Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists

Friedman, Joseph I.

doi:10.1007/s00213-004-1794-x

Cited by 173 publications

(114 citation statements)

References 82 publications

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“…123 In a similar approach, cholinesterase inhibitors have been assessed as a potential treatment to improve cognitive deficits in schizophrenia. 124 Most studies have so far used donepezil as an add-on medication in the treatment of schizophrenia ( Table 2). The addition of donepezil (5 mg) to the standard antipsychotic treatment in a small cohort of elderly subjects with schizophrenia was shown to cause a modest improvement in cognitive measurements.…”

Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 99%

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

249

211

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Although the neurotransmitter dopamine plays a prominent role in the pathogenesis and treatment of schizophrenia, the dopamine hypothesis of schizophrenia fails to explain all aspects of this disorder. It is increasingly evident that the pathology of schizophrenia also involves other neurotransmitter systems. Data from many streams of research including preclinical and clinical pharmacology, treatment studies, post-mortem studies and neuroimaging suggest an important role for the muscarinic cholinergic system in the pathophysiology of schizophrenia. This review will focus on evidence that supports the hypothesis that the muscarinic system is involved in the pathogenesis of schizophrenia and that muscarinic receptors may represent promising novel targets for the treatment of this disorder.

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Section: Use Of Cholinesterase Inhibitors In Schizophreniamentioning

confidence: 99%

Towards a muscarinic hypothesis of schizophrenia

Raedler

Bymaster

Tandon³

et al. 2006

Mol Psychiatry

249

211

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“…Furthermore, in the M 1 mAChR knockout mouse, the induction of hippocampal long-term potentiation, synaptic plasticity, and learning and working memory are impaired (Anagnostaras et al, 2003;Wess, 2004;Shinoe et al, 2005). Therefore, M 1 mAChR activation offers a novel approach to potentially treat cognitive impairment in diseases such as Alzheimer's disease and, more recently, schizophrenia (Friedman, 2004).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

Langmead

Austin

Branch

et al. 2008

British J Pharmacology

122

137

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Background and purpose: M 1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtypeselective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-nbutyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M 1 mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. Experimental approach: In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. Key results: Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M 1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M 1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. Conclusions and implications: These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M 1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M 1 mAChR. (2008) 154, 1104-1115 doi:10.1038/bjp.2008 published online 5 May 2008 Keywords: muscarinic receptors; selective agonist; allosteric; AC-42; 77-LH-28-1; calcium mobilization; inositol phosphate; cell firing; network oscillations There is a wide array of pharmacological tools with which to study mAChRs. For example, N-methyl scopolamine, quinuclidinylbenzilate, pirenzepine and darifenacin are among numerous mAChR antagonists, and ACh and oxotremorine-M among mAChR agonists, which have been used in unlabelled and radiolabelled forms to characterize the localization, pharmacology and function of mAChRs. Unfortunately, most of these pharmacological tools exhibit poor selectivity between mAChR subtypes (Caulfield and Birdsall, 1998;Ellis, 2002). Those agents that do display high degrees of mAChR subtype selectivity are few in number and when discovered are often shown to interact with an allosteric, rather than the orthosteric, site as exemplified by the highly selective M 1 receptor peptide antagonist MT-7 (muscarinic toxin 7; Olianas et al., 2000). British Journal of PharmacologyTherefore, the identification of selective M 1 mAChR agonists would represent a significant advance in mAChR pharmacology and could offer t...

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“…Antipsychotic drugs (APDs), although effective in ameliorating positive symptoms, have limited efficacy in improving negative/cognitive symptoms (Buchanan et al, 2007;Miyamoto et al, 2005). In recent years, therapeutic strategies have focused on enhancing the function of the cholinergic system, because of its central role in cognition and evidence of cholinergic dysfunction in schizophrenia (Friedman, 2004;Raedler et al, 2007;Sarter et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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

Barak

Arad

Levie

et al. 2009

Neuropsychopharmacol

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Schizophrenia symptoms can be segregated into positive, negative and cognitive, which exhibit differential sensitivity to drug treatments. Accumulating evidence points to efficacy of a7 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 a7 nAChR partial agonist SSR180711 using the latent inhibition (LI) model. LI is the reduced efficacy of a previously nonreinforced 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 a7-nAChR agonists. In addition, unexpectedly, SSR180711 (1, 3 mg/kg, i.p.) potentiated LI with strong conditioning in nodrug 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.

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Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists

Cited by 173 publications

References 82 publications

Towards a muscarinic hypothesis of schizophrenia

Towards a muscarinic hypothesis of schizophrenia

Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1

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

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Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists

Cited by 173 publications

References 82 publications

Towards a muscarinic hypothesis of schizophrenia

Towards a muscarinic hypothesis of schizophrenia

Characterization of a CNS penetrant, selective M1muscarinic receptor agonist, 77‐LH‐28‐1

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

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Characterization of a CNS penetrant, selective M₁muscarinic receptor agonist, 77‐LH‐28‐1