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.