Cortical Acetylcholine, Reality Distortion, Schizophrenia, and Lewy Body Dementia: Too Much or Too Little Cortical Acetylcholine?

Sarter, Martin; Bruno, John P.

doi:10.1006/brcg.1998.1035

Cited by 61 publications

(35 citation statements)

References 111 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimer's disease (Cummings and Benson, 1987) and has also been postulated to contribute to the cognitive deficits of various neuropsychiatric disorders, including schizophrenia (Tandon and Greden, 1989;Sarter and Bruno, 1998). There are five known (M 1 -M 5 ) muscarinic acetylcholine receptors in the human genome (Kubo et al, 1986;Bonner et al, 1987;Brann et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

Zhu

Huang

Ichikawa

et al. 2005

Neuropsychopharmacol

129

View full text Add to dashboard Cite

The active moiety of clozapine, the prototypical antipsychotic drug, consists of clozapine and its major metabolite, N-desmethylclozapine (NDMC). Previous studies have suggested that NDMC may be more important than the patent compound itself for the improvement in cognition in patients with schizophrenia treated with clozapine. While the pharmacology of clozapine and NDMC are similar in most respects, NDMC has been shown to be an M 1 muscarinic receptor partial agonist whereas clozapine is an M 1 antagonist in vitro and in vivo. We hypothesized that NDMC may improve cognition by increasing dopamine (DA) and acetylcholine (ACh) release in medial prefrontal cortex (mPFC) via direct stimulation of M 1 receptors, whereas both NDMC and clozapine itself would do so by other mechanisms as well, and that clozapine would inhibit the M1 agonist effect of NDMC. In the present study, using microdialysis in awake, freely moving rats, we found that NDMC at doses of 10 and 20, but not 5 mg/kg, significantly increased DA and ACh release in the mPFC and HIP, but not in the nucleus accumbens (NAC). The M 1 -preferring antagonist, telenzepine (3 mg/kg), completely blocked NDMC (10 mg/kg)-induced increases in cortical DA and ACh release. Clozapine (1.25 mg/kg), which by itself had no effect on DA or ACh release in the cortex, blocked NDMC (10 mg/kg)-induced ACh, but not DA, release in the mPFC. The 5-HT 1A receptor antagonist, WAY100635 (0.2 mg/kg) blocked NDMC (20 mg/kg)-induced cortical DA but not ACh release. These findings suggest that: (1) NDMC is an M 1 agonist while clozapine is an M 1 antagonist in vivo; (2) M 1 agonism of NDMC can contribute to the release of cortical ACh and DA release; (3) NDMC, because of its M 1 agonism, may more effectively treat the cognitive impairments observed in schizophrenia than clozapine itself; and (4) M 1 receptor agonism may be a valuable target for the development of drugs that can improve cognitive deficit in schizophrenia, and perhaps other neuropsychiatric disorders as well.

show abstract

Section: Introductionmentioning

confidence: 99%

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

Zhu

Huang

Ichikawa

et al. 2005

Neuropsychopharmacol

129

View full text Add to dashboard Cite

show abstract

“…Combining fMRI data of all time points, we found an increase in connectivity with the visual network which was mostly associated with effects on T = 6 h. The medial and lateral cholinergic pathways, originating from Meynert's basal nucleus, supply a large portion of the brain and merge in the posterior occipital lobe [Selden et al, 1998]. In dementia and schizophrenia, it is hypothesized that cholinergic dysregulation is responsible for psychotic manifestations and AChEIs have been successfully used for treatment of visual hallucinations [Bentley et al, 2008; Sarter and Bruno, 1998]. ACh release in the primary visual cortex is increased during visual stimulation pointing to ACh as influencing visual processing and learning mechanisms [Dotigny et al, 2008; Kang et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

Time related effects on functional brain connectivity after serotonergic and cholinergic neuromodulation

Klaassens

Rombouts

Winkler

et al. 2016

Human Brain Mapping

View full text Add to dashboard Cite

Psychopharmacological research, if properly designed, may offer insight into both timing and area of effect, increasing our understanding of the brain's neurotransmitter systems. For that purpose, the acute influence of the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was repeatedly measured in 12 healthy young volunteers with resting state functional magnetic resonance imaging (RS‐fMRI). Eighteen RS‐fMRI scans were acquired per subject during this randomized, double blind, placebo‐controlled, crossover study. Within‐group comparisons of voxelwise functional connectivity with 10 functional networks were examined (P < 0.05, FWE‐corrected) using a non‐parametric multivariate approach with cerebrospinal fluid, white matter, heart rate, and baseline measurements as covariates. Although both compounds did not change cognitive performance on several tests, significant effects were found on connectivity with multiple resting state networks. Serotonergic stimulation primarily reduced connectivity with the sensorimotor network and structures that are related to self‐referential mechanisms, whereas galantamine affected networks and regions that are more involved in learning, memory, and visual perception and processing. These results are consistent with the serotonergic and cholinergic trajectories and their functional relevance. In addition, this study demonstrates the power of using repeated measures after drug administration, which offers the chance to explore both combined and time specific effects. Hum Brain Mapp 38:308–325, 2017. © 2016 Wiley Periodicals, Inc.

show abstract

“…Indeed, the potential importance of aberrant cholinergic signaling has already been suggested as a possible mechanism in the development of schizophrenia: schizophrenics exhibit increased use of nicotine (Lohr and Flynn 1992), altered interactions between cholinergic and glutamatergic synapses (Timofeeva and Levin 2011), and abnormal regulation of cholinergic activity that may be related to hallucinations (Sarter and Bruno 1998). In addition, several animal models of schizophrenia, including adolescent delivery of kynurenic acid (an ␣7-nicotinic receptor antagonist and glycine-site NMDA antagonist) (Akagbosu et al 2010;Trecartin and Bucci 2011) and neonatal ventral hippocampal lesions (Alexander et al 2009;Brooks et al 2011), implicate disrupted cholinergic signaling as a key factor in abnormal neurodevelopment.…”

Section: Discussionmentioning

confidence: 99%

Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

Ramanathan

Conner

Anilkumar

et al. 2015

Journal of Neurophysiology

View full text Add to dashboard Cite

Ramanathan DS, Conner JM, Anilkumar AA, Tuszynski MH. Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits. J Neurophysiol 113: 1585-1597, 2015. First published December 10, 2014 doi:10.1152/jn.00408.2014.-Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia.

show abstract

Cortical Acetylcholine, Reality Distortion, Schizophrenia, and Lewy Body Dementia: Too Much or Too Little Cortical Acetylcholine?

Cited by 61 publications

References 111 publications

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic Receptors

Time related effects on functional brain connectivity after serotonergic and cholinergic neuromodulation

Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

Contact Info

Product

Resources

About