REDD1 is essential for stress-induced synaptic loss and depressive behavior.

Major depressive disorder (MDD) affects up to 17% of the population, causing profound personal suffering and economic loss. Clinical and preclinical studies have revealed that prolonged stress and MDD are associated with neuronal atrophy of cortical and limbic brain regions, but the molecular mechanisms underlying these morphological alterations have not yet been identified. Here, we show that stress increases levels of REDD1 (regulated in development and DNA damage responses-1), an inhibitor of mTORC1 (mammalian target of rapamycin complex-1; ref. 10), in rat prefrontal cortex (PFC). This is concurrent with a decrease in phosphorylation of signaling targets of mTORC1, which is implicated in protein synthesis-dependent synaptic plasticity. We also found that REDD1 levels are increased in the postmortem PFC of human subjects with MDD relative to matched controls. Mutant mice with a deletion of the gene encoding REDD1 are resilient to the behavioral, synaptic and mTORC1 signaling deficits caused by chronic unpredictable stress, whereas viral-mediated overexpression of REDD1 in rat PFC is sufficient to cause anxiety- and depressive-like behaviors and neuronal atrophy. Taken together, these postmortem and preclinical findings identify REDD1 as a critical mediator of the atrophy of neurons and depressive behavior caused by chronic stress exposure.

Discovery of N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine as a potent, selective, and orally active 5-HT(6) receptor agonist.

N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.

Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications.

RATIONALE: Oxytocin (OT) acts as a neuromodulator/neurotransmitter within the central nervous system (CNS) and regulates a diverse range of CNS functions. Notably, evidence from studies in females has revealed an important role for OT in regulating anxiety behavior. OBJECTIVES: The objective of this study was to examine the effects of OT on both behavioral and autonomic parameters of the anxiety response in male mice using three pharmacologically validated preclinical models of anxiety: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). RESULTS: In the FPT, both peripherally (3-30 mg/kg i.p.) and centrally (1-10 microg i.c.v.) administered OT produced dose-dependent increases in punished crossings, indicating an anxiolytic-like effect. The effects of centrally administered OT in the FPT were blocked with peripheral administration of a brain-penetrant OT receptor (OTR) antagonist WAY-162720 (30 mg/kg i.p.), and the effects of peripherally administered OT were blocked with central administration of a non-penetrant OTR antagonist L-371,257, suggesting OT acts centrally. In the EZM, centrally administered OT (0.1-1.0 microg, i.c.v.) produced significant increases in the percentage time spent in the open quadrants of the maze, comparable to alprazolam (0.5-1.0 microg, i.c.v.). In SIH, OT (1-10 mg/kg i.p.) dose-dependently attenuated stress-induced increases in core body temperature, comparable to the reference anxiolytic chlordiazepoxide (CDP) (10 mg/kg i.p.). CONCLUSIONS: These results provide specific behavioral and autonomic evidence of anxiolytic-like effects for oxytocin in males and, together with previously reported observations in females, suggest the potential utility of OTR agonism as a therapeutically relevant mechanism of action for novel anxiolytics in both sexes.

Comparison of the effects of antidepressants on norepinephrine and serotonin concentrations in the rat frontal cortex: an in-vivo microdialysis study.

The present study employed in-vivo microdialysis techniques in the freely moving rat to systematically compare the neurochemical effects of various antidepressant agents on extracellular concentrations of norepinephrine (NE) and serotonin (5-HT) in the frontal cortex. We found that acute administration of the tricyclic antidepressant, desipramine (3-30 mg/kg, s.c.) and the dual serotonin/norepinephrine reuptake inhibitor, venlafaxine (3-30 mg/kg, s.c.), produced dose-dependent and robust increases in cortical NE concentrations (498% and 403%, respectively). Conversely, acute injection of the selective serotonin reuptake inhibitors, fluoxetine (30 mg/kg, s.c.) and paroxetine (1-10 mg/kg, s.c.), did not alter forebrain NE concentrations. However, paroxetine did produce a significant increase in cortical NE concentrations (164%) when administered at 30 mg/kg. These changes in NE were not paralleled by 5-HT, which showed no increase following administration of desipramine, venlafaxine, paroxetine or fluoxetine. Combination treatment with the 5-HT1A receptor antagonist, WAY-100635 (0.3 mg/kg, s.c.), significantly enhanced extracellular 5-HT concentrations following venlafaxine (10 and 30 mg/kg), fluoxetine (30 mg/kg) and paroxetine (3-30 mg/kg). Alternatively, WAY-100635 produced no augmentation of the antidepressant-induced changes in extracellular NE. Collectively, these studies show that paroxetine, at low to intermediate doses, and fluoxetine are selective for 5-HT versus NE systems, whereas venlafaxine produces similar effects on both 5-HT and NE levels at the effective doses tested.