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Expertise: endocannabinoïdes, stress, exercice physique

135 publication(s) since Janvier 1985:

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2008 | Med Sci (Paris)   IF 0.4
[New insights in stress-induced synaptic adaptations]
Groc L, Chaouloff F


The endocannabinoid system recently emerged as an important modulator of many neuronal functions. Among them, the control of anxiety and acquired fear represents nowadays one of the most interesting fields of research. Despite contrasting results obtained by the use of cannabinoid receptor agonists in experimental animals, there is growing evidence that the physiological activation of the endocannabinoid system plays a central role in the control of basal anxiety levels and in the modulation of fear responses. This review will summarise recent data on the role of the endocannabinoid system in most commonly used tests of anxiety and in the processing of acquired fear, with particular attention to its involvement in fear extinction. Finally, a neurobiological model possibly able to implement the role of the endocannabinoid system in these processes will be proposed.

Acute stress affects NMDA receptor (NMDAR)-dependent synaptic plasticity in the CA1 region of the hippocampus, with long-term potentiation and long-term depression (LTD) being, respectively, diminished and facilitated by acute exposure to stress. Here, we examined whether this facilitatory effect of stress on NMDAR-dependent LTD extends to metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral-CA1 synapses. Application of a low dose (50 microM) of the selective group 1 mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) promoted LTD in slices from stressed, but not from control, rats. Pretreatment of stressed rats with the glucocorticoid receptor (GR) antagonist RU38486 prevented the facilitation of DHPG-induced LTD (DHPG-LTD), indicating the involvement of corticosterone secretion and, in turn, stimulation of GRs. Finally, pretreatment of slices with an mGluR1, but not an mGluR5, antagonist blunted the sensitizing effect of stress on DHPG-LTD. These results indicate that acute stress, through corticosterone stimulation of GRs, facilitates the expression of mGluR1-dependent DHPG-LTD in the hippocampal CA1 region.

03/2003 | Behav Pharmacol   IF 1.8
Wistar-Kyoto rats are sensitive to the hypolocomotor and anxiogenic effects of mCPP.
Durand M, Mormede P, Chaouloff F

Wistar-Kyoto (WKY) rats, but not spontaneously hypertensive rats (SHRs), are insensitive to the acute hypolocomotor and anxiogenic effects of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, in elevated plus-maze tests. Several observations suggest that these strain-dependent effects involve postsynaptic serotonin (5-HT) receptors. In keeping with the recent finding that citalopram-elicited anxiety in Sprague-Dawley rats, as measured in the social interaction test, involves 5-HT(2C) receptor stimulation, we tested the hypothesis that this receptor is prone to subsensitivity in WKY rats, compared to SHRs. Thus, we first examined the acute behavioural effects of the 5-HT(2B/2C) receptor agonist, mCPP, in SHRs and WKY rats exposed to an elevated plus-maze; in addition, because WKY rats display anxiety and hypolocomotion, compared to SHRs, we next used the 5-HT(2B/2C) receptor antagonist, SB-206553, to test whether 5-HT(2C) receptors are tonically active in WKY rats. The results confirmed that WKY rats and SHRs differ in locomotor activity and anxiety-related behaviours, and showed that pretreatment with mCPP decreased locomotion in both strains. In contrast, the strains differed with respect to mCPP-elicited anxiety, as WKY rats were sensitive to the lowest dose of mCPP, while only the highest dose increased anxiety in SHRs. Finally, elevated plus-maze behaviours of SHRs and WKY rats were found to be insensitive to SB-206553 pretreatment. This study therefore suggests that 5-HT(2C) receptors (at least those which mediate mCPP-induced hypolocomotion and anxiety) are neither desensitized nor tonically active in WKY rats.

02/2003 | Eur J Neurosci   IF 2.8
Rat strain differences in peripheral and central serotonin transporter protein expression and function.
Fernandez F, Sarre S, Launay JM, Aguerre S, Guyonnet-Duperat V, Moisan MP, Ebinger G, Michotte Y, Mormede P, Chaouloff F

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.

24/01/2003 | Brain Res   IF 2.9
Fox odour affects corticosterone release but not hippocampal serotonin reuptake and open field behaviour in rats.
Dias Soares D, Fernandez F, Aguerre S, Foury A, Mormede P, Chaouloff F

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).

Previous studies have shown that Fischer 344 (F344) and Lewis (LEW) rats may differ with respect to their behavioural and neurochemical responses to several drugs of abuse, including amphetamines. Herein, we have examined whether such strain differences extend to a ring-substituted amphetamine, namely 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), a recreationally-used drug endowed with euphoric, but also long-term neurotoxic effects. Beside strain differences in baseline locomotor activity (F344>LEW), it was found that the subcutaneous administration of 10 mg/kg, but not 5 mg/kg, MDMA increased locomotor activity in F344 rats only. On the other hand, such a treatment increased to similar extents extracellular dopamine (DA) levels in the nucleus accumbens of F344 and LEW rats, thus suggesting that genetic differences in MDMA locomotor effects are not accounted for by accumbal DA release.

12/2002 | dialogues clin neurosci   IF 4.9
Neurogenetics of emotional reactivity to stress in animals.
Chaouloff F

There is much evidence for the involvement of central monoaminergic systems, the key targets of stress, in the regulation of mood. Animal and human findings indicate that genetics play a role in the etiology of mood disorders, and so we selected divergent inbred rat strains according to their anxiety-related behaviors on exposure to novel environments. We compared these strains for psychoneuroendocrine response to stressors and/or antidepressants. Molecular genetic studies were also performed to localize the genomic regions associated with these strain-dependent anxiety profiles. We then examined human results indicating that allelic variations in the serotonin transporter (5-HTT) may play a role in the etiology of neuroticism and depression. Thus, we compared inbred rat strains for the 5-HTT, with regard to central and peripheral (platelet) protein expression and function, and the consequences of local application of a selective serotonin reuptake inhibitor (SSRI) on extracellular serotonin (5-HT) levels. Our results indicate that spontaneously hypertensive rats and Lewis rats (LEW) selectively diverge in terms of anxiety-related behaviors and that this divergence is located on chromosome 4. The use of social defeat in LEW and the analysis of its psychoneuroendocrine consequences strongly suggest that such a paradigm, which is sensitive to repeated SSRI treatment, models posttraumatic stress disorder. The Wistar-Kyoto rat may be an adequate model to study the consequences of a genetically driven hypersensitivity to stress and noradrenergic antidepressants. Our most recent findings show that the Fischer 344 and LEW strains differ in protein expression and function of hippocampal and platelet 5-HTT; the divergence in protein expression is not due to allelic variations in the gene-coding sequences and leads to marked differences in extracellular 5-HT levels under basal conditions or SSRI. These examples illustrate how the use of inbred rat strains may complement our knowledge on the genetics of behavior, in the same way as the use of transgenic mice.

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.

07/2002 | Psychoneuroendocrinology   IF 4
Molecular genetic approaches to investigate individual variations in behavioral and neuroendocrine stress responses.
Mormede P, Courvoisier H, Ramos A, Marissal-Arvy N, Ousova O, Desautes C, Duclos M, Chaouloff F, Moisan MP

A large response range can be observed in both behavioral and neuroendocrine responses to environmental challenges. This variation can arise from central mechanisms such as those involved in the shaping of general response tendencies (temperaments) or involves only one or the other output system (behavioral vs. endocrine response). The participation of genetic factors in this variability is demonstrated by family and twin studies in humans, the comparison of inbred strains and selection experiments in animals. Those inbred strains diverging for specific traits of stress reactivity are invaluable tools for the study of the molecular bases of this genetic variability. Until recently, it was only possible to study biological differences between contrasting strains, such as neurotransmitter pathways in the brain or hormone receptor properties, in order to suggest structural differences in candidate genes. The increase of the power of molecular biology tools allows the systematic screening of significant genes for the search of molecular variants. More recently, it was possible to search for genes without any preliminary functional hypothesis (mRNA differential expression, nucleic acid arrays, QTL search). The approach known as quantitative trait loci (QTL) analysis is based on the association between polymorphic anonymous markers and the phenotypical value of the trait under study in a segregating population (such as F2 or backcross). It allows the location of chromosomal regions involved in trait variability and ultimately the identification of the mutated gene(s). Therefore, in a first step, those studies skip the 'black box' of intermediate mechanisms, but the knowledge of the gene(s) responsible for trait variability will point out to the pathway responsible for the phenotypical differences. Since variations in stress-related responses may be related to numerous pathological conditions such as behavioral and mood disorders, drug abuse, cardiovascular diseases or obesity, and production traits in farm animals, these studies can be expected to bring significant knowledge for new therapeutic approaches in humans and improved efficiency of selection in farm animals.