ssr180711 and Schizophrenia

Attentional set shifting, a measure of executive function, is impaired in schizophrenia patients. Current standard of care has little therapeutic benefit for treating cognitive dysfunction in schizophrenia; therefore, novel drugs and animal models for testing novel therapies are needed. The NMDA receptor antagonist, MK-801, produces deficits in a rat maze-based set-shifting paradigm, an effect which parallels deficits observed on tests of executive function in schizophrenia patients. Alpha7 nicotinic acetylcholine receptor (nAChR) agonists, currently under clinical development by several companies, show promise in treating cognitive symptoms in schizophrenia patients and can improve cognition in various animal models.. The objectives of the present study were to determine whether the MK-801 deficit in set shifting could be reproduced in a drug discovery setting and to determine whether cognitive improvement could be detected for the first time in this task with alpha7 nAChR agonists.. The data presented here replicate findings that a systemic injection of the NMDA receptor antagonist MK-801 can induce a deficit in set shifting in rats. Furthermore, the deficit could be reversed by the atypical antipsychotic clozapine as well as by several alpha7 nAch receptor agonists (SSR-180711, PNU-282987, GTS-21) with varying in vitro properties.. Results indicate that the MK-801 set-shift assay is a useful preclinical tool for measuring prefrontal cortical function in rodents and can be used to identify novel mechanisms for the potential treatment of cognitive deficits in schizophrenia.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Antipsychotic Agents; Attention; Benzamides; Benzylidene Compounds; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clozapine; Cognition Disorders; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Discovery; Male; Maze Learning; Neuropsychological Tests; Pyridines; Rats; Rats, Sprague-Dawley; Schizophrenia; Set, Psychology

Repeated phencyclidine (PCP) administration in mice reproduces several histopathological features of schizophrenia, such as reduced synaptophysin and parvalbumin mRNA expression in the frontal cortex. These changes can be prevented by co-administering the α7 nicotinic acetylcholine receptor (nAChR) agonist SSR180711 with PCP, but it is not known to what extent PCP-induced changes can be normalized once they have already occurred. Here we use semi-quantitative in situ hybridization to show that repeated administration of SSR180711 (3 mg/kg b.i.d. for 5 days) subsequent to repeated PCP administration (10 mg/kg/day for 10 days) is able to mitigate the reduction of synaptophysin mRNA expression induced by PCP in two prefrontal cortical regions, the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (VLO). This effect is accompanied by a normalization of the PCP-induced increase in Arc mRNA expression in the same regions. In contrast, subsequent administration of SSR180711 does not affect PCP-induced decreases in parvalbumin mRNA in the mPFC, and glutamate decarboxylase 67 mRNA in the mPFC or VLO. These data demonstrate that it is possible to restore some, but not all, of the molecular dysregulations induced by repeated PCP administration with an α7 nAChR agonist. They also suggest that the previously demonstrated cognitive improvement with SSR180711 subsequent to PCP treatment does not require normalization of parvalbumin expression, but may instead be related to a restoration of synaptophysin and/or Arc levels in the frontal cortex. These data lend support to the potential for development of α7 nAChR agonists for the treatment of cognitive deficits in schizophrenia.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cytoskeletal Proteins; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Nicotinic Agonists; Phencyclidine; Prefrontal Cortex; Receptors, Nicotinic; Schizophrenia; Synaptophysin

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.

Topics: Acoustic Stimulation; alpha7 Nicotinic Acetylcholine Receptor; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Cognition Disorders; Conditioning, Psychological; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Male; Neural Inhibition; Neuroprotective Agents; Nicotinic Agonists; Nitroarginine; Rats; Rats, Wistar; Receptors, Nicotinic; Reinforcement, Psychology; Schizophrenia