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Corticosteroid-mediated stress responses require the activation of complex brain circuits involving mitochondrial activity, but the underlying cellular and molecular mechanisms are scantly known. The endocannabinoid system is implicated in stress coping, and it can directly regulate brain mitochondrial functions via type 1 cannabinoid (CB1) receptors associated with mitochondrial membranes (mtCB1). In this study, we show that the impairing effect of corticosterone in the novel object recognition (NOR) task in mice requires mtCB1 receptors and the regulation of mitochondrial calcium levels in neurons. Different brain circuits are modulated by this mechanism to mediate the impact of corticosterone during specific phases of the task. Thus, whereas corticosterone recruits mtCB1 receptors in noradrenergic neurons to impair NOR consolidation, mtCB1 receptors in local hippocampal GABAergic interneurons are required to inhibit NOR retrieval. These data reveal unforeseen mechanisms mediating the effects of corticosteroids during different phases of NOR, involving mitochondrial calcium alterations in different brain circuits.

Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT

This study investigated in male mice how age modulates the effects of acute 17β-estradiol (E2) on dorsal CA1 (dCA1)-dependent retention of temporal associations, which are critical for declarative memory. E2 was systemically injected to young (3-4 months old) and aged (22-24 months old) adult mice either (i) 1 h before the acquisition of an auditory trace fear conditioning (TFC) procedure allowing the assessment of temporal memory retention 24 h later or (ii) during in vivo electrophysiological recordings of CA3 to dCA1 synaptic efficacy under anesthesia. In young mice, E2 induced parallel dose-dependent reductions in memory and synaptic efficacy, i.e. an impairment in TFC retention and a long-term (NMDA receptor-dependent) depression of dCA1 synaptic efficacy as assessed by field excitatory postsynaptic potentials. In contrast, E2 tended to improved TFC retention whilst failing to change synaptic efficacy in aged mice. Age-dependent effects of E2 treatment were confirmed by immunohistochemical analyses of TFC acquisition-elicited dCA1 Fos activation. Thus, such an activation was respectively reduced and enhanced in young and aged E2-treated mice, compared to vehicle treatments. Hippocampal mRNA expression of estrogen receptors by RT-PCR analyses revealed an age-related increase in each receptor mRNA expression. In keeping with the key role of the endocannabinoid system in memory processes and CA3 to dCA1 synaptic plasticity, we next examined the role of cannabinoid type 1 receptors (CB

SUMMARYObesity-related pathologies and anorexia nervosa are increasingly considered as opposite ends of eating disorders (ED) spectrum. Accordingly, accumulating evidence points to opposite dysregulations of common brain systems in these pathologies, the Nucleus Accumbens (NAc) in particular. However, to which extent alterations in NAc activity are sufficient to elicit ED-like behavioral dimensions remains to be established. Using acute, bidirectional, chemogenetic modulation of each NAc medium spiny neuron (MSN) subpopulation, we found that D1-MSNs and D2-MSNs oppositely regulate the balance between food intake and exercise-induced energy expenditure. As opposed to the limited effect of repeated chemogenetic manipulations of each MSN subpopulation, the concomitant manipulation of both MSN subpopulation had sustained effects. Repeated activation of D1-MSNs combined with repeated inhibition of D2-MSNs biased behavior toward activity-related energy expenditure leading to weight/fat loss, whilst the opposite manipulations favored energy intake and hence weight/fat gain. These results suggest that dysregulations of NAc dopaminoceptive MSN network might be at the core of EDs.

International audience; Physical exercise, which can be addictogenic on its own, is considered a therapeutic alternative for drug craving. Exercise might thus share with drugs the ability to strengthen excitatory synapses onto ventral tegmental area (VTA) dopaminergic neurones, as assessed by the ratio of AMPA receptor (AMPAR)‐mediated excitatory postsynaptic currents (EPSCs) to NMDA receptor (NMDAR)‐mediated EPSCs. As did acute cocaine, amphetamine, or Δ9‐tetrahydrocannabinol (THC) pretreatments, an acute 1‐h wheel‐running session increased the AMPAR/NMDAR ratio in VTA dopaminergic neurones. To dissect the respective influences of wheel‐running seeking and performance, mice went through an operant protocol wherein wheel‐running was conditioned by nose poking under fixed ratio schedules of reinforcement. Conditioned wheel‐running increased the AMPAR/NMDAR ratio to a higher extent than free wheel‐running, doing so although running performance was lower in the former paradigm than in the latter. Thus, the cue‐reward association, rather than reward consumption, played a major role in this increase. The AMPAR/NMDAR ratio returned to baseline levels in mice that had extinguished the cued‐running motivated task, but it increased after a cue‐induced reinstatement session. The amplitude of this increase correlated with the intensity of exercise craving, as assessed by individual nose poke scores. Finally, cue‐induced reinstatement of running seeking proved insensitive to acute cocaine or THC pretreatments. Our study reveals for the first time that the drive for exercise bears synaptic influences on VTA dopaminergic neurones which are reminiscent of drug actions. Whether these influences play a role in the therapeutic effects of exercise in human drug craving remains to be established.

Recent surveys have revealed close links between cannabis and exercise. Specifically, cannabis usage before and/or after exercise is an increasingly common habit primarily aimed at boosting exercise pleasure, motivation, and performance whilst facilitating post-exercise recovery. However, whether these beliefs reflect the true impact of cannabis on these aspects of exercise is unknown. This study has thus examined the effects of cannabis' main psychoactive ingredient, namely Δ

SUMMARYThe idea that the effects of drugs largely depend on subcellular target location is emerging as a novel predictive factor of their beneficial or adverse outcomes. G protein-coupled type-1 cannabinoid receptors (CB1) are regulators of several brain functions as well as the main targets of cannabinoid-based medicines.Besides their classical location at plasma membranes, CB1receptors are present at different locations within cells, including in association to mitochondrial membranes (mtCB1). Here we report the generation and characterization of a mutant mouse line, which lack mtCB1receptors.

International audience; The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior

International audience; Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior.

Recent surveys have revealed close links between cannabis and exercise. Specifically, cannabis usage before and/or after exercise is an increasingly common habit primarily aimed at boosting exercise pleasure, motivation, and performance whilst facilitating post-exercise recovery. However, whether these beliefs reflect the true impact of cannabis on these aspects of exercise is unknown. This study has thus examined the effects of cannabis' main psychoactive ingredient, namely Δ9-tetrahydrocannabinol (THC), on (i) mouse wheel-running preference and performance and (ii) running motivation and seeking behaviour. Wheel-running preference and performance were investigated using a T-maze with free and locked wheels located at the extremity of either arm. Running motivation and seeking were assessed by a cued-running operant task wherein wheel-running was conditioned by nose poking. Moreover, because THC targets cannabinoid type 1 (CB1) receptors, i.e. receptors previously documented to control running motivation, this study also assessed the role of these receptors in running preference, performance, and craving-like behaviour. Whilst acute blockade or genetic deletion of CB1 receptors decreased running preference and performance in the T-maze, THC proved ineffective on either variable. The failure of THC to affect running variables in the T-maze extended to running motivation, as assessed by cued-running under a progressive ratio (PR) reinforcement schedule. This ineffectiveness of THC was not related to the treatment protocol because it successfully increased motivation for palatable food. Although craving-like behaviour, as indexed by a cue-induced reinstatement of running seeking, was found to depend on CB1 receptors, THC again proved ineffective. Neither running motivation nor running seeking were affected when CB1 receptors were further stimulated by increasing the levels of the endocannabinoid 2-arachidonoylglycerol. These results, which suggest that the drive for running is insensitive to the acute stimulation of CB1 receptors, raise the hypothesis that cannabis is devoid of effect on exercise motivation. Future investigation using chronic administration of THC, with and without other cannabis ingredients (e.g. cannabidiol), is however required before conclusions can be drawn.

Introduction Anorexia nervosa (AN), mostly observed in female adolescents, is the most fatal mental illness. Its core is a motivational imbalance between exercise and feeding in favour of the former. Although several animal models of AN have been proposed, none of them specifically assesses the motivation for exercise and/or feeding. In keeping with this issue, we recently developed an operant conditioning-based model wherein motivation for each of these two rewards can be examined singly or within a choice setting in mice [1] . By means of this model, we have recently examined whether infant-early adolescent stress (post-weaning social isolation), one precipitating factor in AN, affects in a sex-dependent manner the reinforcing values of either reward [2] . Methods Stressed and control male/female C57Bl/6 N mice were exposed, when 5-weeks old, to a cued-reward motivated instrumental task wherein wheel-running sequences and palatable food pellets, each reward provided singly, were conditioned by nose-poke responses. These responses obeyed fixed ratio (FR) reinforcement schedules for 10 sessions before being tested under a progressive ratio (PR) schedule of reinforcement for one session. Thereafter, mice underwent 10 FR sessions wherein they had the choice between either reward, the last 5 sessions being performed under food restriction conditions. Infant-adolescent stress, which began at postnatal day 22 (first postweaning day), consisted in individual housing, as compared to controls, which were all collectively housed (3/cage). Results Whether wheel-running and palatable food were provided separately or within a choice paradigm, post-weaning isolation-reared males responded to similar extents for each reward when the three other mouse groups displayed increased responding for wheel-running. The negative impact of the early stressor on male nose poke responding for wheel-running, compared to that measured in the other mouse groups, extended to the running performance during each rewarded sequence (i.e. reward consumption). When food-restricted, motivation for food overpassed progressively that for running in all groups, with females reaching higher levels than males. Conclusions Although the stress model that we used did not trigger a sex-dependent imbalance between exercise and feeding drives that would be reminiscent of what is observed in anorectic girls, we believe that the quest for other stress models, possibly combined with genetics, could prove fruitful to model some endophenotypic traits of AN.

Laboratory rodents provided chronic unlimited access to running wheels display increased neurogenesis in the hippocampal dentate gyrus. In addition, recent studies indicate that such an access to wheels stimulates dendritic arborization in newly formed neurons. However, (i) the presence of the running wheel in the housing environment might also bear intrinsic influences on the number and shape of new neurons and (ii) the dendritic arborization of new neurons might be insensitive to moderate daily running activity (i.e., several hours). In keeping with these uncertainties, we have examined neurogenesis and dendritic arborization in newly formed granular cells in adult C57Bl/6N male mice housed for 3 weeks under standard conditions, with a locked wheel, with a running wheel set free 3 h/day, or with a running wheel set permanently free. The results indicate that the presence of a blocked wheel in the home cage increased cell proliferation, but not the number of new neurons while running increased in a duration-dependent manner the number of newborn neurons, as assessed by DCX labeling. Morphological analyses of the dendritic tree of newborn neurons, as identified by BrdU-DCX co-staining, revealed that although the presence of the wheel stimulated their dendritic architecture, the amplitude of this effect was lower than that elicited by running activity, and was found to be running duration-dependent.

Several studies have indicated that animal models of exercise, such as voluntary wheel running, might be endowed with anxiolytic properties. Using the light/dark test of unconditioned anxiety, we have reported that one confounding factor in the estimation of wheel running impacts on anxiety might be the housing condition of the sedentary controls. The present mouse study analyzed whether the aforementioned observation in the light/dark test (i) could be repeated in the elevated plus-maze and social interaction tests of unconditioned anxiety, (ii) extended to conditioned anxiety, as assessed during cued fear recall tests, and (iii) required unlimited daily access to the running wheel. Housing with a locked wheel or with a free wheel that allowed limited or unlimited running activity triggered anxiolysis in the light/dark test, but not in the elevated plus-maze test, compared to standard housing. In the social interaction test, the duration, but not the number, of social contacts was increased in mice provided unlimited (but not limited) access to a wheel, compared to standard housing or housing with a locked wheel. Lastly, freezing responses to a cue during fear recall tests indicated that the reduction in freezing observed in mice provided limited or unlimited access to the wheels was fully accounted for by housing with a wheel. Besides confirming that the housing condition of the sedentary controls might bias the estimation of the effects of wheel running on anxiety, this study further shows that this estimation is dependent on the test used to assess anxiety.

This study examined the respective influences of cannabinoid type-1 (CB1) receptors expressed either in forebrain GABAergic neurons, in cortical glutamatergic neurons, or in astrocytes on the turnover rates of the endocannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), and the non-cannabinoid N-acylethanolamides, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), in mouse forebrain regions. To this end, conditional mutant mice lacking CB1 receptors from either of these cell types were pre-treated systemically with JZL195, a dual inhibitor of fatty acid amide hydrolase, the enzyme degrading AEA, PEA, and OEA, and of monoacylglycerol lipase, the main 2-AG-degrading enzyme. The analyses of frontocortical, hippocampal, and striatal AEA, 2-AG, PEA, and OEA concentrations revealed that their respective baseline concentrations were not influenced by the mouse genotype. On the other hand, the accumulation of frontocortical and/or hippocampal 2-AG levels in JZL195-pre-treated mice was dependent on the mouse genotype. Thus, JZL195-induced 2-AG accumulation rates were diminished in the frontal cortex of mice lacking CB1 receptors in glutamatergic neurons while their respective values were increased in the frontal cortex and hippocampus of mice lacking these receptors in astrocytes. These genotypic differences occurred with parallel and proportionate changes in the fractional rate constants for degradation of 2-AG, thus providing a mechanism whereby the baseline levels of 2-AG remained constant between genotypes. Besides suggesting a cell-type-specific control of frontocortical and/or hippocampal 2-AG synthesis and degradation rates by CB1 receptors, this study highlights the interest of assessing endocannabinoid turnover rates when questioning the status of the endocannabinoid system.

Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side-effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy. The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. In order to capture THC-induced positive psychotic-like symptoms (e.g. perceptual delusions), we adapted a behavioral paradigm based on associations between different sensory modalities and selective devaluation, allowing the measurement of mental sensory representations in mice. Acting at hippocampal CB1 receptors, THC impaired the correct processing of mental sensory representations (reality testing) in an antipsychotic- and pregnenolone-sensitive manner. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.

The biosynthetic and catabolic enzymes of the endocannabinoids tightly regulate endocannabinoid-mediated activation of the cannabinoid CB1 receptor. Monitoring the activities of these endocannabinoid hydrolases in different brain regions is, therefore, key to gaining insight into spatiotemporal control of CB1 receptor-mediated physiology. We have employed a comparative chemical proteomics approach to quantitatively map the activity profile of endocannabinoid hydrolases in various mouse brain regions at the same time. To this end, we used two different activity-based probes: fluorophosphonate-biotin (FP-biotin), which quantifies FAAH, ABHD6, and MAG-lipase activity, and MB108, which detects DAGL-α, ABHD4, ABHD6, and ABHD12. In total, 32 serine hydrolases were evaluated in the frontal cortex, hippocampus, striatum, and cerebellum. Comparison of endocannabinoid hydrolase activity in the four brain regions revealed that FAAH activity was highest in the hippocampus, and MAGL activity was most pronounced in the...

Brain mitochondrial activity is centrally involved in the central control of energy balance. When studying mitochondrial functions in the brain, however, discrepant results might be obtained, depending on the experimental approaches. For instance, immunostaining experiments and biochemical isolation of organelles expose investigators to risks of false positive and/or false negative results. As an example, the functional presence of cannabinoid type 1 (CB1) receptors on brain mitochondrial membranes (mtCB1) was recently reported and rapidly challenged, claiming that the original observation was likely due to artifact results. Here, we addressed this issue by directly comparing the procedures used in the two studies. Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria. These data further underline the importance of adapted experimental procedures to study brain mitochondrial functions.

Background We have shown that the endogenous stimulation of cannabinoid type-1 (CB 1 ) receptors is a prerequisite for voluntary running in mice, but the precise mechanisms through which the endocannabinoid system exerts a tonic control on running performance remain unknown. Methods We analyzed the respective impacts of constitutive/conditional CB 1 receptor mutations and of CB 1 receptor blockade on wheel-running performance. We then assessed the consequences of ventral tegmental area (VTA) CB 1 receptor blockade on the wheel-running performances of wildtype (gamma-aminobutyric acid [GABA]- CB 1 +/+ ) and mutant (GABA- CB 1 –/– ) mice for CB 1 receptors in brain GABA neurons. Using in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity were examined in GABA- CB 1 +/+ and GABA- CB 1 –/– mice. Results Conditional deletion of CB 1 receptors from brain GABA neurons, but not from several other neuronal populations or from astrocytes, decreased wheel-running performance in mice. The inhibitory consequences of either the systemic or the intra-VTA administration of CB 1 receptor antagonists on running behavior were abolished in GABA- CB 1 –/– mice. The absence of CB 1 receptors from GABAergic neurons led to a depression of VTA DA neuronal activity after acute/repeated wheel running. Conclusions This study provides evidence that CB 1 receptors on VTA GABAergic terminals exert a permissive control on rodent voluntary running performance. Furthermore, it is shown that CB 1 receptors located on GABAergic neurons impede negative consequences of voluntary exercise on VTA DA neuronal activity. These results position the endocannabinoid control of inhibitory transmission as a prerequisite for wheel-running performance in mice.

This study has investigated the role of hypothalamic and amygdalar type-1 cannabinoid (CB1) receptors in the emotional and neuroendocrine responses to stress. To do so, we used the Cre/loxP system to generate conditional mutant mice lacking the CB1 gene in neurons expressing the transcription factor single-minded 1 (Sim1). This choice was dictated by former evidence for Sim1-Cre transgenic mice bearing Cre activity in all areas expressing Sim1, which chiefly includes the hypothalamus (especially the paraventricular nucleus, the supraoptic nucleus, and the posterior hypothalamus) and the mediobasal amygdala. Genomic DNA analyses in Sim1-CB1(-/-) mice indicated that the CB1 allele was excised from the hypothalamus and the amygdala, but not from the cortex, the striatum, the thalamus, the nucleus accumbens, the brainstem, the hippocampus, the pituitary gland, and the spinal cord. Double-fluorescent in situ hybridization experiments further indicated that Sim1-CB1(-/-) mice displayed a weaker CB1 receptor mRNA expression in the paraventricular nucleus of the hypothalamus and the mediobasal part of the amygdala, compared to wild-type animals. Individually housed Sim1-CB1(-/-) mice and their Sim1-CB1(+/+) littermates were exposed to anxiety and fear memory tests under basal conditions as well as after acute/repeated social stress. A principal component analysis of the behaviors of Sim1-CB1(-/-) and Sim1-CB1(+/+) mice in anxiety tests (open field, elevated plus-maze, and light/dark box) revealed that CB1 receptors from Sim1-expressing neurons exert tonic, albeit opposite, controls of locomotor and anxiety reactivity to novel environments. No difference between genotypes was observed during the recall of contextual fear conditioning or during active avoidance learning. Sim1-CB1(-/-), but not Sim1-CB1(+/+), mice proved sensitive to an acute social stress as this procedure reverted the increased ambulation in the center of the open field. The stimulatory influence of repeated social stress on body and adrenal weights, water intake, and sucrose preference was similar in the two genotypes. On the other hand, repeated social stress abolished the decrease in cued-fear conditioned expression that was observed in Sim1-CB1(-/-) mice, compared to Sim1-CB1(+/+) mice. This study suggests that CB1 receptors located on Sim1-expressing neurons exert a tonic control on locomotor reactivity, unconditioned anxiety, and cued-fear expression under basal conditions as well as after acute or repeated stress.

The balance between novelty seeking and safety assessment is a key feature of adaptive behavior, and alterations in this equilibrium can lead to neuropsychiatric disorders. Excessive novelty seeking is a main form of pathological impulsivity, which is among the symptoms that define attention deficit hyperactivity disorder (ADHD). There is growing evidence that the endocannabinoid system (ECS) plays an important role in the control of this balance, but little is known about the underlying neuronal mechanisms. In this study, we aimed at dissecting the neurocircuits under the control of the ECS in novelty-induced behavioral inhibition. To reach this goal, we combined pharmacological, genetic and behavioral tools. Mice were repeatedly exposed to novel palatable food or a novel object and their responses to these stimuli were analyzed over several days. The results confirmed that systemic blockade of cannabinoid type-1 (CB(1)) receptors strongly decreases palatable food intake, but its impact onto the response to novelty is less pronounced. Using conditional mutant mice lacking the CB(1) receptor either in cortical glutamatergic or in GABAergic neurons, we found that the ECS exerts opposite functions on the balance between novelty seeking and behavioral inhibition. Whereas CB(1) receptors expressed in cortical glutamatergic neurons favors novelty seeking, CB(1)-dependent control of inhibitory GABAergic neurons promotes behavioral inhibition. These data show a tightly regulated influence of the ECS on impulsive behaviors and suggest the involvement of endocannabinoid signaling in the pathophysiological modulation of ADHD and related disorders.

Laboratory rodents provided chronic unlimited access to running wheels display increased neurogenesis in the hippocampal dentate gyrus. In addition, recent studies indicate that such an access to wheels stimulates dendritic arborization in newly formed neurons. However, (i) the presence of the running wheel in the housing environment might also bear intrinsic influences on the number and shape of new neurons and (ii) the dendritic arborization of new neurons might be insensitive to moderate daily running activity (i.e., several hours). In keeping with these uncertainties, we have examined neurogenesis and dendritic arborization in newly formed granular cells in adult C57Bl/6N male mice housed for 3 weeks under standard conditions, with a locked wheel, with a running wheel set free 3 h/day, or with a running wheel set permanently free. The results indicate that the presence of a blocked wheel in the home cage increased cell proliferation, but not the number of new neurons while running increased in a duration-dependent manner the number of newborn neurons, as assessed by DCX labeling. Morphological analyses of the dendritic tree of newborn neurons, as identified by BrdU-DCX co-staining, revealed that although the presence of the wheel stimulated their dendritic architecture, the amplitude of this effect was lower than that elicited by running activity, and was found to be running duration-dependent.

Stress research is a rapidly evolving field that encompasses numerous disciplines ranging from neuroscience to metabolism. With many new researchers migrating into the field, navigating the hows and whys of specific research questions can sometimes be enigmatic given the availability of so many models in the stress field. Additionally, as with every field, there are many seemingly minor experimental details that can have dramatic influences on data interpretation, although many of these are unknown to those not familiar with the field. The aim of this overview is to provide some suggestions and points to guide researchers moving into the stress field and highlight relevant methodological points that they should consider when choosing a model for stress and deciding how to structure a study. We briefly provide a primer on the basics of endpoint measurements in the stress field, factors to consider when choosing a model for acute stress, the difference between repeated and chronic stress, and importantly, influencing variables that modulate endpoints of analysis in stress work.

Female Fischer 344 (F344) rats have been shown to display increased serotonin transporter (5-HTT) gene expression in the dorsal raphe, compared to female Lewis (LEW) rats. Herein, we explored, by means of synaptosomal preparations and in vivo microdialysis, whether central, but also peripheral, 5-HTT protein expression/function differ between strains. Midbrain and hippocampal [3H]paroxetine binding at the 5-HTT and hippocampal [3H]serotonin (5-HT) reuptake were increased in male and female F344 rats, compared to their LEW counterparts, these strain differences being observed both in rats of commercial origin and in homebred rats. Moreover, in homebred rats, it was found that these strain differences extended to blood platelet 5-HTT protein expression and function. Saturation studies of midbrain and hippocampal [3H]paroxetine binding at the 5-HTT, and hippocampal and blood platelet [3H]5-HT reuptake, also revealed significant strain differences in Bmax and Vmax values. Although F344 and LEW rats differ in the activity of the hypothalamo-pituitary-adrenal (HPA) axis, manipulations of that axis revealed that the strain differences in hippocampal [3H]paroxetine binding at 5-HTTs and [3H]5-HT reuptake were not accounted for by corticosteroids. Hippocampal extracellular 5-HT levels were reduced in F344 rats, compared to LEW rats, with the relative, but not the absolute, increase in extracellular 5-HT elicited by the local administration of citalopram being larger in F344 rats. Because the aforementioned strain differences did not lie in the coding sequences of the 5-HTT gene, our results open the promising hypothesis that F344 and LEW strains model functional polymorphisms in the promoter region of the human 5-HTT gene.

Group-housed Sprague-Dawley (SD) rats exposed for 1 h to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT, a component of fox feces) did not display changes in hippocampal serotonin (5-HT) metabolism and [3H]5-HT reuptake, compared to water or butyric acid. Such an observation extended to isolated SD and Fischer 344 rats. When group-housed SD rats were tested 1 week after a 1-h exposure to TMT, hippocampal 5-HT metabolism, [3H]5-HT reuptake, and [3H]paroxetine binding at the 5-HT transporter remained unchanged. This study questions TMT as a specific predatory stimulus as both butyric acid and TMT increased plasma corticosterone levels whilst leaving intact open field behaviour (at least in group-housed SD rats).

The respective influences of the corticotropic axis and sympathetic activity on 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) immediate effects on body temperature and long-term neurotoxicity, as assessed by decreases in hippocampal and striatal [(3)H]5-hydroxytryptamine ([(3)H]5-HT) reuptake, [(3)H]paroxetine binding at 5-HT transporters (5-HTT), and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels, were examined in Fischer 344 rats. On each of the two injections of MDMA (5 or 10 mg/kg s.c. once a day for 2 consecutive days) body temperature rapidly increased in a dose-dependent manner. Six days after the last injection of 10 mg/kg MDMA, [(3)H]5-HT reuptake, [(3)H]paroxetine binding and 5-HT and 5-HIAA levels were decreased in the hippocampus and, to a lower extent, in striatum. Prior adrenalectomy (1 week beforehand), which weakened the immediate hyperthermic effect of MDMA, prevented the long-term MDMA-elicited reduction in hippocampal and striatal [(3)H]paroxetine binding. Supplementation of adrenalectomised Fischer 344 rats with corticosterone almost reinstated the immediate hyperthermic effect of MDMA and restored MDMA-elicited reduction in hippocampal and striatal [(3)H]paroxetine binding. In a final set of experiments, Fischer 344 rats were pretreated (30 min before each of the two injections of 10 mg/kg MDMA) with the ganglionic blocker chlorisondamine (2.5 mg/kg). This pretreatment markedly reduced the amplitudes of the immediate hyperthermia and long-term declines in hippocampal [(3)H]5-HT reuptake and [(3)H]paroxetine binding at 5-HTT, and in hippocampal and striatal 5-HT and 5-HIAA levels. These results suggest that sympathetic activity (possibly through its control of body temperature), but not corticotropic activity, plays a key role in MDMA-elicited neurotoxicity in Fischer 344 rats.

The search for the molecular bases of neuro-behavioural traits in Spontaneously Hypertensive Rats (SHR), an animal model of Attention Deficit Hyperactivity Disorder (ADHD), led to the discovery of two quantitative trait loci related to the locomotor activity in the centre of the open field. In the present study, rats from an F2 intercross between the SHR and Lewis strains were selected with markers on the basis of their genotype at these two loci. We obtained a ‘high line’ in which rats have the alleles increasing the trait, and a ‘low line’ with the lowering alleles. In activity cages with a dim light, the low line was more active than the high line. The reverse was found in the open field, and the inhibition of locomotor activity in the low line (as compared to the high line) was directly related to the aversiveness of the situation (larger in the centre than in the periphery, and in high light than in low light), and was more intense in males than in females. This inhibition is not attributable to a classical ‘anxiety’ factor as measured in the elevated plus maze, in which the open arms behaviours were not different between the lines. The high line also showed a deficit in prepulse inhibition of the acoustic startle reflex. The present data show that the two loci previously described in a SHR × Lewis intercross as related to the activity in the centre of the open field are indeed involved in a behavioural inhibition trait. The marker-based selected lines described here are unique tools for the study of the neurobiological bases of this trait and the molecular foundations of its variability of genetic origin.

SUMMARY 1. The aim of the present study was to assess the cardiovascular differences among five inbred rat strains (n = 16 per strain), including spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) rats, Wistar Furth (WF) rats, Fischer (F344) rats and Lewis (Lew) rats and the usual outbred Wistar (W) rat strain (n = 25). 2. These strains were compared under resting conditions for blood pressure (BP) and heart rate (HR) levels and for their baroreceptor–HR reflex sensitivity. In addition, their responses to an acoustic startle stimulus were measured. 3. A consistent rise in BP was observed among the groups as a result of the noise stimulus. This rise in systolic BP (SBP) averaged (±SEM) 37 ± 2 mmHg in the SHR and 34 ± 4 mmHg in F344 rats, while the response was only 23 ± 3 mmHg in WKY rats. Pulse pressure (PP) was increased following noise in all groups. The delay for the BP response for all groups combined was 1.6 ± 0.1 s. 4. Most animals had minimal HR variations, except F344 rats, responding with a 42 ± 13 b.p.m. decrease 3.0 s after the stimulus (i.e. 1.3 s after the maximal 34 ± 4 mmHg SBP rise). 5. The highest SBP (160 ± 3 mmHg) and diastolic BP (104 ± 3 mmHg) were observed in inbred SHR. Other groups were normotensive. Resting PP was elevated for SHR (56 ± 2 mmHg) compared with the other groups (40 ± 2 mmHg). The highest HR was found in F344 and WF rats, with 389 ± 11 and 372 ± 7 b.p.m., respectively. The lowest HR was observed in SHR and Lewis rats, with 335 ± 7 and 323 ± 7 b.p.m., respectively. The least sensitive baroreflex function was observed in SHR (0.8 ± 0.1 b.p.m./mmHg) compared with the other strains (1.4 ± 0.2 b.p.m./mmHg). 6. The present study confirms the importance of genetic factors on the cardiovascular responses of rats to a noise startle stimulus. Two inbred normotensive rat strains, namely F344 and WKY rats, which exhibit a substantial difference in pressor response to noise, may be used to unravel the mechanisms of sympathetic activation.

In order to determine the effect of chronic and acute stress on muscle mitochondrial metabolism, two strains of rats were selected on the basis of their different hypothalamo-pituitary-adrenal (HPA) axis responses to different stressors [Spontaneous Hypertensive Rats (SHR) and Lewis rats]. For 8 weeks animals were stressed by daily exposure to either a novel environment (SHR: n=16, Lewis: n=16) or forced exercise (SHR: n=16, Lewis: n=16). An unstressed group was left undisturbed (SHR: n=5, Lewis: n=5). Half of the stressed animals (n=32) were submitted to an acute stress (1-h immobilization). The mitochondrial responses of plantaris muscle [cytochrome-c-oxidase (COX), citrate synthase and succinate dehydrogenase activities, the latter two being measured as indices of functional mitochondrial amount] in the presence of different physiological plasma corticosterone (CORT) concentrations were analyzed. The novel environment and forced exercise stress induced different levels of plasma CORT which were negatively correlated with the amount of functional mitochondria in the plantaris muscle. Therefore, a chronic intermittent stress is able to induce an increase in plasma CORT which may be related to deleterious changes in muscle mitochondrial metabolism. Lastly, the acute stress was not associated with a decrease in functional mitochondria but with an increase in COX activity. This suggests that the relationship between CORT and muscle mitochondrial metabolism depends both on the level and duration of endogenous glucocorticoids exposure.

The Lewis, Fischer 344, Brown Norway, Spontaneously Hypertensive, and Wistar–Kyoto inbred rat strains were, respectively, compared for the lethal and neurotoxic effects of acute p -chloroamphetamine (PCA, 2.5–10 mg/kg i.p.). The lethal properties of the amphetamine were recorded within 24 h after its administration whereas neurotoxicity (as assessed by frontocortical 5-hydroxytryptamine (5-HT) reuptake and 5-HT transporter binding assays) was analyzed 1 week after PCA administration. Preliminary experiments indicated that neither the rapid hyperlocomotor and/or the hypoexploratory effect of PCA nor the in vitro potency of PCA to inhibit frontocortical [ 3 H]5-HT reuptake varied between strains. On the other hand, strain differences were observed with respect to the rapid fatal effects of the 5 and 10 mg/kg doses of PCA administration. Lastly, frontocortical [ 3 H]5-HT reuptake and [ 3 H]citalopram binding at 5-HT transporters diminished in a dose-dependent, but strain-independent, manner 1 week after the acute injection of PCA. This study reveals an independency between the mechanisms underlying the fatal effects of PCA on the one hand, and the long-term damaging effects of PCA on serotonergic neurons on the other hand.

Streptozotocin (STZ)-elicited diabetes reduces central serotonin (5-hydroxytryptamine, 5-HT) synthesis/metabolism, but whether this reduction leads to decreased release of 5-HT has only scarcely been investigated. We have thus analysed the impact of STZ diabetes on hippocampal extracellular 5-HT levels both under basal conditions and during restraint stress, a procedure known to stimulate hippocampal 5-HT synthesis/metabolism and release. The pretreatment with STZ (3 weeks beforehand) and the 1 h restraint session respectively decreased and increased hippocampal 5-HT metabolism, as assessed by tissue analysis of 5-HT and 5-hydroxyindoleacetic acid. On the other hand, hippocampal microdialysis revealed no difference in basal levels of extracellular 5-HT levels in (conscious) vehicle- and STZ-pretreated rats, but a differential effect of restraint. Thus, extracellular 5-HT levels increased throughout restraint (maximal increase: 194%) in vehicle-, but not in STZ-pretreated rats. In the latter rat group, plasma corticosterone levels were, however, increased, thus indicating a significant aversiveness to stress. Lastly, because anxiety-related behaviours may be affected by hippocampal serotonergic systems, resting and restrained vehicle- and STZ-pretreated rats were compared (immediately after stress) in an elevated plus-maze of anxiety. Pretreatment with STZ reduced the percent number of open arm entries and the number of closed arm entries, indicating increased anxiety and reduced locomotor activity, respectively. Restraint tended to increase anxiety-related behaviours in all rats, but this trend never reached significance. Our results confirm that gross analyses of 5-HT metabolism do not yield information on 5-HT release, and suggest that the prevalence of diabetes among patients suffering affective disorders could be related to the lack of hippocampal serotonergic response to aversive stimuli.

Recent studies have underlined the impact of genetic factors in anxiety profiles. In this context, we have initiated a series of experiments aiming to select, among six inbred strains of rats, a pair of strains that contrasts the most in fear-related behaviours measured in the open field, the elevated plus-maze, the black and white box and the social interaction test. Significant interstrain differences were found for all behavioural measures. A factor analysis of all variables produced three independent factors explaining 85.1% of the total variance. Factor 1 had high loadings from variables related to the approach/avoidance towards aversive stimuli (e.g., center of the open field, open arms of the plus-maze and white compartment of the black/white box). Variables related to general activity in novel environments (e.g., total locomotion in the open field and closed-arm entries in the plus-maze) loaded highly on Factor 2. Defecation and time of social interaction loaded positively on Factor 3. To verify whether elevated plus-maze variables loading on Factor 1 were associated to anxiety, the effects of single doses of diazepam and pentylenetetrazole were examined in Lewis and SHR rats, i.e., the most contrasting strains regarding Factor 1. Variables with high loadings on this factor changed in opposite ways in response to diazepam and pentylenetetrazole treatments. This study suggests, thus, that Lewis and SHR strains may constitute a useful model for studying the neurobiological mechanisms underlying the interindividual differences in baseline levels of anxiety.

Food deprivation stimulates the activity of the hypothalamo-pituitary-adrenal axis and brain serotonin (5-hydroxytryptamine, 5-HT) synthesis. Because midbrain somato-dendritic 5-HT 1A autoreceptors may obey homologous and heterologous (e.g. by glucocorticoids) down-regulation, we have analyzed whether 24 hr of fasting affects midbrain 5-HT 1A receptor binding and sensitivity in Lewis and SHR rats (i.e. strains that differ in behavioral/neuroendocrine responses to stressors). Fasting affected neither [ 3 H]8-hydroxy-2-(di- N -propylamino)tetralin ([ 3 H]8-OH-DPAT) binding at 5-HT 1A autoreceptors nor 8-OH-DPAT-induced inhibition of midbrain 5-HT synthesis (an index of 5-HT 1A autoreceptor sensitivity). Because fasting increased 5-HT precursor (tryptophan) levels to similar extents in the midbrains of saline- and 8-OH-DPAT-treated rats, we conclude that food deprivation does not affect 5-HT 1A autoreceptors. In turn, our results suggest that the differential effects of 5-HT 1A receptor agonists on food intake, in fed and fasted rats may be independent from 5-HT 1A autoreceptors. © 1997 Elsevier Science Ltd.

Corticosteroids modulate the expression and/or functions of several serotonin (5-hydroxytryptamine; 5-HT) receptors. Conversely, analyses of the effects of corticosteroids upon 5-HT reuptake systems have been scarce and contradictory. Herein, the diurnal rhythm of midbrain [ 3 H]citalopram binding to 5-HT transporters was analysed in sham and 11 day adrenalectomised rats. In addition, adrenalectomised rats were either complemented or not with corticosterone pellets (12.5–200 mg). Analyses of body weight increases and plasma adrenocorticotropic and corticosterone levels indicated that the protocol allowed the stimulation of mineralocorticoid receptors (MRs; 12.5 mg pellets) or the stimulation of both MRs and glucocorticoid receptors (GRs; 50–200 mg pellets). However, besides the observation of a slight, but significant diurnal (corticosteroid-independent) rhythm in 5-HT transporter binding (morning>evening), it was found that neither adrenalectomy nor corticosteroid receptor stimulation affected midbrain [ 3 H]citalopram binding.

Male rats from six inbred rat strains (Spontaneously Hypertensive Rat, Wistar Kyoto, Brown Norway, Wistar Furth, Fischer 344, and Lewis) have been compared for their behavioral reactivity when placed in several nonsocial (elevated plus-maze, open field) and social (social interaction in aversive and neutral environment, resident–intruder test, chronic social stress) settings. In addition, a factorial analysis was performed to assess how the variables measured in these different tests related to each other. Besides significant strain-related differences in all tests, the factorial analysis showed that, in nonsocial environments, the strains contrasted essentially along two independent behavioral traits, the propensity to approach or avoid an aversive stimulus and general motor activity in novel environments (two indices of emotionality). In the social settings, marked interstrain differences were observed regarding the expression of aggressive behaviors but these differences were not related to the respective levels on the two nonsocial components of reactivity. Furthermore, large genetic differences were observed in variations of body weight induced by a chronic social stressor paradigm. The factorial analysis suggested a lack of relationship between the effect of social stressors on body weight and the measures of emotionality and general activity obtained in the nonsocial tests. Conversely, these variations were influenced by the levels of aggressiveness and sociability. Taken together, these results show (i) that the behavioral variability observed in rats, in social and nonsocial environments, is influenced by genetic factors and (ii) that the behavioral reactivity to social stimulations is a specific feature, dissociable from the levels of the different components of emotionality (approach/avoidance and general activity) as evaluated by the behavioral responses to nonsocial settings.

The bed nucleus of the stria terminalis (BNST) exerts a coordinated modulation of the psychoneuroendocrine responses to stress. However, how acute stress impacts on BNSTin vivoplasticity is a crucial question that still remains unanswered. Here, neurons from the anterior portion of the BNST (aBNST) were recordedin vivoduring and after stimulation of their medial prefrontal cortical (mPFC) afferents. In C57BL/6N mice, a 1 h restraint stress induced a switch from long-term depression (LTD) to long-term potentiation (LTP) in the aBNST after a 10 Hz mPFC stimulation. This switch was independent from glucocorticoid receptor stimulation. Because the endocannabinoid system regulates aBNST activity, we next examined the role of cannabinoid type-1 receptors (CB1-Rs) in these changes. Mutant mice lacking CB1-Rs (CB1−/−mice) displayed a marked deficit in the ability to develop plasticity under control and stress conditions, compared with their wild-type littermates (CB1+/+mice). This difference was not accounted for by genetic differences in stress sensitivity, as revealed by Fos immunohistochemistry analyses. Local blockade of CB1-Rs in the aBNST and the use of mutant mice bearing a selective deletion of CB1-Rs in cortical glutamatergic neurons indicated that stress-elicited LTP involved CB1-Rs located on aBNST excitatory terminals. These results show that acute stress reverts LTD into LTP in the aBNST and that the endocannabinoid system plays a key role therein.

International audience; Interest has recently surged in the use of social stress models, especially social defeat. Such interest lies both in the recognition that stressors of social origin play a major role in human psychopathologies and in the acknowledgement that natural and hence ethologically-based stress models have important translational value. The use of the most recent technology has allowed the recognition of the mechanisms through which social defeat might have enduring psychoneuroendocrine effects, especially social avoidance and anhedonia, two behaviours relevant to human depression. In view of the sensitivity of these behavioural outcomes to repeated antidepressant treatments, the social defeat model has been proposed as a possible animal model of depression. The present survey is aimed at examining the limits of such an interpretation and focuses on methodological aspects and on the relevance of social defeat to the study of anxiety-related pathologies.

Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB 1 ) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB 1 receptor blockade, we combined the acute injection of the CB 1 receptor antagonist rimonabant with the use of conditional CB 1 -knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB 1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB 1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB 1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB 1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB 1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB 1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.

Recent studies have shown that arthritis-susceptible Lewis female rats display a marked hypoactivity of the hypothalamo-pituitary-adrenal (HPA) axis and decreased concentrations of hippocampal serotonin receptors (5-HT1A), when compared with arthritis-resistant Fischer 344 female rats. Although previous studies have suggested that these inter-strain differences may extend to several behaviours, the hypothesis that Fischer 344 and Lewis differ in their anxiety and locomotor scores when placed in novel environments has been only scarcely tested. The present study has thus analysed the behaviours of male Fischer 344 and Lewis rats placed successively in activity cages, in an open field (low and high aversive conditions), and in two animal models of anxiety (the elevated plus-maze, the black/white box). Moreover, because the present study was conducted with male rats, we have also checked whether the HPA axis- and 5-HT1A receptor-related differences previously described between female Fischer 344 and Lewis rats extended to males. Under basal conditions: (i) activity of the HPA axis; and (ii) hippocampal 5-HT1A receptor binding and activity of tryptophan hydroxylase (the rate-limiting enzyme in 5-HT biosynthesis) were decreased in Lewis rats, compared with Fischer 344 rats. In addition, the response of the HPA axis to a mild stress (10 min in a novel environment) was lower in Lewis rats than in Fischer 344. When placed in activity cages, Lewis rats displayed a lower locomotor activity, compared with Fischer 344 rats. In the open-field, Lewis rats crossed a lower number of inner squares and groomed less than Fischer 344 rats. In the elevated plus-maze and in the black/white box, Fischer 344 and Lewis rats exhibited similar ‘anxious’ profiles as none of the rats visited the open arms (elevated plus-maze) and the white compartment (black/white box). This study, which extends earlier neurochemical and neuroendocrine findings in females, suggests that both strains display high levels of anxiety but markedly differ in their locomotor activities. Whether the latter strain difference is due to alterations in the HPA axis and/or the central serotonergic systems is an issue that remains to be explored.

The plasticity of excitatory synapses is an essential brain process involved in cognitive functions, and dysfunctions of such adaptations have been linked to psychiatric disorders such as depression. Although the intracellular cascades that are altered in models of depression and stress-related disorders have been under considerable scrutiny, the molecular interplay between antidepressants and glutamatergic signaling remains elusive. Using a combination of electrophysiological and single nanoparticle tracking approaches, we here report that the cognitive enhancer and antidepressant tianeptine (S 1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt) favors synaptic plasticity in hippocampal neurons both under basal conditions and after acute stress. Strikingly, tianeptine rapidly reduces the surface diffusion of AMPA receptor (AMPAR) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent mechanism that enhances the binding of AMPAR auxiliary subunit stargazin with PSD-95. This prevents corticosterone-induced AMPAR surface dispersal and restores long-term potentiation of acutely stressed mice. Collectively, these data provide the first evidence that a therapeutically used drug targets the surface diffusion of AMPAR through a CaMKII-stargazin-PSD-95 pathway, to promote long-term synaptic plasticity.

International audience; The endocannabinoid system (ECS) tightly controls emotional responses to acute aversive stimuli. Repeated stress alters ECS activity but the role played by the ECS in the emotional consequences of repeated stress has not been investigated in detail. This study used social defeat stress, together with pharmacology and genetics to examine the role of cannabinoid type-1 (CB(1)) receptors on repeated stress-induced emotional alterations. Seven daily social defeat sessions increased water (but not food) intake, sucrose preference, anxiety, cued fear expression, and adrenal weight in C57BL/6N mice. The first and the last social stress sessions triggered immediate brain region-dependent changes in the concentrations of the principal endocannabinoids anandamide and 2-arachidonoylglycerol. Pretreatment before each of the seven stress sessions with the CB(1) receptor antagonist rimonabant prolonged freezing responses of stressed mice during cued fear recall tests. Repeated social stress abolished the increased fear expression displayed by constitutive CB(1) receptor-deficient mice. The use of mutant mice lacking CB(1) receptors from cortical glutamatergic neurons or from GABAergic neurons indicated that it is the absence of the former CB(1) receptor population that is responsible for the fear responses in socially stressed CB(1) mutant mice. In addition, stress-induced hypolocomotor reactivity was amplified by the absence of CB(1) receptors from GABAergic neurons. Mutant mice lacking CB(1) receptors from serotonergic neurons displayed a higher anxiety but decreased cued fear expression than their wild-type controls. These mutant mice failed to show social stress-elicited increased sucrose preference. This study shows that (i) release of endocannabinoids during stress exposure impedes stress-elicited amplification of cued fear behavior, (ii) social stress opposes the increased fear expression and delayed between-session extinction because of the absence of CB(1) receptors from cortical glutamatergic neurons, and (iii) CB(1) receptors on central serotonergic neurons are involved in the sweet consumption response to repeated stress.Neuropsychopharmacology advance online publication, 21 March 2012; doi:10.1038/npp.2012.36.

The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines have been selected upon their divergent active avoidance behaviours. On the basis of open-field behavioural analyses, it has been suggested that RLA rats display more emotionality than RHA rats. Herein, we have analysed the behaviours of male RHA and RLA rats in three tests putatively related to anxiety, namely the elevated plus-maze, the black/white box, and the social interaction test. In the elevated plus-maze, neither the number of total arm entries nor the percent number of open arm entries were different between the Roman lines. Alternatively, RLA rats spent more time on the open arms, compared to RHA rats. In the black/white box, both the latency to enter the black compartment, the number of shuttles, the time spent in the white compartment, and the general activity in the white compartment were higher in RLA rats, compared to their RHA counterparts. Lastly, socially isolated RHA and RLA behaved similarly when exposed to a social interaction test. It is suggested that under particular experimental conditions male RLA rats display less anxiety than male RHA rats, and that the open-field test may provide indices of activity rather than indices of anxiety.

An overview of the literature on the emotional impacts of wheel running reveals contradictory findings. Among the hypotheses underlying such a discrepancy, that related to the different housing conditions of the controls, i.e., standard housing without any object or housing with blocked running wheels, merits attention. We addressed this point in C57Bl/6N mice by examining the consequences of chronic wheel running on anxiety, context fear recall, and behavioral despair compared either to standard control housing or to housing with blocked wheels. Compared to standard housing, wheel running proved anxiolytic while facilitating fear memory. On the other hand, wheel running increased behavioral despair but influenced neither anxiety nor fear memory when compared to housing with blocked wheels. This study suggests that investigations aimed at measuring the emotional consequences of wheel running should take into consideration the housing conditions of the controls to which are compared the runners.