Essential role of neocortical acetylcholine in spatial memory

Winkler, Jürgen; Suhr, Steven T.; Gage, Fred H.; Thal, Leon J.; Fisher, Lisa J.

doi:10.1038/375484a0

Cited by 275 publications

(113 citation statements)

References 27 publications

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“…Disruption of the septo-hippocampal and nucleus basalis of Meynart-cortical cholinergic projection pathways in animal models produce memory deficits that can be reversed by cholinergic supplementation strategies (eg physostigmine administration (Mandel et al, 1989) or ACh-producing cell grafts at the lesion site (Winkler et al, 1995). Memory impairment can be induced in healthy human subjects with scopolamine, while cholinomimetics drugs can enhance memory in healthy individuals (Sitaram et al, 1978).…”

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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“…ACh is released at the neuromuscular junction (NMJ), as well as at autonomic synapses, and also modulates a variety of central circuits that support arousal, attention, reward, learning, and memory (1)(2)(3)(4). Lethal deficits in cholinergic function occur with exposure to irreversible acetylcholinesterase (AChE) inhibitors (5).…”

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confidence: 99%

Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice

Ferguson

Bazalakova²,

Savchenko³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

150

132

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Presynaptic acetylcholine (ACh) synthesis and release is thought to be sustained by a hemicholinium-3-sensitive choline transporter (CHT). We disrupted the murine CHT gene and examined CHT؊͞؊ and ؉͞؊ animals for evidence of impaired cholinergic neurotransmission. Although morphologically normal at birth, CHT؊͞؊ mice become immobile, breathe irregularly, appear cyanotic, and die within an hour. Hemicholinium-3-sensitive choline uptake and subsequent ACh synthesis are specifically lost in CHT؊͞؊ mouse brains. Moreover, we observe a time-dependent loss of spontaneous and evoked responses at CHT؊͞؊ neuromuscular junctions. Consistent with deficits in synaptic ACh availability, we also observe developmental alterations in neuromuscular junction morphology reminiscent of changes in mutants lacking ACh synthesis. Adult CHT؉͞؊ mice overcome reductions in CHT protein levels and sustain choline uptake activity at wild-type levels through posttranslational mechanisms. Our results demonstrate that CHT is an essential and regulated presynaptic component of cholinergic signaling and indicate that CHT warrants consideration as a candidate gene for disorders characterized by cholinergic hypofunction.

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“…The atypical APDs, (Perry et al 1999) and working memory (Winkler et al 1995), and thus, may be important to either the cognitive dysfunction of schizophrenia or the ability of antipsychotic drugs (APDs) to improve some or all aspects of that cognitive deficit (Meltzer and McGurk 1999). The atypical APDs, clozapine, olanzapine, risperidone, and quetiapine, have, in fact, been reported to improve some domains of cognitive dysfunction (see Meltzer and McGurk 1999; Purdon 1999 for reviews), in addition to psychopathology (Leucht et al 1999) in schizophrenia, more so than typical APDs, e.g., haloperidol and phenothiazines.…”

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confidence: 99%

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

Ichikawa

2002

Neuropsychopharmacology

224

124

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The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, (Perry et al. 1999) and working memory (Winkler et al. 1995), and thus, may be important to either the cognitive dysfunction of schizophrenia or the ability of antipsychotic drugs (APDs) to improve some or all aspects of that cognitive deficit (Meltzer and McGurk 1999). The atypical APDs, clozapine, olanzapine, risperidone, and quetiapine, have, in fact, been reported to improve some domains of cognitive dysfunction (see Meltzer and McGurk 1999; Purdon 1999 for reviews), in addition to psychopathology (Leucht et al. 1999) in schizophrenia, more so than typical APDs, e.g., haloperidol and phenothiazines. The basis for these advantages is unclear.The atypical APDs share in common a relatively more potent antagonist action at serotonin (5-HT) 2A NO . 3 al. 1989;Schotte et al. 1996) and ␣ 1 -and ␣ 2 -adrenoceptors (Hertel et al. 1999). These features have been related to their ability to increase DA release in the mPFC (Hertel et al. 1999; Kuroki et al. 1999; Ichikawa et al. 2001). However, a possible role for ACh in mediating these effects is receiving increasing attention. Clozapine and olanzapine, but not risperidone, quetiapine, ziprasidone, or iloperidone (Schotte et al. 1996;Bymaster et al. 1999), have significant direct agonist or antagonist effects upon various subtypes of muscarinic ACh receptors (mAChRs) (Tandon 1999), whereas the typical APDs, thioridazine and mesoridazine, are also potent mAChR antagonists (Niedzwiecki et al. 1989a,b;Bolden et al. 1992). Furthermore, trihexyphenidyl and biperiden (Bolden et al. 1992), mAChR antagonists which reduce typical APD-induced extrapyramidal symptoms (EPS), have been reported to cause complex clinical effects in patients with schizophrenia, e.g., working memory impairment (King 1990) and worsening of psychosis while decreasing negative symptoms (Tandon et al. 1992). It is possible that clozapine and olanzapine influence clinical symptoms in schizophrenia via a direct effect upon main cholinergic transmission (Zorn et al. 1994; Bymaster et al. 1996).As has been demonstrated in rodents (Everitt and Robbins 1997) and primates (Mrzljak et al. 1995), the nucleus basalis magnocellularis (NBM) or the basal forebrain consisting of the substantia innominata, the nucleus of Meynert, and the horizontal limb of the diagonal band, project cholinergic neurons to the cortex, whereas cholinergic interneurons exist mostly in the striatum (STR) and nucleus accumbens (NAC) (Kawaguchi et al. 1995). These three regions are involved in various actions of APDs (Ichikawa and Meltzer 1999): 1) the medial prefrontal cortex (mPFC) has been suggested to be involved in the neural circuitry important for negative symptoms and cognition, e.g., working memory (Goldman-Rakic and Selemon 1997); 2) the STR is centrally involved in motor function; and 3) the NAC plays a key ...

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Essential role of neocortical acetylcholine in spatial memory

Cited by 275 publications

References 27 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

Lethal impairment of cholinergic neurotransmission in hemicholinium-3-sensitive choline transporter knockout mice

Atypical, but Not Typical, Antipsychotic Drugs Increase Cortical Acetylcholine Release without an Effect in the Nucleus Accumbens or Striatum

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