Abstract
Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of α7 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 α7 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 α7-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.
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This research was supported by the Israel Science Foundation (grant no. 1234/07, IW) and by the Josef Sagol Fellowship Program in Brain Studies at Tel-Aviv University (SB).
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The reported experiments are part of a research collaboration supported by Sanofi-Aventis. The authors have neither conflicts of interest to report, nor any involvement to disclose, financial or otherwise, that may bias the conduct, interpretation, or presentation of this work. Organizations from which the authors have received compensation for professional services: GG and MDB are employees of Sanofi-Aventis.
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Barak, S., Arad, M., De Levie, A. et al. Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia. Neuropsychopharmacol 34, 1753–1763 (2009). https://doi.org/10.1038/npp.2008.232
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