Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625

Marquis, Karen L.; Comery, Thomas A.; Jow, Flora; Navarra, Rachel; Grauer, Steven M.; Pulicicchio, Claudine; Kelley, Cody; Brennan, Julie; Roncarati, Renza; Scali, Carla; Haydar, Simon N.; Ghiron, Chiara; Terstappen, Georg C.; Dunlop, John

doi:10.1007/s00213-011-2357-6

Cited by 19 publications

(8 citation statements)

References 29 publications

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“…Evidence from animal and human studies have indicated that α7 nAChRs may serve as a therapeutic targets for improving cognition, memory, and sensory gating deficits in schizophrenia (Bitner et al, 2007; Freedman et al, 2008; Hajos and Rogers, 2010; Marquis et al, 2011; Rezvani et al, 2009; Young and Geyer, 2013). Numerous α7 nAChR agonists have shown to exert procognitive effects in preclinical models and some of them are currently in clinical development for cognitive symptoms of schizophrenia.…”

Section: Resultsmentioning

confidence: 99%

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Parikh

Kutlu

Gould

2016

Schizophrenia Research

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Introduction The prevalence of tobacco use in the population with schizophrenia is enormously high. Moreover, nicotine dependence is found to be associated with symptom severity and poor outcome in patients with schizophrenia. The neurobiological mechanisms that explain schizophrenia-nicotine dependence comorbidity are not known. This study systematically reviews the evidence highlighting the contribution of nicotinic acetylcholine receptors (nAChRs) to nicotine abuse in schizophrenia. Methods Electronic data bases (Medline, Google Scholar, and Web of Science) were searched using the selected key words that match the aims set forth for this review. A total of 275 articles were used for the qualitative synthesis of this review. Results Substantial evidence from preclinical and clinical studies indicated that dysregulation of α7 and β2-subunit containing nAChRs account for the cognitive and affective symptoms of schizophrenia and nicotine use may represent a strategy to remediate these symptoms. Additionally, recent meta-analyses proposed that early tobacco use may itself increase the risk of developing schizophrenia. Genetic studies demonstrating that nAChR dysfunction that may act as a shared vulnerability factor for comorbid tobacco dependence and schizophrenia were found to support this view. The development of nAChR modulators was considered an effective therapeutic strategy to ameliorate psychiatric symptoms and to promote smoking cessation in schizophrenia patients. Conclusions The relationship between schizophrenia and smoking is complex. While the debate for the self-medication versus addiction vulnerability hypothesis continues, it is widely accepted that a dysfunction in the central nAChRs represent a common substrate for various symptoms of schizophrenia and comorbid nicotine dependence.

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Section: Resultsmentioning

confidence: 99%

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Parikh

Kutlu

Gould

2016

Schizophrenia Research

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“…The followup study, however, demonstrated that any contribution to antipsychotic activity through galantamine is primarily mediated via muscarinic, but not nicotinic, acetylcholine receptors (Wadenberg et al, 2011). Nevertheless, α7-nAChRs might also participate in antipsychotic activity because the α7-nAChR agonist WYE-103914/SEN34625 potentiated the efficacy profile of risperidone in the CAR test (Marquis et al, 2011). To our knowledge, WYE-103914/SEN34625 is the only α7-nAChR agent that has been tested in this model.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 86%

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats

et al. 2016

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“…Recent studies have identified α 7 nAChRs as therapeutic targets for improving cognition, memory, and gating deficits in schizophrenia (Bodnar et al , 2005; Olincy et al , 2006; Bitner et al , 2007; Freedman et al , 2008; Rezvani et al , 2009; Hajos and Rogers, 2010; Marquis et al , 2011). This study in rats suggests that activation of α 7 nAChRs may have the added benefit of curbing motivation to smoke cigarettes.…”

Section: Discussionmentioning

confidence: 99%

“…This study also questioned whether local infusion of a selective agonist of α 7 nAChRs, PNU 282987 (Bodnar et al , 2005), into the NAc shell and anterior cingulate cortex would lead to reductions in responding maintained by NIC during PR. The α 7 agonists are currently being explored as therapeutics to improve cognition, working memory, and sensory-gating deficits in schizophrenia (Bodnar et al , 2005; Olincy et al , 2006; Bitner et al , 2007; Freedman et al , 2008; Rezvani et al , 2009; Thomsen et al , 2009; Hajos and Rogers, 2010; Castner et al , 2011; Marquis et al , 2011). A positive finding would have implications for smoking cessation therapies in general.…”

Section: Introductionmentioning

confidence: 99%

Alpha7 Nicotinic Acetylcholine Receptors Modulate Motivation to Self-Administer Nicotine: Implications for Smoking and Schizophrenia

Brunzell

McIntosh

2011

Neuropsychopharmacol

101

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Individuals diagnosed with schizophrenia have an exceptionally high risk for tobacco dependence. Postmortem studies show that these individuals have significant reductions in α7 nicotinic acetylcholine receptors (nAChRs) in several brain areas. Decreased α7-mediated function might not only be linked to schizophrenia but also to increased tobacco consumption. The purpose of this study was to determine whether pharmacological blockade of α7 nAChRs would increase motivation of rats to intravenously self-administer nicotine (NIC) during a progressive ratio schedule of reinforcement (PR). Before PR, rats received local infusions of 0, 10, or 20 pmol of a selective α7 nAChR antagonist, α-conotoxin ArIB [V11L,V16D] (ArIB) into the nucleus accumbens (NAc) shell or the anterior cingulate cortex, brain areas that contribute to motivation for drug reward. We additionally sought to determine whether local infusion of 0, 10, or 40 nmol of a selective α7 nAChR agonist, PNU 282987, into these brain areas would decrease motivation for NIC use. Infusion of ArIB into the NAc shell and anterior cingulate cortex resulted in a significant increase in active lever pressing, breakpoints, and NIC intake, suggesting that a decrease in α7 nAChR function increases motivation to work for NIC. In contrast, PNU 282987 infusion resulted in reductions in these measures when administered into the NAc shell, but had no effect after administration into the anterior cingulate cortex. These data identify reduction of α7 nAChR function as a potential mechanism for elevated tobacco use in schizophrenia and also identify activation of α7 nAChRs as a potential strategy for tobacco cessation therapy.

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Preclinical assessment of an adjunctive treatment approach for cognitive impairment associated with schizophrenia using the alpha7 nicotinic acetylcholine receptor agonist WYE-103914/SEN34625

Abstract: These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.

Cited by 19 publications

References 29 publications

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

nAChR dysfunction as a common substrate for schizophrenia and comorbid nicotine addiction: Current trends and perspectives

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats

Alpha7 Nicotinic Acetylcholine Receptors Modulate Motivation to Self-Administer Nicotine: Implications for Smoking and Schizophrenia

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