Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC 50 ¼ 18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID 50 : 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 mM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB 1 receptors): it reversed the decrease in electrically evoked [3 H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF 1 and V 1b receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF 1 receptor antagonist SSR125543A, the V 1b receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF 1 and V 1b receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants. Keywords: depression; hippocampus; vasopressin; corticotrophin Despite extensive investigation, the mechanisms by which antidepressants exert their therapeutic effects are far from being fully understood. The dentate gyrus of the hippocampal formation is a brain region, which has focused much attention with respect to the effects of stress and the action of antidepressants. It is one of the few brain regions where adult neurogenesis has been documented in different species, including humans.1 Neurogenesis is defined by the proliferation of progenitor cells, giving rise to cells that migrate into the granule cell layers, and ultimately differentiate into neurons.2,3 Among the regulatory factors of neurogenesis, stressful events have been identified as potent inhibitors of dentate cell proliferation. [4][5][6][7][8] Chronic antidepressant treatment was reported to increase the rate of neurogenesis in adult brain. 9,10 Together, these findings led to the proposal that suppression of hippocampal neurogenesis in response to stress could be part of the structural remodelling occurring under pathological conditions and, accordingly, that restoration of this form of neural plasticity could be involved in the therapeutic effects of antidepressant treatment. [11][12][13] The precise mechanisms by which stress exerts these deleterious effects on hippocampal neurogenesis are unclear. However, this reduction appears to be mediated partly via st...
The characterization of the first selective orally active and brain-penetrant b 3 -adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stressinduced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the b 3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide.Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the b 3 adrenoceptor suggested that these effects of SR58611A are mediated by b 3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of b 3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.
The biochemical and pharmacological properties of a novel non-peptide antagonist of the bradykinin (BK) B 1 receptor, SSR240612 [(2R)-2-[((3R)The compound selectivity for B 1 versus B 2 receptors was in the range of 500-to 1000-fold. SSR240612 inhibited Lys 0 -desAr 9 -BK (10 nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC 50 of 1.9 nM. It also antagonized des-Arg 9 -BK-induced contractions of isolated rabbit aorta and mesenteric plexus of rat ileum with a pA 2 of 8.9and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited desArg 9 -BK-induced paw edema in mice (3 and 10 mg/kg p.o. and 0.3 and 1 mg/kg i.p.). Moreover, SSR240612 reduced capsaicin-induced ear edema in mice (0.3, 3 and 30 mg/kg p.o.) and tissue destruction and neutrophil accumulation in the rat intestine following splanchnic artery occlusion/reperfusion (0.3 mg/kg i.v.). The compound also inhibited thermal hyperalgesia induced by UV irradiation (1 and 3 mg/kg p.o.) and the late phase of nociceptive response to formalin in rats (10 and 30 mg/kg p.o.). Finally, SSR240612 (20 and 30 mg/kg p.o.) prevented neuropathic thermal pain induced by sciatic nerve constriction in the rat. In conclusion, SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B 1 receptor antagonist.Kinins are 9 to 11 amino acid peptides known to be important mediators of pain, inflammation, and cardiovascular homeostasis. They are released in injured tissues from kininogen by activation of plasma or tissue kallikreins (Bhoola et al., 1992). Kinins exert their biological activities via the activation of two subtypes of G-protein coupled receptors, denoted B 1 and B 2 receptors (Regoli and Barabe, 1980;Regoli et al., 1998). Bradykinin (BK) and Lys 0 -BK are natural endogenous agonists of bradykinin B 2 receptors, whereas their kininase I-hydrolyzed metabolites des-Arg 9 -BK and Lys 0 -des-Arg 9 -BK are specific agonists of bradykinin B 1 receptors. B 1 peptide antagonists were obtained by replacing the C-terminal Phe residue of agonists by Leu. Human and rabbit B 1 receptors have a higher affinity for Lys 0 -desArticle, publication date, and citation information can be found at
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