Schizophrenia has been initially associated with dysfunction in dopamine neurotransmission. However, the observation that antagonists of the glutamate N-methyl-D-aspartate (NMDA) receptor produce schizophrenic-like symptoms in humans has led to the idea of a dysfunctioning of the glutamatergic system via its NMDA receptor. As a result, there is a growing interest in the development of pharmacological agents with potential antipsychotic properties that enhance the activity of the glutamatergic system via a modulation of the NMDA receptor. Among them are glycine transporter-1 (GlyT1) inhibitors such as SSR103800, which indirectly enhance NMDA receptor function by increasing the glycine (a co-agonist for the NMDA receptor) levels in the synapse. This study aimed at investigating the potential antipsychotic-like properties of SSR103800, with a particular focus on models of hyperactivity, involving either drug challenge (ie, amphetamine and MK-801) or transgenic mice (ie, NMDA Nr1(neo-/-) and DAT(-/-)). Results showed that SSR103800 (10-30 mg/kg p.o.) blocked hyperactivity induced by the non-competitive NMDA receptor antagonist, MK-801 and partially reversed spontaneous hyperactivity of NMDA Nr1(neo-/-) mice. In contrast, SSR103800 failed to affect hyperactivity induced by amphetamine or naturally observed in dopamine transporter (DAT(-/-)) knockout mice (10-30 mg/kg p.o.). Importantly, both classical (haloperidol) and atypical (olanzapine, clozapine and aripiprazole) antipsychotics were effective in all these models of hyperactivity. However, unlike these latter, SSR103800 did not produce catalepsy (retention on the bar test) up to 30 mg/kg p.o. Together these findings show that the GlyT1 inhibitor, SSR103800, produces antipsychotic-like effects, which differ from those observed with compounds primarily targeting the dopaminergic system, and has a reduced side-effect potential as compared with these latter drugs.Neuropsychopharmacology advance online publication, 16 September 2009; doi:10.1038/npp.2009.144.

The involvement of the beta(3) adrenoceptor in the antidepressant-like effects of the beta(3)-adrenoceptor agonist amibegron is addressed in the chronic mild stress, using adrenergic beta(3)-receptor knockout (Adrb3(tm1Lowl)) mice. Amibegron (3mg/kg/day, i.p., 33 days), attenuated the physical alteration due to the application of repeated stress in wild-type littermates, but not in knockout mice. This result suggests that the beta(3) adrenoceptor plays a predominant role in mediating antidepressant-like actions of amibegron.

Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of alpha7 nicotinic receptor (nAChR) agonists for cognitive deficits in schizophrenia but their activity against positive symptoms is thought to be minimal. The present study examined potential pro-cognitive and antipsychotic activity of the novel selective alpha7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously non-reinforced stimulus to gain behavioral control when paired with reinforcement, compared with a novel stimulus. Here, no-drug controls displayed LI if non-reinforced pre-exposure to a tone was followed by weak but not strong conditioning (2 vs 5 tone-shock pairings). MK801 (0.05 mg/kg, i.p.)-treated rats as well as rats neonatally treated with nitric oxide synthase inhibitor L-NoArg (10 mg/kg, s.c.) on postnatal days 4-5, persisted in displaying LI with strong conditioning, whereas amphetamine (1 mg/kg)-treated rats failed to show LI with weak conditioning. SSR180711 (0.3, 1, 3 mg/kg, i.p.) was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal L-NoArg; these models are believed to model cognitive aspects of schizophrenia and activity here was consistent with previous findings with alpha7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in no-drug controls and reversed amphetamine-induced LI disruption, two effects considered predictive of activity against positive symptoms of schizophrenia. These findings suggest that SSR180711 may be beneficial not only for the treatment of cognitive symptoms in schizophrenia, as reported multiple times previously, but also positive symptoms.Neuropsychopharmacology advance online publication, 21 January 2009; doi:10.1038/npp.2008.232.

RATIONALE: SSR103800 and SSR504734 are novel glycine transport 1 (GlyT1) inhibitors with therapeutic potential for the treatment of schizophrenia. OBJECTIVE: The present studies investigated the effects of GlyT1 inhibitors in acute pharmacological and neurodevelopmental models of schizophrenia using latent inhibition in the rat; these latent inhibition (LI) models are believed to be predictive for treatments of positive, negative, and cognitive aspects of schizophrenia. MATERIALS AND METHODS: LI, the poorer conditioning to a previously irrelevant stimulus, was measured in a conditioned emotional response procedure in male rats. The effects of SSR103800 or SSR504734 (both at 1, 3, and 10 mg/kg, i.p.) were determined on amphetamine-induced disrupted LI, MK-801-induced abnormally persistent LI, and neurodevelopmentally induced abnormally persistent LI in adult animals that had been neonatally treated with a nitric oxide synthase inhibitor. RESULTS: SSR103800 (1 and 3 mg/kg) and SSR504734 (1 and 10 mg/kg) potentiated LI under conditions where LI was not present in nontreated controls and SSR103800 (1 mg/kg) reversed amphetamine-induced disrupted LI while not affecting LI on its own. Additionally, SSR103800 (1 and 3 mg/kg) and SSR504734 (3 and 10 mg/kg) reversed abnormally persistent LI induced by MK-801. In the neurodevelopmental model, SSR504734 (3 and 10 mg/kg) reverted the LI back to control (normal) levels. CONCLUSIONS: These preclinical data, from acute and neurodevelopmental models, suggest that GlyT1 inhibition may exhibit activity in the positive, negative, and cognitive symptom domains of schizophrenia.

On native human, rat and mouse glycine transporter-1(GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM, respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.

Gene microarrays may enable the elucidation of neurobiological changes underlying the pathophysiology and treatment of major depression. However, previous studies of antidepressant treatments were performed in healthy normal rather than 'depressed' animals. Since antidepressants are devoid of mood-changing effects in normal individuals, the clinically relevant rodent transcriptional changes could remain undetected. We investigated antidepressant-related transcriptome changes in a corticolimbic network of mood regulation in the context of the unpredictable chronic mild stress (UCMS), a naturalistic model of depression based on socio-environmental stressors. Mice subjected to a 7-week UCMS displayed a progressive coat state deterioration, reduced weight gain, and increased agonistic and emotion-related behaviors. Chronic administration of an effective (fluoxetine) or putative antidepressant (corticotropin-releasing factor-1 (CRF(1)) antagonist, SSR125543) reversed all physical and behavioral effects. Changes in gene expression differed among cingulate cortex (CC), amygdala (AMY) and dentate gyrus (DG) and were extensively reversed by both drugs in CC and AMY, and to a lesser extent in DG. Fluoxetine and SSR125543 also induced additional and very similar molecular profiles in UCMS-treated mice, but the effects of the same drug differed considerably between control and UCMS states. These studies established on a large-scale that the molecular impacts of antidepressants are region-specific and state-dependent, revealed common transcriptional changes downstream from different antidepressant treatments and supported CRF(1) targeting as an effective therapeutic strategy. Correlations between UCMS, drug treatments, and gene expression suggest distinct AMY neuronal and oligodendrocyte molecular phenotypes as candidate systems for mood regulation and therapeutic interventions.Neuropsychopharmacology advance online publication, 4 June 2008; doi:10.1038/npp.2008.76.

Defensive responses include an array of specific behaviors, including flight, freezing, risk assessment, and defensive threat/attack, that are elicited by unconditioned threat stimuli such as predators or predator odors. Some individual defensive behaviors are selectively responsive to drugs effective against generalized anxiety disorder or panic, providing a rationale for their use in investigation of compounds that may be useful in treating these disorders. In addition, defensive behaviors toward predators and some predator odors show rapid conditioning to contextual stimuli, whereas other predator odors do not, although they too elicit defensiveness. This pattern suggests that the ability of a predator odor to predict danger may be a determinant of the degree to which that odor supports aversive conditioning. Predators and predator odors are also increasingly used in studies of brain systems potentially related to emotionality. These factors indicate the need for selective, reliable, and convenient tests of defensiveness to predators and predator odors using rat and mouse subjects.

BACKGROUND: Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs. METHODS: Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling. RESULTS: Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists. CONCLUSIONS: Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

The involvement of the noradrenergic system, particularly the beta1 and beta2 receptors, in depressive disorders has been frequently shown. Recently, however, it has been shown that the beta3 receptor may also contribute since amibegron (SR58611A), a selective beta3 receptor agonist, has antidepressant-like effects. The present experiment sought to confirm the antidepressant potential of amibegron by studying its effects in an animal model of depression, the Flinders Sensitive Line (FSL) rat. The FSL rat is innately highly immobile in the forced swim test and exhibits a decrease in immobility after chronic, not acute antidepressant treatment. FSL rats were treated for 14 consecutive days with amibegron (0.3, 1.0, or 3.0 mg/kg), fluoxetine (5 mg/kg) or desipramine (5 mg/kg) as positive controls, and vehicle, while the control strain, the Flinders Resistant Line (FRL) rats, was given either vehicle or 1.0 mg/kg amibegron. About 23-25 h after the last injection the rats were tested in the forced swim test. All doses of amibegron and the two active controls, fluoxetine and desipramine, significantly reduced immobility in the FSL rats. Thus, amibegron had a selective antidepressant-like effect in this study, confirming its antidepressant potential.

Central tachykinins have been shown to play a role in the modulation of stress-related behaviours. Saredutant, a tachykinin NK2 receptor antagonist, displayed mixed anxiolytic- and antidepressant-like activities in rodents. The present study aimed at further characterizing its psychotropic properties. Saredutant was tested in the rat social interaction test to further confirm its anxiolytic-like activity, and in a variety of behavioural models sensitive to antidepressant drugs. In the rat social interaction test, saredutant (20 mg/kg, i.p.) significantly increased the time spent in interaction, as did the prototypical anxiolytic agents, diazepam (1 mg/kg, i.p.) and buspirone (1 mg/kg, s.c.), but not the antidepressant, fluoxetine. In a differential reinforcement of low rate-72s task, saredutant (3 mg/kg, i.p.) displayed an antidepressant-like activity by increasing reinforced response rate and percentage of responses emitted in the inter-response time bin [49-96 s]. In bulbectomized rats, saredutant (20 mg/kg, i.p.) restored the deficit of acquisition of passive avoidance. In rat pups separated from their mother, saredutant (3-10 mg/kg, s.c.) reduced ultrasonic distress calls. Finally, in the chronic mild stress paradigm in mice, a 29-day treatment regimen with saredutant (10 mg/kg, i.p.) attenuated stress-induced physical degradation. Importantly, in the depression models, the effects of saredutant were comparable to those obtained under similar experimental conditions by reference antidepressants such as fluoxetine or imipramine. Together, these results suggest further that the NK2 receptor may represent an attractive target for the treatment of both depressive and anxiety disorders.