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

Abstract

Current antipsychotic treatments fail to fully address the range of symptoms of schizophrenia, particularly with respect to social and occupational dysfunctions. Recent work has highlighted the role of nicotinic in both cognitive and attentional deficits as well as deficient processing of repetitive sensory information. The predilection for schizophrenia patients to be extremely heavy cigarette smokers may be related to their attempt to compensate for a reduction in hippocampal α7 nicotinic cholinergic receptors by delivering exogenous ligand to the remaining receptors. Studies in rodent models of both learning and memory deficits and deficits in sensory inhibition have confirmed a role for α7 subtype of the nicotinic cholinergic receptors in these processes. Rodent studies also demonstrated the efficacy of a selective partial α7 nicotinic agonist, DMXBA, to improve these deficits. Subsequent human clinical trials demonstrated improved sensory inhibition in 12 schizophrenia patients and showed improvement in several subtests of the RBANS learning and memory assessment instrument. These data suggest that therapeutic agents selected for α7 nicotinic activity may have utility in treating certain symptoms of schizophrenia. KeywordsSchizophrenia; nicotinic receptors; DMXBA; P50 auditory evoked potential; cognitive deficits; nicotine Although the positive symptoms such as hallucinations and delusions of schizophrenia are partially treated with the available antipsychotic medications, social and occupational dysfunction remains a major issue in treating this disorder. Cognitive deficits have been identified as more closely related to ability to adequately function [1]. In the search for new and more effective therapeutic agents for schizophrenia, recent attention has turned the nicotinic cholinergic receptors system. α7 and P50 Auditory GatingPeople with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed

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

“…Importantly, although the former characteristic of this drug is in line with many reports on a7 agonists (Arendash et al, 1995;Levin et al, 1999;Meyer et al, 1998;Olincy and Stevens, 2007;Pichat et al, 2007;Timmermann et al, 2007;Wishka et al, 2006), the latter capacity to the best of our knowledge is demonstrated here for the first time. Thus, this study suggests that a7-nAChR (partial) agonists can be viewed as promising targets not only for cognitive impairments in schizophrenia, but for treating the wide spectrum of symptoms in schizophrenia, including positive symptoms.…”

“…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 .…”

“…A growing body of data demonstrates that a7-nAChR agonists facilitate cognitive function in a variety of learning and memory tasks in rodents and humans (eg Levin et al, 1999;Olincy and Stevens, 2007). Of particular relevance to attentional and sensory gating deficits in schizophrenia (Adler et al, 1998;Heinrichs, 2005;Lubow, 2005), a7-nAChR agonists alleviate both types of deficits in humans and animals Olincy et al, 2006;Timmermann et al, 2007;Wishka et al, 2006).…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…208,209 A large body of evidence supports the involvement of neuronal nAChRs in cognitive functions. For example, selective-a7 agonists show efficacy in learning and memory tasks in animals 40 and a role of the a4b2-subunit in cognition is supported by KO and antagonist studies. 20 Thus, genetic variations in nAChRs that influence neurocognitive functions may affect smoking behavior through this mediation, as discussed above for personality traits.…”

“…39 a7-nAChRs may have a role in cognitive deficits in schizophrenia; in a small trial the a7-nicotinic agonist, anabaseine, appeared to have positive effects on neurocognition in patients with schizophrenia. 40 The use of nicotinic agonists or antagonists in these and other CNS disorders is under intense research. The neurobiology of ND The neurobiology of dependence on nicotine and other drugs of abuse is related to the brain limbic system.…”