SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (II) Efficacy in Experimental Models Predictive of Activity Against Cognitive Symptoms of Schizophrenia

Abstract

SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective a7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the a7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801-or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective a7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

“…We show that SSR180711 was able to alleviate abnormally persistent LI produced by acute MK801 and neonatal NOS blockade; these models are believed to model cognitive aspects of schizophrenia and the activity here was consistent with previous findings with a7-nAChR agonists (Arendash et al, 1995;Hashimoto et al, 2008;Levin et al, 1999;Meyer et al, 1998;Olincy and Stevens, 2007;Pichat et al, 2007;Timmermann et al, 2007;Wishka et al, 2006). Rather unexpectedly SSR180711 potentiated LI in normal rats and reversed amphetamine-induced LI disruption, two models considered predictive of activity against positive symptoms of schizophrenia (Gray et al, 1991;Kilts, 2001;Lipska, 2004;Lipska and Weinberger, 2000;Moser et al, 2000;Powell and Miyakawa, 2006;Smith et al, 2007;Weiner, 1990Weiner, , 2003 .…”

“…MK801-induced attentional perseveration is reversed by atypical APDs and glycinergic NMDA-enhancers but not typical APDs (Black et al, 2008;GaislerSalomon et al, 2008;Gaisler-Salomon and Weiner, 2003;Lipina et al, 2005), consistent with the differential efficacy of these treatments for negative/cognitive symptoms (Harvey et al, 2005;Heresco-Levy et al, 2005). As SSR180711 was shown to reverse NMDA blockade-induced cognitive deficits (impaired novelty discrimination and object recognition as well as memory deficits in the Morris water maze; Hashimoto et al, 2008;Pichat et al, 2007) here we expected that it would reverse MK801-induced persistent LI.…”

“…At low doses boosting a7-nAChR signaling without causing desensitization of the receptor, SSR180711 was shown to produce several electrophysiological, neurochemical and behavioral effects predictive of activity against cognitive impairments of schizophrenia, (Biton et al, 2007;Hashimoto et al, 2005;Pichat et al, 2007). Here, pro-cognitive and antipsychotic activities of SSR180711 were evaluated in the latent inhibition (LI) model of schizophrenia.…”

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

“…SSR180711, a selective α7 nicotinic cholinergic receptor partial agonist from Sanofi-Adventis, enhances episodic memory in the object recognition task in rats preadministered methyllycaconitine, an α7 nicotinic cholinergic receptor antagonist and in mice. However, when administered to α7 knockout mice, there is not enhancement of long-term episodic memory [122]. AR-R 17779, an AstraZeneca product, is an acetylcholine analogue with full agonist properties at the α7 nicotinic cholinergic receptor.…”

SSR180711, a Novel Selective α7 Nicotinic Receptor Partial Agonist: (1) Binding and Functional Profile

“…The pharmacological profile of SSR180711 in experimental models predictive of therapeutic activity on cognitive symptoms of schizophrenia is presented in a companion article (Pichat et al, 2006).…”