The nucleus reuniens: a key node in the neurocircuitry of stress and depression.

The hippocampus and prefrontal cortex (PFC) are connected in a reciprocal manner: whereas the hippocampus projects directly to the PFC, a polysynaptic pathway that passes through the nucleus reuniens (RE) of the thalamus relays inputs from the PFC to the hippocampus. The present study demonstrates that lesioning and/or inactivation of the RE reduces coherence in the PFC-hippocampal pathway, provokes an antidepressant-like behavioral response in the forced swim test and prevents, but does not ameliorate, anhedonia in the chronic mild stress (CMS) model of depression. Additionally, RE lesioning before CMS abrogates the well-known neuromorphological and endocrine correlates of CMS. In summary, this work highlights the importance of the reciprocal connectivity between the hippocampus and PFC in the establishment of stress-induced brain pathology and suggests a role for the RE in promoting resilience to depressive illness.

WIN55,212-2 impairs non-associative recognition and spatial memory in rats via CB1 receptor stimulation.

Endogenous and exogenous cannabinoids modulate learning and memory primarily via the cannabinoid type 1 receptor (CB1R). A variety of experimental procedures has focused on the role of CB1R in various aspects of learning and memory processes. However, the picture still remains unclear as there is a lack of information on the effects of relatively low doses of CB1R agonists in relation to their effects on locomotion. The present study sought to investigate CB1R activation, using a range of relatively low doses of the CB1R agonist WIN55,212-2, on multiple aspects of learning and memory in rats. For this purpose, non-associative learning was examined using the habituation of locomotion paradigm, recognition memory was evaluated with the novel object recognition task, and the radial water maze test was selected to assess rats' spatial memory. The ability of the CB1R antagonist, SR141716A, to counteract WIN55,212-2-induced behavioral effects was also tested. WIN55,212-2 (0.3, but not 0.03 or 0.1mg/kg) disrupted non-associative learning, different aspects of short- and long-term recognition memory (storage and retrieval) and retention of spatial memory. The 0.3mg/kg dose of WIN55,212-2 also decreased ambulatory, but not vertical (rearing), activity in non-habituated rats. These effects appeared to be CB1R dependent since pretreatment with SR141716A (0.03 mg/kg) prevented the WIN55,212-2-induced behavioral effects. The present findings further support and extend the complex impact of exogenous cannabinoids on learning and memory in relation to their effects on locomotion.

Cannabinoids negatively modulate striatal glutamate and dopamine release and behavioural output of acute D-amphetamine.

The cannabinoid system plays a regulatory role in neurotransmission and is involved in the central actions of psychostimulants. This complex interaction between the cannabinoid system and psychostimulants represents a potential pharmacological target for psychosis and addiction. However, most studies have focused on cocaine, therefore, it is unclear whether these findings can be extended to other psychostimulants such as the amphetamines. The present study investigated the effects of WIN55,212-2, a synthetic cannabinoid and SR141716A, a CB1 receptor antagonist, on D-amphetamine-induced locomotor activity and extracellular dopamine and glutamate release in the striatum. Rats were either observed for locomotor activity or glutamate and dopamine neurotransmitter release in the striatum using in vivo microdialysis following intraperitoneal co-administration of D-amphetamine with WIN55,212-2 or SR141716A. Our results demonstrated that d-amphetamine per se induced hyperlocomotion and enhanced dopamine and glutamate release, as expected. WIN55,212-2 dampened these effects when co-administered with d-amphetamine, while alone it displayed its characteristic biphasic motor profile coupled with increases in dopamine and decreases in glutamate release. SR141716A at high doses reduced D-amphetamine-induced hyperlocomotion and completely reversed enhanced dopamine and glutamate release but alone had no effect. These findings validate the capacity of the cannabinoid system to modulate amphetamine-induced behaviour and its neurochemical output, in a state-dependent manner, providing insight into aspects of the neurobiological substrate that underlies amphetamines' psychotogenic and addictive properties.

Sex-dependent neurochemical effects of environmental enrichment in the visual system.

Sex differences in the visual system have been reported in aspects of human vision, such as color perception, peripheral vision and even in the activation of the primary visual cortex. Similarly sex differences have been identified in the visual system of laboratory animals such as monkeys and rats. On the other hand, environmental enrichment (EE) has long been known to affect visual tissues. Taking into consideration the variation in the experimental approaches concerning EE and the sex differences in the visual system, we investigated in male and female rats the serotonergic and dopaminergic effects of EE in the retina and the visual cortex at different time points (i.e. P0-25, P0-P90 and P90-P150). Early EE in adulthood increased the serotonergic activity of the male visual cortex and the female retina (P0-P90). In addition early enrichment (P0-P90) increased dopaminergic activity in the female retina and in the visual cortex of both sexes. Late enrichment increased the serotonergic activity in the retina and visual cortex of both sexes (P90-P150), but increased the dopaminergic activity in the visual cortex only in male animals. In the present study we expose marked sex differences in the neurochemistry of visual tissues and we demonstrate for the first time that EE can in fact modify the serotonergic and dopaminergic neurotransmission in the retina and visual cortex. Overall, the present study underpins the sex-dependent neurochemical status of the visual system and provides insights into the different mechanisms underlying visual processing in the two sexes.

Sertraline behavioral response associates closer and dose-dependently with cortical rather than hippocampal serotonergic activity in the rat forced swim stress.

The rat Forced Swim Test (FST) is widely used to investigate the response to antidepressant treatment. Selective serotonin reuptake inhibitors (SSRIs) elongate swimming duration during the FST, while climbing duration is unaffected. In the present study, we aimed to correlate behavioral effects of the SSRI sertraline in the FST with respective changes in the serotonergic activity of the hippocampus and the prefrontal cortex. Male rats were subjected to the standard FST (two swim sessions in two consecutive days) and between the two sessions they received three i.p. injections of sertraline (10 mg/kg or 40 mg/kg) or vehicle. All rats were killed immediately after the second FST session. Unstressed animals received the same administration schemes and were killed in equivalent time-points. Serotonin and its metabolite 5-HIAA were assayed in the hippocampus and the prefrontal cortex with the use of high-performance liquid chromatography (HPLC-ED) and their ratio 5-HIAA/5-HT was calculated. Sertraline enhanced swimming and decreased immobility duration at both doses. Serotonergic activity was not altered by the 2-day swim stress in either brain region, while subchronic sertraline treatment enhanced 5-HT levels and decreased 5-HIAA/5-HT in the hippocampus and the prefrontal cortex. The serotonin turnover rate (5-HIAA/5-HT ratio) decrease is probably indicative of reduced 5-HT metabolism, as a result of 5-HT reuptake inhibition. This effect was significant in the prefrontal cortex of unstressed rats only after a higher dose of sertraline. In the prefrontal cortex, but not in the hippocampus, immobility duration was negatively correlated with 5-HT tissue levels, whereas swimming duration was positively correlated with 5-HT. These results indicate that after antidepressant treatment, behavior during the FST can be predictive of respective serotonergic changes, especially in the prefrontal cortex.

5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor mRNA modulation by antidepressant treatment in the chronic mild stress model of depression: sex differences exposed.

It is well established that women experience major depression at roughly twice the rate of men. Interestingly, accumulating clinical and experimental evidence shows that the responsiveness of males and females to antidepressant pharmacotherapy, and particularly to tricyclic antidepressants (TCAs), is sex-differentiated. Herein, we investigated whether exposure of male and female rats to the chronic mild stress (CMS) model of depression, as well as treatment with the TCA clomipramine may affect serotonergic receptors' (5-HTRs) mRNA expression in a sex-dependent manner. Male and female rats were subjected to CMS for 4 weeks and during the next 4 weeks they concurrently received clomipramine treatment (10 mg/ml/kg). CMS and clomipramine's effects on 5-HT(1A)R, 5-HT(2A)R, and 5-HT(2C)R mRNA expression were assessed by in situ hybridization histochemistry in selected subfields of the hippocampus and in the lateral orbitofrontal cortex (OFC), two regions implicated in the pathophysiology of major depression. CMS and clomipramine treatment induced sex-differentiated effects on rats' hedonic status and enhanced 5-HT(1A)R mRNA expression in the cornu ammonis 1 (CA1) hippocampal region of male rats. Additionally, CMS attenuated 5-HT(1A)R mRNA expression in the OFC of male rats and clomipramine reversed this effect. Moreover, 5-HT(2A)R mRNA levels in the OFC were enhanced in females but decreased in males, while clomipramine reversed this effect only in females. CMS increased 5-HT2CR mRNA expression in the CA4 region of both sexes and this effect was attenuated by clomipramine. Present data exposed that both CMS and clomipramine treatment may induce sex-differentiated and region-distinctive effects on 5-HTRs mRNA expression and further implicate the serotonergic system in the manifestation of sexually dimorphic neurobehavioral responses to stress.

Citalopram-mediated anxiolysis and differing neurobiological responses in both sexes of a genetic model of depression.

Disorders such as depression and anxiety exhibit strong sex differences in their prevalence and incidence, with women also differing from men in their response to antidepressants. Furthermore, receptors for corticotrophin releasing hormone (CRHR1) and arginine vasopressin receptor subtype 1b (AVPR1b) are known to contribute to the regulation of mood and anxiety. In the present study, we compared the anxiety profile and CRHR1 and AVPR1b expression levels in control Sprague-Dawley (SD) rats and rats of the SD-derived Flinders Sensitive Line (FSL), a genetic model of depression. Additionally, given the apparent sex differences in the therapeutic efficacy of antidepressants and because antidepressants are commonly used to treat comorbid anxiety and depressive symptoms, we assessed whether the anxiolytic effects of an antidepressant occur in a sex-dependent manner. Male and female FSL rats were treated with citalopram 10 mg/kg once daily for 14 days and were then tested in the open field and the elevated plus maze paradigms. Upon completion of the behavioural analysis, AVPR1b and CRHR1 expression levels were monitored in the hypothalamus and the prefrontal cortex (PFC) using Western blotting. According to our results, male FSL rats were more anxious than control SD rats, a difference abolished by citalopram treatment. Baseline anxiety levels were similar in female FSL and SD rats, and citalopram further reduced anxiety in female FSL rats. Importantly, whereas citalopram altered AVPR1b expression in the hypothalamus of male FSL rats, its actions on this parameter were restricted to the PFC in female FSL rats. In both sexes of FSL rats, citalopram did not alter CRHR1 expression in either the hypothalamus or PFC. Our results demonstrate that antidepressant treatment reduces anxiety levels in FSL rats of both sexes: the magnitude of treatment effect was related to the starting baseline level of anxiety and the antidepressant elicited sexually differentiated neurobiological responses in specific brain regions.

Δ(9)-THC and WIN55,212-2 affect brain tissue levels of excitatory amino acids in a phenotype-, compound-, dose-, and region-specific manner.

Endocannabinoids are involved in excitatory neurotransmission initiated by glutamate and aspartate. The aim of the present study was to investigate the effects of the cannabinoid agonists, Δ(9)-THC and WIN55,212-2, on tissue (prefrontal cortex, dorsal striatum, nucleus accumbens, hippocampus, amygdala and hypothalamus) levels of glutamate and aspartate in two rat phenotypes, high responders (HR) and low responders (LR), differentiated according to their response to a novel environment. HR displayed increased motor activity but no difference in basal levels of glutamate and aspartate as compared to LR. Both cannabinoids increased ambulatory activity at the low doses, this effect was observed only in HR following Δ(9)-THC, but in both HR and LR following WIN55,212-2. The cannabinoids primarily increased glutamate levels in the prefrontal cortex, dorsal striatum, nucleus accumbens and hippocampus, while the high dose of WIN55,212-2 decreased glutamate levels in the amygdala and both doses in the hypothalamus; these effects appeared overall more pronounced in HR. In contrast, the cannabinoids primarily decreased aspartate levels in all brain regions, except in the dorsal striatum, where an increase was seen after both doses of Δ(9)-THC and WIN55,212-2 as well as in the nucleus accumbens after the low dose of Δ(9)-THC in HR; these effects also appeared overall more pronounced in HR. Present results show that exogenous cannabinoids affect tissue levels of glutamate and aspartate in a phenotype-, compound-, dose-, and brain region-dependent manner.

Pharmacogenetic insights into depression and antidepressant response: does sex matter?

It is known that the frequency of men and women suffering from stress-related neuropsychiatric disorders is all but proportionally distributed. Notably, women are far more susceptible than men to the precipitation of depressive symptomatology. Some studies attribute this sex-specific vulnerability to the pronounced genetic predisposition that women may present towards the development of depressive disorders. Furthermore, clinical evidence support the notion that antidepressant response is also characterized by sex-specific manifestations; women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Despite the fact that the contribution of the "genome" remains elusive when it comes to major depression, intriguing evidence has recently emerged pointing to sexually dimorphic influences of certain polymorphisms in genes related to the pathophysiology of major depression and antidepressant response, such as the serotonin transporter (5-HTT), serotonin 1A (5HT1A) receptor, monoamine oxidase A (MAO-A) and others. Given that the ultimate goal of pharmacogenetics is to provide "tailor-made" pharmacotherapies based on the genetic makeup of an individual, the factor of "sex" needs to be carefully addressed in disorders that are characterized by sex specific manifestations. The aim of the present article is to highlight the impact of sex in depression and in antidepressant pharmacoresponse by providing intriguing insights from the field of pharmacogenetics.

Sex differences in oxidant/antioxidant balance under a chronic mild stress regime.

The deterioration of homeostasis between oxidant/antioxidant species may represent an important mechanism linking psychological stress to cardiovascular risk despite the many sex differences in stress responsiveness. The goal of the present study was to investigate the influence of chronic mild stress (CMS), a widely accepted animal model of depression, on oxidative homeostasis-allostasis markers and sICAM-1, a marker of endothelial injury, in the serum of Wistar rats, by taking into account the effect of sex. After six weeks of exposure to mild unpredictable environmental stressors, both male and female rat groups displayed typical changes in hedonic status (anhedonia), which is a core symptom of human depression. Control female rats had higher (nitrite and nitrate) NOx, lower malondealdehyde (MDA) levels with lower activity of antioxidant enzymes and sICAM-1 levels than did control males. CMS induced oxidant/antioxidant responses in both sexes. Females tended to increase their nitric oxide (NO) levels further, while MDA levels did not reach those of males, thus retaining significantly higher NO bioavailability than in males. Concerning the antioxidant enzymes, CMS-females exhibited significantly higher glutathione peroxidase (GPx) activity and lower glutathione reductase (GR) and superoxide dismutase (SOD) activity compared to CMS-males. The CMS response in females was accompanied by lower sICAM-1 levels than in males, suggesting lower endothelial injury. In conclusion, the results of the present study showed that CMS induces different oxidative stress and compensatory responses in both sexes probably due to differences in the mechanisms regulating oxidant/antioxidant pathways.

Neurochemical and behavioral alterations in an inflammatory model of depression: sex differences exposed.

It is firmly established that women experience major depression (MD) at roughly twice the rate of men and that dysregulation of the immune system is associated with the appearance and course of this condition. In the present study, we sought to identify whether "sickness behavior", an inflammatory model of MD, is characterized by sexual dimorphism by focusing on both neurochemical and behavioral responses. Therefore, we investigated the serotonergic and dopaminergic activity of various brain regions implicated in the pathophysiology of affective disorders (hypothalamus, hippocampus, prefrontal cortex, amygdala and striatum) in response to a mild lipopolysaccharide (LPS) challenge, in rats of both sexes. According to our results, at 2 h post-LPS administration (100 microg/kg i.p.), the neurochemical substrate was primarily altered in female rats with the serotonergic function being markedly enhanced in all brain regions examined. Dopaminergic activation following immune system sensitization with LPS was not apparent in male rats and only modest in female rats with the exception of striatum. LPS administration also affected sickness-associated behaviors to a different extent in male and female rats, as assessed in the forced swim test (FST), the hot plate test (HPT) and the open-field arena. LPS-treated female rats coped better with the stressful FST procedure, as evidenced by an increase in swimming duration. The effects of LPS treatment appeared to be more robust in male rats, as far as suppression of locomotor activity is concerned, while the antinociceptive properties of LPS were evident in both sexes though showing sex-dependent kinetics. Moreover, when traditional measures of sickness (i.e. sucrose consumption, social exploration, food intake) were assessed, males and females appeared to be similarly affected, except for food intake. These data are the first to demonstrate that the serotonergic system is affected to a greater extent in female rats at 2 h post-LPS administration and further contribute to our understanding regarding sexual dimorphism upon sickness establishment.

Sex-related differential response to clomipramine treatment in a rat model of depression.

Research in affective disorders is often performed without considering sex differences, although women are predominantly affected. Consequently, the potential sex-dependent action of antidepressants remains elusive. We investigated whether Flinders sensitive line (FSL) of rats, a model of depression, would present sex-differentiated responses to antidepressant treatment. FSL and Sprague-Dawley rats were treated with clomipramine 10 mg/kg/day for 14 days. Subsequently, they were subjected to either a single session of the forced swim test or an estimation of serotonergic function in the prefrontal cortex, hippocampus, amygdala and hypothalamus. Male FSL displayed increased immobility duration, decreased active behaviours, increased serotonin tissue levels and a reduced serotonin turnover rate in most brain areas studied. Female FSL showed a distinct profile, consisting of decreased immobility latency, increased climbing duration, limited serotonergic deviations and no difference in the serotonin turnover rate in comparison with controls. Interestingly, despite baseline differences, clomipramine treatment reversed all relevant behavioural responses and increased the serotonin turnover rate in both sexes. However, the latter effect was remarkably more pronounced in females. It is concluded that, in this animal model of depression, chronic clomipramine treatment attenuated baseline sex differences in the phenotype while maintaining or intensifying the sex differentiation in the serotonergic endophenotype.

Activation of somatostatin receptors in the globus pallidus increases rat locomotor activity and dopamine release in the striatum.

RATIONALE: Somatostatin and its receptors have been localized in brain nuclei implicated in motor control, such as the striatum, nucleus accumbens, ventral pallidum, and globus pallidus (GP). OBJECTIVES: The objective of this study was to investigate the role of somatostatin receptors (sst(1,2,4)) in the GP on dopamine (DA)-mediated behaviors, such as locomotor activity, and to examine the GP-striatum circuitry by correlating the effect of somatostatin in the GP with the release of DA in the striatum. MATERIALS AND METHODS: Animals received saline, somatostatin (60, 120, 240 ng/0.5 microl per side) or the following selective ligands: L-797,591 (sst(1) analog, 60, 120, 240 ng/0.5 microl per side), L-779,976 (sst(2) analog, 120, 240, 480 ng/0.5 microl per side), L-803,087 (sst(4) analog; 120, 240, 480 ng/0.5 microl per side), L-796,778 (sst(3) analog, 240 ng/0.5 microl per side), SRA-880 (sst(1) selective antagonist + somatostatin, 120 ng/0.5 microl per side), CYN154806 (sst(2) selective antagonist + somatostatin, 120 ng/0.5 microl per side) bilaterally in the GP of the rat. Locomotor activity was measured for 60 min. The effect of somatostatin, administered intrapallidally, on the extracellular concentrations of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the striatum was also studied in the behaving rat using in vivo microdialysis methodology. RESULTS: Somatostatin increased the locomotor activity of the rat in a dose-dependent manner. This effect was mediated by activation of the sst(1), sst(2), and sst(4) receptors. Selective sst agonists increased locomotor activity in a statistical significant manner, while selective sst(1) and sst(2) antagonists reversed the somatostatin-mediated locomotor activity to control levels. DA levels increased in the striatum after intrapallidal infusion of somatostatin (240 ng/side). CONCLUSIONS: These data provide behavioral and neurochemical evidence of the functional role of somatostatin receptors in the GP-striatum circuitry.

Glutamate levels and activity of the T cell voltage-gated potassium Kv1.3 channel in patients with systemic lupus erythematosus.

OBJECTIVE: Alterations in glutamate homeostasis and Kv1.3 voltage-gated potassium channel function have been independently associated with T cell dysfunction, whereas selective blockade of Kv1.3 channels inhibits T cell activation and improves T cell-mediated manifestations in animal models of autoimmunity. Because low extracellular glutamate concentrations enhance the activity of this channel in normal T cells ex vivo, we undertook this study to examine serum glutamate concentrations and Kv1.3 channel activity in patients with systemic lupus erythematosus (SLE). METHODS: We used high-performance liquid chromatography for glutamate measurements, and we used the whole-cell patch-clamp technique for electrophysiologic studies performed in freshly isolated, noncultured peripheral T cells. RESULTS: Mean +/- SD serum concentrations of glutamate were lower in patients with either clinically quiescent SLE (77 +/- 27 microM [n = 18]) or active SLE (61 +/- 36 microM [n = 16]) than in healthy controls (166 +/- 64 microM [n = 24]) (both P < 0.0001). The intrinsic gating properties of the Kv1.3 channels in lupus T cells were found to be comparable with those in healthy control-derived T cells. Notably, electrophysiologic data from SLE patient-derived T cells exposed to extracellular glutamate concentrations similar to their respective serum levels (50 microM) demonstrated Kv1.3 current responses enhanced by almost 20% (P < 0.01) compared with those subsequently obtained from the same cell in the presence of glutamate concentrations within control serum levels (200 microM). CONCLUSION: Based on the key role of Kv1.3 channel activity in lymphocyte physiology, an enhancing in vivo effect of low serum glutamate concentrations on the functional activity of this channel may contribute to lupus T cell hyperactivity. Studies to further elucidate Kv1.3 responses in SLE, as well as the possible pathogenetic role of this unsuspected metabolic abnormality, may have therapeutic implications for SLE patients.

Sex differences in the effects of two stress paradigms on dopaminergic neurotransmission.

Sex differences in behavioral and neurobiological responses to stress are considered to modulate the prevalence of some psychiatric disorders, including major depression. In the present study, we compared dopaminergic neurotransmission and behavior in response to two different stress paradigms, the Forced Swim Test (FST) and the Chronic Mild Stress (CMS). Male and female rats were subjected to one session of swim stress for two consecutive days (FST) or to a variety of mild stressors alternating for six weeks (CMS). Subsequently, the tissue levels of dopamine (DA) and its metabolites (HVA and DOPAC) in the hippocampus, the hypothalamus, the prefrontal cortex and the striatum were measured using high-performance liquid chromatography (HPLC). The ratios HVA/DA and DOPAC/DA were also calculated as indices of the dopaminergic activity. Results from the FST determined that males exhibited lower immobility, higher climbing duration and increased dopaminergic activity in the prefrontal cortex and the hippocampus compared to females. CMS induced alterations in sucrose intake in both sexes, while it only decreased dopaminergic activity in the prefrontal cortex of females. These findings show that FST and CMS have different effects on the dopaminergic activity of discrete brain regions depending on the sex of the animal. These data support the growing evidence that females display a differential response and adaptation to stress than males.

Individual responses to novelty are associated with differences in behavioral and neurochemical profiles.

Experimental animals can be differentiated on the basis of their horizontal or vertical activity to high responders (HR) and low responders (LR) upon exposure to a novel environment. These individual differences have been associated with behavioral and neurobiological differences in a number of experimental procedures used for studying sensitivity to psychostimulants, anxiety, depression, and cognitive function. In the present study, we differentiated the rats to HR and LR based on their vertical activity upon exposure to a novel environment. Additionally, we ascertained whether HR and LR rats differ in a battery of tests such as passive avoidance (PA), object recognition (OR), and the water-maze (WM) that provide indices for cognitive function and the forced swim test (FST), an animal model of affective responsivity and antidepressant-like activity. Potential differences in neurochemical indices between the two phenotypes were also examined. HR rats displayed impaired non-spatial object recognition memory, but enhanced spatial performance, as compared to LR rats. FST induced "depressive-like" symptoms in both phenotypes that were differently manifested in HR versus LR rats. Neurochemical findings revealed distinct differences in serotonergic and dopaminergic activity in the striatum and the prefrontal cortex of HR as compared to LR rats. The above results show that HR and LR rats exhibit important differences in a battery of tests related to cognitive performance or affective responsivity, which may be associated with differences in certain neurobiological parameters.

A study of the role of serotonin in the anxiolytic effect of nitrous oxide in rodents.

RATIONALE: In earlier studies, we have shown that nitrous oxide (N2O)-induced behavioral effects in rats and mice are mediated by benzodiazepine receptors. OBJECTIVES: This two-part study was conducted in order to investigate the possible role of serotonin (5-HT) in the behavioral effects of N2O by clarifying its effects on regional brain concentrations of 5-HT and assessing the influence of 5-HT antagonist and reuptake inhibiting drugs on the anxiolytic-like behavioral effect of N2O. METHODS: In experiment A, male, 150-200 g Sprague-Dawley rats were killed following a 15-min exposure to room air or 70% N2O. The frontal cortex, hippocampus, corpus striatum and hypothalamus were dissected out and analyzed by HPLC with electrochemical detection for content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA); dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were also measured. In experiment B, male 18-22 g NIH Swiss mice were pretreated with the 5-HT2 antagonist cinanserin, the 5-HT3 antagonist LY-278,584, the 5-HT reuptake inhibitor fluoxetine or saline and tested in the light/dark exploration test under 70% N2O 30 min after pretreatment. RESULTS: In experiment A, N2O produced differential effects on 5-HT neurons in distinct brain areas. There was increased 5-HT turnover in the hypothalamus, decreased turnover in the frontal cortex but no changes in either hippocampus or corpus striatum. By comparison, dopamine turnover in these brain regions was unaltered by N2O exposure. In experiment B, pretreatment with neither cinanserin, LY-278,584 nor fluoxetine had any appreciable effect on the N2O-induced increase in time spent in the light compartment. Only cinanserin significantly reduced the N2O-induced increase in transitions. CONCLUSIONS: While neurochemical results suggest an effect of N2O on brain 5-HT function, there was no effect of 5-HT2 or 5-HT3 antagonists or 5-HT reuptake inhibitor on N2O-induced anxiolytic-like behavior.

Effect of platelet-activating factor (PAF) receptor antagonist (BN52021) on acetaminophen-induced acute liver injury and regeneration in rats.

BACKGROUND: Platelet-activating factor (PAF) is an endogenous lipid mediator that plays a key role in catalyzing various pro-inflammatory processes associated with acute liver injury. In the present study, the possible influence of PAF-R antagonist (BN52021) on the protection of liver injury after 4-hydroxyacetanilide, N-acetyl-p-aminophenol, paracetamol (APAP) intoxication was investigated. METHODS: Thereby, one group of rats was treated with a toxic dose of APAP (3.5 g/kg body weight (b.w.). The animals were killed at 56, 66, 72, 84 and 96 h after treatment. RESULTS: APAP was found to cause an acute hepatic injury, evident by alterations of biochemical (serum enzymes: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase) and liver histopathological (degree of necrosis and apoptosis) indices, which was followed by liver regeneration, evident by three independent indices ([3H] thymidine incorporation into hepatic DNA, liver thymidine kinase activity and hepatocyte mitotic index). The protective effects of BN52021 were qualified during post-treatment time by: (1) significant reduction of hepatic injury as showed by all biochemical and histological parameters, (2) high decrease of regenerating activity showed by three regenerative markers and (3) remarkable increase of PAF-acetylhydrolase (PAF-AH) activity. CONCLUSION: These results suggest that PAF may play an important role in APAP-induced liver injury and regeneration, and PAF-R antagonist (BN52021) attenuates liver damage.

Efficacy of antidepressants in child and adolescent depression: a meta-analytic study.

OBJECTIVES: To examine whether antidepressant drugs are superior to placebo in the treatment of juvenile depression. METHOD: Extensive literature search was done to retrieve all randomised controlled and all uncontrolled trials describing children and adolescents with a diagnosis of depression who underwent any antidepressant drug treatment. In order to combine results, separate analyses using random effect models were conducted first for controlled and then for both controlled and open studies. RESULTS: 18 controlled and 23 open trials were submitted to meta-analysis. Tricyclics showed no significant benefit over placebo. Odds ratios for SSRIs were 1.84 (95% CI 1.35-2.50) for controlled and 1.83 (95% CI 1.40-2.40) for controlled and uncontrolled studies suggesting a significant benefit over placebo. Combining all antidepressants also gave confidence interval excluding the value one. CONCLUSIONS: Despite some promising data concerning the use of SSRIs in the treatment of adolescent depression, caution is warranted until the long-term safety of these agents can be demonstrated. Insufficient data are available to judge even the short term merits of these agents in prepubertal children. There is no evidence to support the use of tricyclics in this population.