Decreased protein level of nicotinic receptor α7 subunit in the frontal cortex from schizophrenic brain

Guan, Zhi‐Zhong; Zhang, Xiao; Blennow, Kaj; Nordberg, Agneta

doi:10.1097/00001756-199906030-00028

Cited by 264 publications

(157 citation statements)

References 10 publications

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“…Decreases in muscarinic receptor availability has been further shown in the cortex, basal ganglia, and thalamus of living unmedicated patients compared with a matched control group, using [ 123 I]iodoquinuclidinyl benzilate single positron emission computed tomography (Raedler et al, 2003). Decreased binding of a-bungarotoxin (Freedman et al, 1995) or decreased immunoreactivity to a(7) nicotinic acetylcholine receptors (nAChR) (Guan et al, 1999) in postmortem hippocampal and cortical tissue from patients with schizophrenia in comparison to matched controls also implicate this receptor subtype in the neuropathophysiology of schizophrenia. Studies in smokers with and without schizophrenia have further indicated a role for the a(4)b(2) nAChR.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: Significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Keefe

Malhotra

Meltzer

et al. 2007

Neuropsychopharmacol

134

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Altered expression of central muscarinic and nicotinic acetylcholine receptors in hippocampal and cortical regions may contribute to the cognitive impairment exhibited in patients with schizophrenia. Increasing cholinergic activity through the use of a cholinesterase inhibitor (ChEI) therefore represents a possible strategy for cognitive augmentation in schizophrenia. We examined the efficacy and safety of the ChEI donepezil as cotreatment for mild to moderate cognitive impairment in schizophrenia or schizoaffective disorder in a prospective, 12-week, placebo-controlled, double-blind, parallel-group study. In total, 250 patients (18-55 years) with schizophrenia or schizoaffective disorder who were clinically stabilized on risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole, alone or in combination, were enrolled at 38 outpatient psychiatric clinics in the United States. Patients were randomized to donepezil 5 mg q.d. for 6 weeks then 10 mg q.d. for 6 weeks, or placebo administered as oral tablets. The primary outcome measure was the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) neurocognitive battery composite score. In the intent-to-treat sample (donepezil, n ¼ 121; placebo, n ¼ 124), both treatments showed improvement in the composite score from baseline to week 12. At week 12, cognitive improvement with donepezil was similar to that with placebo (last-observation-carried-forward effect size, 0.277 vs 0.411; p ¼ 0.1182) and statistically significantly inferior for the observed-cases analysis (0.257 vs 0.450; p ¼ 0.044). There was statistically significant improvement in the Positive and Negative Syndrome Assessment Scale negative symptoms score for placebo compared with donepezil, while total and positive symptom scores were similar between both treatments. Statistically significant improvements in positive symptoms score and Clinical Global Impression-Improvement for donepezil compared with placebo were noted at Week 6. Treatment-emergent adverse events (AEs) were observed for 54.5% of donepezil-and 61.3% of placebo-treated patients; most AEs were rated as mild to moderate in severity. Donepezil was safe and well-tolerated but was not effective compared with placebo as a cotreatment for the improvement of cognitive impairment in this patient population. A significant and surprisingly large placebo/practice effect was observed among placebotreated patients, and is a serious consideration in future clinical trial study designs for potential cognitive enhancing compounds in schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: Significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Keefe

Malhotra

Meltzer

et al. 2007

Neuropsychopharmacol

134

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“…In addition to the deficits in P50 evoked potentials and the functional promoter polymorphisms in the CHRNA7 region, people with schizophrenia also have abnormalities in expression and regulation of central nicotinic cholinergic receptors. Decreased α7 nicotinic cholinergic receptor binding has been noted in the reticular nucleus of the thalamus, the hippocampus, the cingulate cortex and the frontal lobe regions [49,50,51,52].…”

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confidence: 99%

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

Olincy

Stevens

2007

Biochemical Pharmacology

125

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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

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“…Patients with schizophrenia have a deficiency of α7 nicotinic receptors in the hippocampus and frontal cortex [29,30]. In particular, α7 receptors in the hippocampus appear to be important for the cognitive impairment [31][32][33].…”

Section: Nicotinic Systems and The Cognitive Impairment Of Schizophreniamentioning

confidence: 99%

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

Levin

Rezvani

2007

Biochemical Pharmacology

108

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People with schizophrenia often have substantial cognitive impairments, which may be related to nicotinic receptor deficits, (α7 and α4β2), documented in the brains of people with schizophrenia. The large majority of people with schizophrenia smoke cigarettes. Thus, nicotinic interactions with antipsychotic drugs are widespread. Complementary co-therapies of novel nicotinic ligands are being developed to add to antipsychotic therapy to treat the cognitive impairment of schizophrenia. Thus, it is critical to understand the interaction between nicotinic treatments and antipsychotic drugs. Nicotinic interactions with antipsychotic drugs, are complex since both nicotine and antipsychotics have complex actions. Nicotine stimulates and desensitizes nicotinic receptors of various subtypes and potentiates the release of different neurotransmitters. Antipsychotics also act on a verity of receptor systems. For example, clozapine acts as an antagonist at a variety of neurotransmitter receptors such as those for dopamine, serotonin, norepinepherine and histamine. In a series of studies, we have found that in normally functioning rats, moderate doses of clozapine impair working memory and that clozapine blocks nicotine-induced memory and attentional improvement. Clozapine and nicotine can attenuate each other's beneficial effects in reversing the memory impairment caused by the psychototmimetic drug dizocilpine. A key to the clozapine-induced attenuation of nicotineinduced cognitive improvement appears to be its 5HT 2 antagonist properties. The selective 5HT 2 antagonist ketanserin has a similar action of blocking nicotine-induced memory and attentional improvements. It is important to consider the interactions between nicotinic and antipsychotic drugs to develop the most efficacious treatment for cognitive improvement in people with schizophrenia.

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Decreased protein level of nicotinic receptor α7 subunit in the frontal cortex from schizophrenic brain

Cited by 264 publications

References 10 publications

Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: Significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: Significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial

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

Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function

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