

The influence of Sutherlandia frutescens on adrenal steroidogenic cytochrome P450 enzymes.

AIM OF THE STUDY: The aim of this study was to investigate whether Sutherlandia frutescens, subsp. microphylla (family: Fabaceae/Leguminosa), which is traditionally used to treat symptoms of chronic stress generally associated with increased circulating glucocorticoids, influences the biosynthesis of these glucocorticoids. METHODS: We investigated the interaction of Sutherlandia frutescens with cytochrome P450 enzymes, CYP17 and CYP21, which catalyse key reactions in glucocorticoid biosynthesis. The binding of progesterone and pregnenolone to these enzymes and their metabolism were assayed in the presence of extracts and the bioactive compounds, l-canavanine, pinitol, GABA, flavonoids and triterpenoid glucosides present in the shrub. RESULTS: While the aqueous and methanol extracts inhibited the type I progesterone-induced difference spectrum (p<0.05), inhibition of pregnenolone binding (p=0.25) was negligible, with the aqueous extract exhibiting greater inhibition. The triterpenoid fraction inhibited both the type I pregnenolone- and progesterone-induced difference spectra and elicited a type II difference spectrum in the absence of substrate. Both pregnenolone and progesterone metabolism were inhibited by the aqueous extract, the inhibition of CYP21 being greater than that of CYP17, influencing the flux through glucocorticoid precursor pathways. CONCLUSION: This attenuation of adrenal P450 enzymes may thus demonstrate a possible mechanism by which Sutherlandia frutescens reduces glucocorticoid levels and alleviates symptoms associated with stress.

Gender differences in zebrafish responses to cocaine withdrawal.

The acute responses to cocaine and its withdrawal contribute to cocaine dependence and potentiate relapse, with gender being one of the genetic factors affecting the outcome. Here we report that in both male and female zebrafish (Danio rerio, AB strain), an initial low-dose cocaine treatment (1.5 muM, immersion) does not acutely change their behavior. The cocaine withdrawal, however, is associated with an anxiety-like state that develops earlier in female zebrafish but is more robust and persistent in males, and can be acutely attenuated by cocaine administration. This is not a result of gender differences in the expression of anxiety-like state, since behavioral responses to an anxiogenic drug, FG-7142, are similar in male and female zebrafish. The basal brain dopamine (DA) levels and the expression of dopamine transporter mRNA (zDAT) show no significant sexual dimorphism. Acute cocaine exposure does not significantly change DA or zDAT. Withdrawal from repeated cocaine administration results in an overall reduction in zDAT, as well as an increase in DA levels. Neither treatment leads to significant gender differences in brain DA or zDAT. The common and gender-specific effects of cocaine on zebrafish, a well-characterized model of vertebrate development and genetics, should help in understanding the mechanisms involved in the anxiety associated with cocaine withdrawal and provide new opportunities in search for therapeutic solutions.

Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior.

Dysfunction of the serotonin system is implicated in sleep and emotional disorders. To test whether these impairments could arise during development, we studied the impact of early-life, transient versus genetic, permanent alterations of serotonin reuptake on sleep-wakefulness patterns, depression-related behavior, and associated physiological features. Here, we show that female mice treated neonatally with a highly selective serotonin reuptake inhibitor, escitalopram, exhibited signs of depression in the form of sleep anomalies, anhedonia, increased helplessness reversed by chronic antidepressant treatment, enhanced response to acute stress, and increased serotoninergic autoinhibitory feedback. This syndrome was not reproduced by treatment in naive adults but resembled the phenotype of mutant mice lacking the serotonin transporter, except that these exhibited decreased serotonin autoreceptor sensitivity and additional anxiety-like behavior. Thus, alteration of serotonin reuptake during development, whether induced by external or genetic factors, causes a depressive syndrome lasting into adulthood. Such early-life impairments might predispose individuals to sleep and/or mood disorders.

Therapeutic potential of 1-methylnicotinamide against acute gastric lesions induced by stress: role of endogenous prostacyclin and sensory nerves.

1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA [6.25-100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI(2)) generation (measured as 6-keto-PGF1alpha), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the selective antagonist of IP/PGI(2) receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP(8-37) or capsazepine. Addition of exogenous PGI(2) or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI(2) and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.

Remifentanil for cesarean section under general anesthesia: effects on maternal stress hormone secretion and neonatal well-being: a randomized trial.

BACKGROUND: Remifentanil may attenuate maternal hemodynamic response during cesarean section under general anesthesia, but could cause transient but significant neonatal depression. We investigated the effect of low-dose remifentanil on maternal neuroendocrine response and fetal wellbeing. METHODS: Forty-two ASA I-II parturients undergoing cesarean section at term under general anesthesia were randomized to receive either fentanyl after delivery (n=21, group C) or remifentanil bolus 0.5 microg/kg before induction followed by a continuous infusion at 0.15 microg x kg(-1)min(-1) until peritoneal incision, then restarted after delivery (n=21, group R). Maternal heart rate and blood pressure, and epinephrine, norepinephrine, adrenocorticotropic hormone (ACTH), and growth hormone levels were measured at baseline, uterine incision, and the end of surgery. Remifentanil was measured in maternal and umbilical arterial and venous blood. One- and 5-minute Apgar scores and umbilical arterial and venous pH were recorded. RESULTS: ACTH was significantly higher in group C at uterine incision (P<0.01). No significant differences were observed in hemodynamics, catecholamines or growth hormone. Apgar scores at 1 (P<0.05) and 5 min (P<0.01) were significantly higher in group C. Mean umbilical pH values were within normal range but significantly higher in group C. Three neonates in group R required intubation but recovered at 5 min without naloxone. Mean+/-SD maternal remifentanil concentration was 1.67+/-1.04 ng/mL. CONCLUSIONS: Remifentanil administration before peritoneal incision partially reduced the hormonal stress response. Maternal benefits must be weighed against transitory but significant neonatal respiratory depression. Neonatal resuscitation facilities are mandatory when remifentanil is used.

Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brain.

Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with beta-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress.

Role for serotonin in the antidepressant-like effect of a flavonoid extract of Xiaobuxin-Tang.

Xiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, has been used for the treatment of depressive disorders for centuries in China. Herein, we explored the antidepressant-like effect and its monoaminergic mechanism of the total flavonoids (XBXT-2) isolated from the extract of XBXT. In present study, single XBXT-2 (25, 50, 100 mg/kg, p.o.) administration significantly potentiated the mouse head-twitch response induced by 5-hydroxytryptophan (5-HTP, a metabolic precursor to serotonin), and also, decreased the immobility time in mouse tail suspension test, which was completely prevented by p-chlorophenylalanine (PCPA, an inhibitor of serotonin synthesis) pretreatment. However, single treatment with XBXT-2 had no effect on yohimbine toxicity and high dose of apomorphine-induced hypothermia in mice. These results indicated that acute treatment with XBXT-2 produced serotonergic, but not noradrenergic activation. In addition, chronic XBXT-2 (25, 50 mg/kg, p.o., 28 days) treatments significantly reversed the depressive-like behaviors in chronically mildly stressed (CMS) rats, including the reduced sucrose preference, deficient locomotor activity and prolonged latency to novelty-suppressed feeding. Furthermore, XBXT-2 normalized the neurotransmitter changes, including the decreased serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in hippocampus and prefrontal cortex in CMS rats. These findings confirm the antidepressant-like effect of XBXT-2 in CMS model of rats, which may be primarily based on its serotonergic activation.

Making a bad thing worse: adverse effects of stress on drug addiction.

Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress-related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder.

Are thirty-five days enough to observe the stress-reducing effect of a semiochemical analogue on chickens (Gallus gallus domesticus) housed under high density?

Two similar 400-m2 buildings, each housing 8,400 broilers of a commonly used industrial strain, were used to test the effectiveness of the semiochemical treatment known as mother hen uropygial secretion analogue (MHUSA). The birds in 1 building were exposed to MHUSA continuously during a 35-d growing period, whereas those in the other building received a placebo. The experiment was then repeated using precisely the same conditions but with the building treatment reversed to control for any building effect. The purpose of the trial was to evaluate the effect of MHUSA on growing performances (live weights) and stress indicators observed from blood samples: heterophil-lymphocyte ratio and corticosterone level. Data analysis (ANOVA) showed that MHUSA-treated broilers had a higher mean growth rate, as shown by increased live weights at both d 17 and 35 (P < or = 0.001 and P < or = 0.001, respectively). After the 35-d growing period, we observed both lower heterophil-lymphocyte ratio (P < or = 0.001) and lower corticosterone level (P < or = 0.05) for birds treated with MHUSA compared with placebo, further indicating that the birds were less stressed. We conclude that constant diffusion of MHUSA in buildings used to house broilers might enhance the welfare and growth of the bird by reducing stress.

Haematology and behaviour of pullets transported by road and administered with ascorbic acid during the hot-dry season.

The effects of ascorbic acid (AA) on pullets transported by road for 6h during the hot-dry season were investigated. Forty Shika Brown pullets administered orally with AA just before transportation served as experimental, while another 40 pullets given sterile water only served as control. Blood samples analyzed before and after transportation in control pullets showed a decrease (P<0.05) in packed cell volume and haemoglobin values, and a significant (P<0.05) increase in the values of heterophil/lymphocyte ratio, total protein and basophil counts post-transportation. In experimental pullets, the post-transportation values were not different (P>0.05) from those obtained pre-transportation. The result showed that the transportation was stressful in control pullets. The behavioural activities of the pullets' post-transportation period indicated that AA facilitated the transition of the state of depression that followed excitation back to excitation immediately after transportation. In conclusion, AA administration ameliorated the adverse effect of road transportation stress during the hot-dry season.

Antidepressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents.

Honokiol and magnolol are the main constituents simultaneously identified in the barks of Magnolia officinalis, which have been used in traditional Chinese medicine to treat a variety of mental disorders including depression. In the present study, we reported on the antidepressant-like effects of oral administration of the mixture of honokiol and magnolol in well-validated models of depression in rodents: forced swimming test (FST), tail suspension test (TST) and chronic mild stress (CMS) model. The mixture of honokiol and magnolol significantly decreased immobility time in the mouse FST and TST, and reversed CMS-induced reduction in sucrose consumption to prevent anhedonia in rats. However, this mixture was unable to affect ambulatory or rearing behavior in the mouse open-field test. CMS induced alterations in 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in various brain regions of rats. An increase in serum corticosterone concentrations and a reduction in platelet adenylyl cyclase (AC) activity were simultaneously found in the CMS rats. The mixture of honokiol and magnolol at 20 and 40 mg/kg significantly attenuated CMS-induced decreases of 5-HT levels in frontal cortex, hippocampus, striatum, hypothalamus and nucleus accumbens. And it markedly increased 5-HIAA levels in frontal cortex, striatum and nucleus accumbens at 40 mg/kg and in frontal cortex at 20 mg/kg in the CMS rats. A subsequent reduction in 5-HIAA/5-HT ratio was found in hippocampus and nucleus accumbens in the CMS rats receiving this mixture. Furthermore, the mixture of honokiol and magnolol reduced elevated corticosterone concentrations in serum to normalize the hypothalamic-pituitary-adrenal (HPA) hyperactivity in the CMS rats. It also reversed CMS-induced reduction in platelet AC activity, via upregulating the cyclic adenosine monophosphate (cAMP) pathway. These results suggested that the mixture of honokiol and magnolol possessed potent antidepressant-like properties in behaviors involved in normalization of biochemical abnormalities in brain 5-HT and 5-HIAA, serum corticosterone levels and platelet AC activity in the CMS rats. Our findings could provide a basis for examining directly the interaction of the serotonergic system, the HPA axis and AC-cAMP pathway underlying the link between depression and treatment with the mixture of honokiol and magnolol.

BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice.

Stress can cause damage and atrophy of neurons in the hippocampus by deregulating the expression of neurotrophic factors that promote neuronal plasticity. The endocannabinoid system represents a physiological substrate involved in neuroprotection at both cellular and emotional levels. The lack of CB1 receptor alters neuronal plasticity and originates an anxiety-like phenotype in mice. In the present study, CB1 knockout mice exhibited an augmented response to stress revealed by the increased despair behavior and corticosterone levels showed in the tail suspension test and decreased brain derived neurotrophic factor (BDNF) levels in the hippocampus. Interestingly, local administration of BDNF in the hippocampus reversed the increased despair behavior of CB1 knockout mice, confirming the crucial role played by BDNF on the emotional impairment of these mutants. The neurotrophic deficiency seems to be specific for BDNF as no differences were found in the levels of nerve growth factor and NT-3, two additional neurotrophic factors. Moreover, BDNF impairment is not related to the activity of its specific tyrosine kinase receptor or the activity of the transcription factor cAMP responsive element binding. These results suggest that the lack of CB1 receptor originates an enhanced response to stress and deficiency in neuronal plasticity by decreasing BDNF levels in the hippocampus that lead to impairment in the responses to emotional disturbances.

Possible GABAergic modulation in the protective effect of zolpidem in acute hypoxic stress-induced behavior alterations and oxidative damage.

Hypoxia is an environmental stressor that is known to elicit alterations in both the autonomic nervous system and endocrine functions. The free radical or oxidative stress theory holds that oxidative reactions are mainly underlying neurodegenerative disorders. In fact among complex metabolic reactions occurring during hypoxia, many could be related to the formation of oxygen derived free radicals, causing a wide spectrum of cell damage. In present study, we investigated possible involvement of GABAergic mechanism in the protective effect of zolpidem against acute hypoxia-induced behavioral modification and biochemical alterations in mice. Mice were subjected to acute hypoxic stress for a period of 2 h. Acute hypoxic stress for 2 h caused significant impairment in locomotor activity, anxiety-like behavior, and antinocioceptive effect in mice. Biochemical analysis revealed a significant increased malondialdehyde, nitrite concentrations and depleted reduced glutathione and catalase levels. Pretreatment with zolpidem (5 and 10 mg/kg, i.p.) significantly improved locomotor activity, anti-anxiety effect, reduced tail flick latency and attenuated oxidative damage (reduced malondialdehyde, nitrite concentration, and restoration of reduced glutathione and catalase levels) as compared to stressed control (hypoxia) (P < 0.05). Besides, protective effect of zolpidem (5 mg/kg) was blocked significantly by picrotoxin (1.0 mg/kg) or flumazenil (2 mg/kg) and potentiated by muscimol (0.05 mg/kg) in hypoxic animals (P < 0.05). These effects were significant as compared to zolpidem (5 mg/kg) per se (P < 0.05). Present study suggest that the possible involvement of GABAergic modulation in the protective effect of zolpidem against hypoxic stress.

Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia.

Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB(1) antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The converse was also true; acute Delta(9)-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Delta(9)-THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.