Stress can increase or decrease anxiety depending on the timing of the stressor

<p>The purpose of these experiments was to determine the immediate and delayed effects of stress on anxiety/depressive behavior. For the open field and elevated plus maze experiments male CD1 mice (Charles River) were used (n=6-8 per group; arrived at 7 weeks of age, tested at 9-11 weeks, handled for 5 days prior to testing). The GFAP-tk mice used for the novelty-suppressed feeding test were as described in Snyder, 2011, Nature. Mice were housed 4/cage, kept on a 12 hour light/dark cycle with lights on at 6 am and were tested during the light phase. Testing was performed either directly from the home cage (controls), immediately following 30 min restraint (stress) or following 30 min restraint with a 30 min post-restraint delay interval (stress+delay).</p> <p>Figure 1: Increased fear/anxiety in the open field immediately following stress. a) The open field was a white plastic box (50cm x 50cm x 50cm) which was divided into outer (o), middle (m), and center (c) regions. Mice were tracked with Ethovision software (Noldus) and latency to approach the center region and time spent in the 3 regions during a 15 min test was calculated. Light intensity was approximately 150 lux. b) The presence of an object (~2 cm diameter, 3 cm tall wire metal cylinder containing a marble) in the center of the open field increased time spent in this subregion, and was therefore included in subsequent experiments (i.e. d-h; ****t-test P</p> <p>Figure 2: Reduced fear/anxiety in the elevated plus maze 30 min after stress. Mice were subjected to a 5 min test in the EPM under bright (~150 lux; a-g) and dark (15 lux; h-n) conditions. The EPM had two open arms and two opaque closed arms and was located in the center of the testing room. a) Stress+delay increased the amount of time spent in the open arm during the first 2.5 min of the test (bin 1; *t-test, P</p> <p>In sum, stress can increase anxiety immediately after termination of the stressor: stressed mice spent less time than controls in the center of the open field. Stress can also reduce anxiety at later times after termination of the stressor: stress+delay mice spent more time in the open arms of the elevated plus maze, stress+delay mice displayed more head dipping behavior in the elevated plus maze, and stress+delay mice ate sooner in the novelty- suppressed feeding test. Also, in the open field, 1/3 of mice in the control and stress groups did not approach the center until 4+ min had elapsed. In contrast, though not significantly different, there was less variability in the stress+delay mice with all approaching the center by ~2 min, consistent with the possibility that stress+delay is reducing anxiety in some of these mice.</p

Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats.

International audienceRATIONALE AND OBJECTIVES: The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT(2c) serotonin receptor antagonist. RESULTS: Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40-50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a "disease-dependent" drug. CONCLUSIONS: These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders

S32006, a novel 5-HT(2C) receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models

Rationale Serotonin (5-HT)(2C) receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states. Objectives Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006. Materials and methods Standard cellular, electrophysiological, neurochemical, and behavioral procedures were used. Results S32006 displayed high affinity for human (h)5-HT(2C) and h5-HT(2B) receptors (pK (i)s, 8.4 and 8.0, respectively). By contrast, it had negligible (100-fold lower) affinity for h5-HT(2A) receptors and all other sites examined. In measures of Gq-protein coupling/phospholipase C activation, S32006 displayed potent antagonist properties at h5-HT(2C) receptors (pK (B) values, 8.8/8.2) and h5-HT(2B) receptors (7.8/7.7). In vivo, S32006 dose-dependently (2.5-40.0 mg/kg, i.p. and p.o.) abolished the induction of penile erections and a discriminative stimulus by the 5-HT(2C) receptor agonist, Ro60,0175, in rats. It elevated dialysis levels of noradrenaline and dopamine in the frontal cortex of freely moving rats, and accelerated the firing rate of ventrotegmental dopaminergic and locus ceruleus adrenergic neurons. At similar doses, S32006 decreased immobility in a forced-swim test in rats, reduced the motor depression elicited by 5-HT(2C) and alpha(2)-adrenoceptor agonists, and inhibited both aggressive and marble-burying behavior in mice. Supporting antidepressant properties, chronic (2-5 weeks) administration of S32006 suppressed "anhedonia" in a chronic mild stress procedure and increased both expression of BDNF and cell proliferation in rat dentate gyrus. Finally, S32006 (0.63-40 mg/kg, i.p. and p.o) displayed anxiolytic properties in Vogel conflict and social interaction tests in rats. Conclusion S32006 is a potent 5-HT(2C) receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models