Physostigmine and cognition in schizotypal personality disorder

Kirrane, Richelle; Mitropoulou, Vivian; Nunn, Melissa; Silverman, Jeremy M.; Siever, Larry J.

doi:10.1016/s0920-9964(00)00059-1

Cited by 33 publications

(20 citation statements)

References 22 publications

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“…It therefore seems logical that activation of the muscarinic/cholinergic pathways in the CNS would be an effective approach to reversing the cognitive deficits in schizophrenia. This approach is supported by recent studies using acetylcholinesterase inhibitors to increase acetylcholine levels in the CNS that have resulted in improved cognitive function in schizophrenia (Buchanan et al, 2003) and schizotypal personality disorder (Kirrane et al, 2001). Conversely, anticholinergic agents that block muscarinic receptors impair cognitive function in subjects with schizophrenia (Minzenberg et al, 2004).…”

Section: Sirmentioning

confidence: 94%

M1 Receptor Agonism, a Possible Treatment for Cognitive Deficits in Schizophrenia

Dean

2004

Neuropsychopharmacol

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SirThe recent report in this journal of a decrease in [ 3 H]pirenzepine binding in Brodmann's area (BA) 24 from subjects with schizophrenia (Zavitsanou et al, 2004) adds to a growing body of evidence that implicates muscarinic receptors in the pathology of schizophrenia (Dean et al, 2003). The significance of these most recent data on [ 3 H]pirenzepine binding is that they show that changes in M1/M4 receptors have some diagnostic specificity as they are not present in bipolar disorder or major depression.Studies of muscarinic receptors in schizophrenia have advanced to allow interpretation of [ 3 H]pirenzepine binding to go beyond simple commentary on changes in M1/M4 receptors in schizophrenia. Of significance to findings on cortical [ 3 H]pirenzepine binding are recent data showing that a decrease in binding of that radioligand in BA 9 from subjects with schizophrenia was associated with a decrease in M1, but not M4, receptor protein and mRNA (Dean et al, 2002). It is therefore intriguing to postulate that decreased [ 3 H]pirenzepine binding in the cortex from subjects with schizophrenia is reflective of widespread decreases in levels of M1 receptors. This hypothesis is supported by a study that has shown a decrease in mRNA for the M1 receptor in BA 6 from subjects with schizophrenia (Mancama et al, 2003).One of the problems in post-mortem CNS studies in schizophrenia is translating findings on changes in receptor densities to functional outcomes relating to the symptoms of the disorder. In the case of the M1 receptor, it is significant that one of the prominent features of M1 receptor knockout mice is that they show abnormalities in cognitive-related behavior (Anagnostaras et al, 2003). This suggests that the M1 receptor has a significant role in maintaining normal cognitive function; this is especially significant given that subjects with schizophrenia have cognitive deficits (Pantelis et al, 1999) and low levels of cortical M1 receptors (Dean et al, 2002). The hypothesis that deficits in cortical M1 receptors may be related to cognitive deficits in schizophrenia has been further advanced by a recent study that showed that a C267C genotype at a A276C single-nucleotide polymorphism in the M1 receptor gene was associated with poor cognitive function in subjects with schizophrenia (Liao et al, 2003). Importantly, the C267C genotype was not associated with either schizophrenia or the severity of positive and negative symptoms. It would therefore seem that the M1 receptor is likely to play an important role in the genesis of cognitive deficits in schizophrenia.Radioligands specific to the M1 receptor that can be used in neuroimaging have yet to be developed. However, a decrease in [ 3 H]QNB binding to the global family of muscarinic receptors has been demonstrated in the prefrontal cortex, and other CNS regions, in drug-free subjects with schizophrenia using single photon emission tomography (Raedler et al, 2003). These data, plus data from post-mortem studies, strongly suggest there is a decrease in M1 receptors...

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Section: Sirmentioning

confidence: 94%

M1 Receptor Agonism, a Possible Treatment for Cognitive Deficits in Schizophrenia

Dean

2004

Neuropsychopharmacol

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“…It has been shown, for instance, that the acetylcholinesterase inhibitor physostigmine, which leads to a general enhancement of cholinergic function, has a positive impact on working memory (Furey et al 1997;Kirrane et al 2001).…”

Section: Working Memory-studies In Humansmentioning

confidence: 99%

Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings

et al. 2011

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“…For example, mAChR and nAChR antagonists, such as scopolamine and mecamylamine, have shown potent amnesiac properties in animals and humans (Domer and Schuller, 1960;Pazzagli and Pepeu, 1965;Rusted and Warburton, 1988;Decker and Majchrzak, 1992;Newhouse et al, 1992Newhouse et al, , 1994Terry et al, 1996), whereas mAChR and nAChR agonists and acetylcholinesterase inhibitors (AChEIs) have augmented normal cognition and/or ameliorated impairments induced by lesions of cholinergic circuitry or antagonism of cholinergic receptors (Aigner and Mishkin, 1986;Elrod et al, 1988;Rupniak et al, 1989;Matsuoka et al, 1991;Levin et al, 1998Levin et al, , 2006Newhouse et al, 2004;Sarter et al, 2009). Furthermore, mAChR and nAChR antagonists have exacerbated existing positive and cognitive symptoms in schizophrenic patients and/or induced psychosis in normal human volunteers (Harington and Kincaid-Smith, 1958;Osterholm and Camoriano, 1982;Hamborg-Petersen et al, 1984;Tandon et al, 1991), whereas mAChR and nAChR agonists and AChEIs have improved certain aspects of the positive and/or negative symptoms, and attentional and memoryrelated deficits (Janowsky et al, 1973;Smith et al, 2006;Harris et al, 2004;Edelstein et al, 1981;Kirrane et al, 2001;Shekhar et al, 2008). Overall, these preclinical and clinical findings support the hypothesis that imbalances in mAChR and/or nAChR signaling may underlie the symptoms associated with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

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Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

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Physostigmine and cognition in schizotypal personality disorder

Cited by 33 publications

References 22 publications

M1 Receptor Agonism, a Possible Treatment for Cognitive Deficits in Schizophrenia

M1 Receptor Agonism, a Possible Treatment for Cognitive Deficits in Schizophrenia

Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

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