The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents.

Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord.

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents.

Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298.

The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia.

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγS binding assays.

Long-lasting memory abnormalities following exposure to the mouse defense test battery: An animal model of PTSD.

Memory dysfunctions are thought to play a crucial role both in the development and the maintenance of posttraumatic stress disorder (PTSD). Patients suffering from this condition persistently re-experience the traumatic event particularly when exposed to trauma-related cues and they display memory alterations. The objective of the present study was to investigate the long-term effects of a traumatic stress exposure on defensive behaviors and memory performance in mice confronted with a natural threat (i.

Neuropeptide Receptor Ligands for the Treatment of Schizophrenia: Focus on Neurotensin and Tachykinins.

There is a wealth of evidence that various neuropeptides and their receptor ligands modulate schizophrenia- related behaviors in preclinical animal models, suggesting that neuropeptide systems may represent potential novel therapeutic targets for the treatment of schizophrenia. In particular, neurotensin and tachykinins have been the subject of significant research efforts, generating compelling preclinical data in the schizophrenia field. However, clinical studies with notably selective tachykinin NK3 receptor antagonists in schizophrenia have been disappointing, and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for this condition.

Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents.

Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice.

The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine.

The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.

Mice deficient in cryptochrome 1 (cry1 (-/-)) exhibit resistance to obesity induced by a high-fat diet.

Disruption of circadian clock enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. Circadian clocks rely on a highly regulated network of transcriptional and translational loops that drive clock-controlled gene expression. Among these transcribed clock genes are cryptochrome (CRY) family members, which comprise Cry1 and Cry2.

Optogenetics to study the circuits of fear- and depression-like behaviors: a critical analysis.

In recent years, the development and extensive use of optogenetics resulted in impressive findings on the neurobiology of anxiety and depression in animals. Indeed, it permitted to depict precisely the role of specific cell populations in various brain areas, including the amygdala nuclei, the auditory cortex, the anterior cingulate, the hypothalamus, the hippocampus and the bed nucleus of stria terminalis in specific aspects of fear and anxiety behaviors. Moreover, these findings emphasized the involvement of projections from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex in eliciting depressive-like behaviors in stress-resilient mice or in inhibiting the expression of such behaviors in stress-vulnerable mice.

Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep-wake disorders.

Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.

50 years of hurdles and hope in anxiolytic drug discovery.

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials.

Phencyclidine decreases tickling-induced 50-kHz ultrasound vocalizations in juvenile rats: a putative model of the negative symptoms of schizophrenia?

The objective of the present study was to examine the idea that the decrease in 50-kHz ultrasonic vocalizations elicited by tickling in juvenile rats following the administration of the psychotomimetic drug phencyclidine (PCP) may represent a valid model of the negative symptoms of schizophrenia. Fifty-kilohertz calls in rodents have been suggested to represent an archaic model of human laughter. Our results showed that daily tickling sessions produced a gradual increase in 50-kHz vocalizations, an effect that reached statistical significance from day 3.

Deep brain stimulation in treatment-resistant depression in mice: comparison with the CRF1 antagonist, SSR125543.

Deep brain stimulation (DBS) has been demonstrated to represent a targeted therapeutic alternative for treatment-resistant depression. In this study, we used the unpredictable chronic mild stress (UCMS) test to validate high-frequency electrical stimulation of the cingulate cortex (CC) as a possible treatment to improve behavioral symptoms associated with a depressive-like state in treatment-resistant mice. The effects of DBS were compared with those of the CRF(1) antagonist, SSR125543.

Further evidence for the sleep-promoting effects of 5-HT₂A receptor antagonists and demonstration of synergistic effects with the hypnotic, zolpidem in rats.

5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias, but unlike hypnotics, they have limited effects on sleep initiation. This study evaluated the effects of several 5-HT₂A antagonists (eplivanserin, volinanserin and AVE8488) alone and/or in combination with the short-acting hypnotic, zolpidem, on the rat sleep profile. A repeated-measures design was used in which rats were treated with eplivanserin (3 and 10 mg/kg, i.

The vasopressin V(1b) receptor antagonist SSR149415 in the treatment of major depressive and generalized anxiety disorders: results from 4 randomized, double-blind, placebo-controlled studies.

Objective: These studies were designed to evaluate the efficacy and tolerability of the first nonpeptide vasopressin V(1b) receptor antagonist, SSR149415, in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).

Method: Studies were randomized 8-week, double-blind, placebo-controlled trials evaluating 100- and 250-mg twice daily doses of SSR149415, placebo, and escitalopram 10 mg/day or paroxetine 20 mg/day, conducted from August 2006 through February 2008. Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for MDD or GAD.

Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models.

Awakening properties of newly discovered highly selective H₃ receptor antagonists in rats.

The objective of the present study was to compare the awakening effects of two newly discovered H₃ receptor antagonists (i.e. SAR110894 and SAR110068) with those of reference H₃ receptor ligands (i.

SAR110894, a potent histamine H₃-receptor antagonist, displays procognitive effects in rodents.

SAR110894 is a novel histamine H₃-R ligand, displaying high and selective affinity for human, rat or mouse H₃-Rs. SAR110894 is a potent H₃-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H₃-Rs demonstrating inverse agonist properties.

Is there still a future for neurokinin 3 receptor antagonists as potential drugs for the treatment of psychiatric diseases?

Selective non-peptide antagonists for the neurokinin 3 (NK(3)) receptor first became available about twenty years ago. Although the understanding of the role of the NK(3) receptor in the brain has been greatly complicated by marked species differences in its distribution and by pharmacological heterogeneity, studies with brain-penetrant non-peptide NK(3) receptor antagonists in animals have indicated that these compounds may find utility in a number of psychiatric diseases, including schizophrenia, anxiety and depressive disorders. However, clinical studies with selective NK(3) receptor antagonists in these psychiatric conditions have been disappointing and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for CNS disorders.

The corticotropin-releasing factor 1 receptor antagonist, SSR125543, and the vasopressin 1b receptor antagonist, SSR149415, prevent stress-induced cognitive impairment in mice.

The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animals. In the present study, their effects on stress-induced deficit in cognitive performances as assessed in a modified object recognition test were investigated in mice. The object recognition task measures the ability of a mouse to remember an object it has previously explored in a learning trial.

AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents.

Rationale: The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia.

Objective: These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia.

The neurokinin NK2 antagonist, saredutant, ameliorates stress-induced conditions without impairing cognition.

The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3-30 mg/kg, per os, p.