Nurr1 repression mediates cardinal features of Parkinson's disease in α-synuclein transgenic mice.

Duplication/triplication mutations of the SNCA locus, encoding alpha-synuclein (ASYN), and loss of function mutations in Nurr1, a nuclear receptor guiding midbrain dopaminergic neuron development, are associated with familial Parkinson's disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions and ASYN expression increases while the expression of Nurr1 decreases. We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice. ASYN(d)/Nurr1+/- (2-hit) mice, contrary to the individual genetic traits, developed phenotypes consistent with dopaminergic dysfunction. Aging '2-hit' mice manifested kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment and cachexia and died prematurely. Pathological abnormalities of phenotypic mice included SN neuron degeneration, extensive neuroinflammation and enhanced ASYN aggregation. Mice with two wt Nurr1 alleles [ASYN(d)/Nurr1+/+] or with reduced ASYN load [ASYN(s)/Nurr1+/-] did not develop the phenotype or pathology. Critically, we found that aging ASYN(d), in contrast to ASYN(s), mice suppress Nurr1-protein levels in a brain region-specific manner, which in addition to Nurr1 hemizygosity is necessary to instigate PD pathogenesis. Our experiments demonstrate that ASYN-dependent PD-related pathophysiology is mediated at least in part by Nurr1 down-regulation.

Forced swim test induces divergent global transcriptomic alterations in the hippocampus of high versus low novelty-seeker rats.

BACKGROUND: Many neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Susceptibility to stress and depression is individually different. The best animal model of individual differences that can be used to study the neurobiology of affect regards spontaneous reactions to novelty. Experimentally, when naive rats are exposed to the stress of a novel environment, they display a highly variable exploratory activity and are classified as high or low responders (HR or LR, respectively). Importantly, HR and LR rats do not seem to exhibit a substantial differentiation in relation to their 'depressive-like' status in the forced swim test (FST), a widely used animal model of 'behavioral despair'. In the present study, we investigated whether FST exposure would be accompanied by phenotype-dependent differences in hippocampal gene expression in HR and LR rats. RESULTS: HR and LR rats present a distinct behavioral pattern in the pre-test session but develop comparable depressive-like status in the second FST session. At 24 h following the second FST session, HR and LR rats (stressed and unstressed controls) were sacrificed and hippocampal samples were independently analyzed on whole rat genome Illumina arrays. Functional analysis into pathways and networks was performed using Ingenuity Pathway Analysis (IPA) software. Notably, hippocampal gene expression signatures between HR and LR rats were markedly divergent, despite their comparable depressive-like status in the FST. These molecular differences are reflected in both the extent of transcriptional remodeling (number of significantly changed genes) and the types of molecular pathways affected following FST exposure. A markedly higher number of genes (i.e., 2.28-fold) were statistically significantly changed following FST in LR rats, as compared to their HR counterparts. Notably, genes associated with neurogenesis and synaptic plasticity were induced in the hippocampus of LR rats in response to FST, whereas in HR rats, FST induced pathways directly or indirectly associated with induction of apoptotic mechanisms. CONCLUSIONS: The markedly divergent gene expression signatures exposed herein support the notion that the hippocampus of HR and LR rats undergoes distinct transcriptional remodeling in response to the same stress regimen, thus yielding a different FST-related 'endophenotype', despite the seemingly similar depressive-like phenotype.

Sex differences in the chronic mild stress model of depression.

A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with 'chronic mild stress', 'chronic unpredictable stress' and 'chronic variable stress' as base terms and 'sex', 'gender', 'females' and 'depression' as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a 'silver bullet' in assessing the role of sex in the neurobiology of major depression.

Effects of environmental enrichment on growth, aggressive behaviour and brain monoamines of gilthead seabream Sparus aurata reared under different social conditions.

The presence of blue or red-brown substrate on the tank bottom has been previously reported as an efficient means of environmental enrichment for gilthead seabream. The present study aimed to investigate whether this enrichment is still beneficial when gilthead seabream is reared under different social conditions (i.e. a lower 4.9 kg m(-3) and a higher 9.7 kg m(-3) density). Water exchange was adjusted according to fish biomass to exclude density effects on water quality. In the enriched tanks single-colour glass gravel was used as substrate (blue and red-brown substrate, or BS and RBS respectively), while control tanks had no gravel. Growth, aggressive behaviour and size distribution results indicated that the lower density created a less favourable social environment. In both densities studied, BS enhanced growth, suppressed aggression and reduced brain serotonergic activity. In the condition of intense social interactions (i.e. the lower density) BS also reduced brain dopaminergic activity. These results along with the negative correlations observed between brain monoamines and fish body mass, indicated that substrate and density effects are socially-induced. However, there may be several biotic and/or abiotic factors interfering with substrate effects that should be investigated before the practical use of a substrate in land-based intensive aquaculture.

The cannabinoid CB1 receptor biphasically modulates motor activity and regulates dopamine and glutamate release region dependently.

Cannabinoid administration modulates both dopaminergic and glutamatergic neurotransmission. The present study examines the effects of high and low dose WIN55,212-2, a CB1 receptor agonist, on extracellular dopamine and glutamate release in vivo via brain microdialysis in the nucleus accumbens (NAc), striatum and prefrontal cortex (PFC) in parallel to its effects on locomotor activity. WIN55,212-2 increased extracellular dopamine in the NAc (1 mg/kg i.p.), striatum (0.1 and 1 mg/kg i.p.) and PFC (1 mg/kg i.p.). Glutamate release was also elevated by WIN55,212-2 in the PFC (1 mg/kg i.p.) whereas in the NAc (0.1 and 1 mg/kg i.p.) and striatum, it was reduced (1 mg/kg i.p.). WIN55,212-2 administration produced hyperlocomotion at the lower dose (0.1 mg/kg i.p.) and hypolocomotion at the higher dose (1 mg/kg i.p.). Co-administration with the CB1 antagonist, SR-141716A (0.03 mg/kg i.p.), prevented the above effects. According to the present results, WIN55,212-2 affected locomotor activity biphasically while exerting converging effects on dopamine activity but diverging effects on glutamate release between cortical and subcortical regions, especially at the higher dose. These findings emphasize the involvement of the CB1 receptor in the simultaneous modulation of dopaminergic and glutamatergic neurotransmission in brain regions involved in reward and locomotion and suggest possible underlying mechanisms of acute cannabinoid exposure and its psychoactive and behavioural manifestations.

Experimental evidence for sildenafil's action in the central nervous system: dopamine and serotonin changes in the medial preoptic area and nucleus accumbens during sexual arousal.

INTRODUCTION: Sildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc). AIM: The aim of this study was to determine whether sildenafil administration alters dopaminergic and serotonergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal. METHODS: An acute (2 days) or chronic (21 days) sildenafil regimen (1 mg/kg) was administered intraperitoneally to male rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact erection sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time. MAIN OUTCOME MEASURES: Tissue levels of DA and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as serotonin (5-HT) and its metabolite 5-HIAA, were measured in the mPOA and NAcc with high-performance liquid chromatography with electrochemical detector. Dopamine ([DOPAC+HVA]/DA) and serotonin (5-HIAA/5-HT) turnovers were also calculated as indices of neurotransmission. RESULTS: In nontrained males, acute and chronic sildenafil treatment increased DA and 5-HT turnover rates in the mPOA and NAcc. In trained rats, acute sildenafil also increased DA and 5-HT turnover rates in both structures, whereas chronic treatment enhanced 5-HT turnover rate only in the mPOA and DA turnover rate only in the NAcc. CONCLUSIONS: Our data confirm that sildenafil enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil-induced effects on serotonergic activity in these brain regions as well. Therefore, present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal.

Functional Interaction Between α-Synuclein and Nurr1 in Dopaminergic Neurons.

Increased expression of alpha-synuclein (ASYN) and decreased expression of Nurr1 are associated with Parkinson's disease (PD) pathogenesis. These two proteins interact functionally and ASYN overexpression suppresses Nurr1 levels. ASYN pan-neuronal overexpression coupled with Nurr1 hemizygosity followed by Nurr1 repression in aging mice results in the manifestation of a typical PD-related phenotype and pathology. Here we investigated in mice the effects of C-terminally truncated ASYN(120) overexpression in dopaminergic (DA-ergic) neurons compounded with Nurr1 hemizygosity ('2-hit-DA'). We report that '2-hit-DA' animals did not manifest a characteristic PD-related phenotype, despite further substantia nigra ASYN-overexpression-dependent and age dependent Nurr1 protein downregulation. However, they displayed increased energy expenditure, reduced striatal dopamine (DA) and prolonged hyperactivity to a novel environment indicating impaired habituation. This DA-ergic dysfunction was observed in young adult '2-hit-DA' mice, persisted throughout life and it was associated with ASYN and Nurr1 synergistic alterations of DAT levels and function. Our experiments indicate that the expression levels of ASYN and Nurr1 are critical in the dysregulation of the nigrostriatal DA system and may be involved in neuropsychiatric aspects of PD.

Of depression and immunity: does sex matter?

It is firmly established that women experience major depression (MD) at roughly twice the rate of men. Contemporary research has indicated that sex hormones comprise crucial orchestrators of the differences in susceptibility associated to sex in MD, as well as in certain infectious and autoimmune diseases. Interestingly, it has been suggested that altered functioning of the immune system may be implicated in the medical morbidity of this affective disorder. To make matters more complicated, data accumulated largely during the last two decades advocate the innate inflammatory immune response as a mechanism that may contribute to the pathophysiology of MD, mainly through alterations in the ability of immune cells to secrete pro-inflammatory cytokines. Although the literature is limited, the bi-directional influences between the brain and the immune system appear to present sex-related motifs whose elucidation is far from being completely achieved but comprises a matter of intensive research. Herein, we provide a first critical glimpse into if and how sex differences in immunity may be implicated in the pathophysiology of MD. The review's major aim is to sensitize clinical scientists of different disciplines to the putative impact of immune sexual dimorphism on MD and to stimulate basic research in a need to delineate the neuroimmunological substrate in the appearance, course and outcome of this stress-related disorder.

Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain.

This study explored the behavioural, neurochemical and molecular effects of Delta9-tetrahydrocannabinol (Delta9-THC) and WIN55,212-2, in two rat phenotypes, distinguished on the basis of their vertical activity upon exposure to a novel environment, as high responders (HR) and low responders (LR). Motor effects were assessed under habituated vs. non-habituated conditions. Dopaminergic activity and DARPP-32 phosphorylation were measured in the dorsal striatum, nucleus accumbens, prefrontal cortex and amygdala. These cannabinoids influenced motor activity in a biphasic manner, i.e. low doses stimulated, whereas high doses suppressed motor activity. Dopamine (DA) biosynthesis was increased in most brain regions studied following Delta9-THC administration mainly in HR rats, and low-dose WIN55,212-2 increased DA biosynthesis in HR rats only. Both high and low doses of Delta9-THC increased DARPP-32 phosphorylation in most brain regions studied in both phenotypes, an effect that was also observed following high-dose WIN55,212-2 administration only in the striatum. The present results provide further support for a key role of cannabinoids in the regulation of motoric responses and elements of dopaminergic neurotransmission and reveal their complex differential effects in distinct rat phenotypes, as seen with other drugs of abuse.

Chronic antidepressant treatment exerts sexually dimorphic immunomodulatory effects in an experimental model of major depression: do females lack an advantage?

Major depression is a stress-related disorder that affects about 20% of the population, with women outnumbering men by 2:1. However, research focusing on stress/antidepressant-related immunomodulation overlooks sex differences, although an established sexual dimorphism also characterizes the immune system. We report for the first time that both chronic clomipramine treatment (10 mg/kg, twice daily) and chronic mild stress (CMS) application in rats, exert sexually dimorphic effects on cellular immunoreactivity (natural killer and lymphokine-activated killer cell cytotoxicity and interleukin-2-induced T-cell proliferation), with females presenting a relatively immunosuppressed phenotype compared to males. Moreover, following chronic antidepressant treatment, thymic monoamines presented sex-related alterations, as well as intriguing associations with peripheral T-cell responses. This study highlights the sex-related effects of chronic clomipramine treatment and CMS application on the cellular arm of immunity, and represents a preliminary exposé of a thymus-dependent route pertaining to the interactions between antidepressants and the immune system.

TPH2 gene variants and anxiety during alcohol detoxification outcome.

Clinical outcome of alcoholism may be partly under genetic control. The serotonergic system is involved in alcohol intake, and it has been widely investigated in alcohol dependence. Recently, attention has been focused on the neuronal tryptophan hydroxylase 2 gene (TPH2). TPH2 variants have been consistently associated with anxiety-related traits; since anxiety is critical for alcohol dependence treatment, in the present paper we investigated 9 SNPs within the THP2 gene in anxiety symptoms during the detoxification procedure. The sample comprised 68 alcohol-dependent patients who where evaluated with the Hamilton Rating Scale for Anxiety, before and after the detoxification procedure. Other psychopathological indicators of outcome, such as depression and anxiety sub-features were also investigated. We did not observe a role for TPH2 variants in the efficacy of treatment in relieving anxiety and other psychopathological symptoms. However, a haplotype that included the promoter rs4570625 polymorphism (associated with anxiety-related traits in previous studies) showed an association with the severity of anxiety symptoms on admission. This preliminary finding, although obtained on a small sample, may provide further support for a role of the TPH2 gene in emotional behaviors. Furthermore, the present study suggests the possible functional significance of the promoter rs4570625 polymorphism. The present preliminary results are of interest in alcoholism, given that comorbidity with anxiety represents a critical problem in treatment settings and response to detoxification.

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models.

Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the C. sativus L. natural compounds trans-crocin 4 and trans-crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer's Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 µM to 1 mM, applied for 24 h or 72 h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans-crocin 4 and trans-crocetin had significant effects against amyloidogenic pathways. Trans-crocin 4 significantly decreased of ß-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans-crocetin treatment led to a reduction in ß- and γ-secretases, as well as to accumulation of cellular AßPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3ß and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans-crocin 4 and trans-crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.

The impact of the hormonal milieu and stress-associated hypothalamic dopaminergic activation on the rapid compensatory adrenal growth in cycling female rats.

OBJECTIVE: We sought to investigate the impact of emotional and surgical stress applied in two hormonally different estrous-cycle phases as well as the hypothalamic dopaminergic involvement on the rapid compensatory adrenal growth (CAG) and the individual adrenal growth (IAG) in rats. DESIGN: After surgery for left and sham adrenalectomy (Adx) carried out on either diestrus-2 (DE-2) or proestrus (PE), CAG and IAG were evaluated in PE or estrus (E), respectively. Hypothalamic dopaminergic activity was also assessed by measuring dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in DE-2, PE and E in controls and in PE and E in sham and left adrenalectomized rats. All groups experienced similar chronic emotional stress assessed by the emotional reactivity score recorded during vaginal screening. RESULTS: In controls, DOPAC levels in DE-2 were higher than in PE and E. In PE, following surgery in DE-2, DOPAC levels and DOPAC/DA ratio were increased compared to PE controls; CAG was not significant, while negative correlations of IAG and CAG with DOPAC/DA ratio were observed. In E, CAG and IAG were significant, while dopaminergic activity was not increased compared to E controls. CONCLUSIONS: The significant CAG and IAG following left Adx in PE but not in DE-2 suggest a pronounced positive impact of the hormonal milieu on this process. The profound attenuation of CAG and IAG in PE suggests a negative effect of stress-associated dopaminergic activation.

Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer's Disease Neuronal Cell Culture Models.

BACKGROUND: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer's disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings. OBJECTIVE: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet. METHODS/RESULTS: After the detailed characterization of the extracts' composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the AßPP overexpressing SH-SY5Y-AßPP and the hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on AßPP and tau processing pathways were investigated in the SH-SY5Y-AßPP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3ß, ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote AßPP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms. CONCLUSIONS: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level.

Estradiol rapidly activates male sexual behavior and affects brain monoamine levels in the quail brain.

Steroids are generally viewed as transcription factors binding to intracellular receptors and activating gene transcription. Rapid cellular effects mediated via non-genomic mechanisms have however been identified and one report showed that injections of estradiol rapidly stimulate chemoinvestigation and mounting behavior in castrated male rats. It is not known whether such effects take place in other species and what are the cellular underlying mechanisms. We show here that a single injection of estradiol (500 microg/kg) rapidly and transiently activates copulatory behavior in castrated male quail pre-treated with a dose of testosterone behaviorally ineffective by itself. The maximal behavioral effect was observed after 15 min. In a second experiment, the brain of all subjects was immediately collected after behavioral tests performed 15 min after injection. The preoptic area--hypothalamus (HPOA), hindbrain, telencephalon and cerebellum were isolated and monoamines measured by HPLC-ED. Estradiol increased levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA/serotonin ratios in the telencephalon and hindbrain independently of whether animals had mated or not. Estradiol also affected these measures in HPOA and cerebellum but this effect was correlated with the level of sexual activity so that significant effects of the treatment only appeared when sexual activity was used as a covariate. Interactions between estradiol effects and sexual activity were also observed for dopamine in the HPOA and for serotonin in the hindbrain and cerebellum. Together, these data demonstrate that a single estradiol injection rapidly activates male sexual behavior in quail and that this behavioral effect is correlated with changes in monoaminergic activity.

Somatostatin modulates dopamine release in rat retina.

The aim of the present study was to determine the possible role of somatostatin as a modulator of dopamine release in rat retina. Basal release of dopamine, and how this is influenced by somatostatin receptor (sst) selective ligands, was examined ex vivo in rat retinal explants. Dopamine levels were quantified by high-pressure liquid chromatography (HPLC) with electrochemical detection. Basal levels of dopamine were measured over 120 min of tissue incubation and found to be 1.17+/-0.35 ng/ml. Somatostatin (10(-6), 10(-5), 10(-4)M) increased dopamine levels in a concentration-dependent manner, while the sst(2) antagonist CYN154806 (10(-4)M) reversed its actions. BIM23014 (sst(2) agonist) increased dopamine levels in a statistically significant manner only at the concentration of 10(-5)M. The sst(1) agonist L797.591 (10(-5), 10(-4)M) also increased dopamine levels, while activation of the sst(3) receptor (sst(3) agonist, L796.778, 10(-4)M) had no effect. These data substantiate a neuromodulatory role for sst(1) and sst(2) somatostatin receptors in the retina and show for the first time somatostatin's influence on dopamine release.

Interleukin-1 alpha and beta, TNF-alpha and HTTLPR gene variants study on alcohol toxicity and detoxification outcome.

Genetic factors may influence the liability to treatment outcome and medical complications in alcoholism. In the present study we investigated the IL-1A rs1800587, IL-1B rs3087258, TNF-alpha rs1799724 and the HTTLPR variants in a sample of 64 alcohol dependents and 47 relatives versus a set of clinical parameters and outcome measures. Alcohol dependents had a less favorable clinical profile compared to relatives (higher cholesterol, triglycerides, glucose, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, gamma-glutamyltransferase). After detoxification, all clinical indexes improved and hepatic enzyme levels were similar in alcohol dependents and relatives, except for the GGT that remained significantly higher in alcohol dependents. Alcoholic depressive and anxiety scores were significantly reduced after detoxification. IL-1A, IL-1B, TNF-alpha and HTTLPR variants were not associated with any baseline clinical index or change after detoxification. In our sample IL-1A, IL-1B, TNF-alpha and HTTLPR do not appear as liability factors for alcohol toxicity or detoxification outcome, however the small sample size may influence the observed results.

A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors.

RATIONALE: There is no consensus on the contribution of adenosine A(1) and A(2A) receptor blockade to motor-activating effects of caffeine. OBJECTIVE: Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A(1) and A(2A) receptor antagonists. METHODS: The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A(2A) receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A(1) receptor agonist N (6)-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined. RESULTS: The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3. CONCLUSIONS: The results indicate a predominant role for A(1) receptors in the motor-activating effects of acutely administered caffeine.

Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains.

Chronic mild stress (CMS) has been reported to induce an anhedonic-like state in rats that resembles some of the symptoms of endogenous depression in humans. In the present study, CMS-induced behavioural responses along with neurochemical alterations in dopaminergic and serotonergic function in prefrontal cortex, striatum, hypothalamus and hippocampus were examined following treatment with imipramine in Wistar and Sprague-Dawley rats. The CMS procedure lasted 7 weeks in total. Once per week, a 1-h preference test for 1% sucrose solution was conducted. Treatment with imipramine (10mg/kg i.p., once daily) commenced after experimental week 3. CMS induced significant reductions in absolute and relative sucrose intake and sucrose preference in both rat strains but their temporal pattern was different especially during the weeks 0-3. These effects were reversed by IMI. An increase in the dopaminergic and a decrease in the serotonergic activity were observed in the prefrontal cortex in both rat strains following CMS. A decrease in the striatal dopaminergic activity and an increased hippocampal serotonergic activity were also seen in both rat strains following CMS. In Wistar rats, dopaminergic and serotonergic activities were enhanced in the hypothalamus whereas in Sprague-Dawley rats no such stress-induced changes were observed. Notably, the clear decrease in sucrose consumption observed in stressed Wistar rats could be directly associated with a respective increase in the dopaminergic hypothalamic activity. Chronic treatment with imipramine normalized all neurochemical alterations induced by CMS. Our results suggest that a specific and regionally differentiated serotonin-dopamine interaction is directly related to the observed stress-induced anhedonia.

Forced swim test: What about females?

In preclinical studies screening for novel antidepressants, male and female animals should be used. However, in a widely used antidepressant test, the forced swim test (FST), sex differences between males and females are not consistent. These discrepancies may discourage the inclusion of females in FST studies. In order to overcome this problem and provide a detailed insight regarding the use of female animals in the FST, we designed the following experiment and we performed a thorough analysis of the relevant literature. Male and female Wistar adult rats were subjected to the FST and sertraline was used as an antidepressant in two doses (10 mg/kg and 40 mg/kg, 3 injections in 24 h). Rodents were subjected in the two FST sessions during all possible combinations of the estrous cycle stages. We found that females exhibited higher levels of immobility than males and this sex difference was alleviated following antidepressant treatment. Sertraline at both doses enhanced swimming in both sexes, but females appeared more responsive to lower sertraline doses regarding immobility levels. Surprisingly, the high sertraline dose enhanced climbing particularly in proestrous and diestrous. Marked sex differences were also observed in the frequency of head swinging, with females exhibiting lower counts than males. Conclusively, when screening for new antidepressants, it is recommended to use standard FST procedures and if possible to include females in all phases of the cycle. Using only one dose of an investigational drug in females in certain phases of the cycle could result to false negative results.