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Muscarinic Receptors pp 121–166Cite as

Muscarinic Receptor Pharmacology and Circuitry for the Modulation of Cognition

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 208))

Abstract

The muscarinic cholinergic system constitutes an important part of the neuronal circuitry that modulates normal cognition. Muscarinic receptor antagonists are well known to produce or exacerbate impairments in attention, learning, and memory. Conversely, both direct-acting muscarinic receptor agonists and indirect-acting muscarinic cholinergic agonists, such as acetylcholinesterase inhibitors, have shown cognition-enhancing properties, including improvements in normal cognitive function, reversal of cognitive deficits induced by muscarinic receptor antagonists, and attenuation of cognitive deficits in psychiatric and neurological disorders, such as Alzheimer’s disease and schizophrenia. However, until recently, the lack of small molecule ligands that antagonize or activate specific muscarinic acetylcholine receptor (mAChR) subtypes with high selectivity has been a major obstacle in defining the relative contributions of individual mAChRs to different aspects of cognitive function and for the development of novel therapeutic agents. These limitations may be potentially overcome by the recent discovery of novel mAChR subtype-selective compounds, notably allosteric agonists and positive allosteric modulators, which exhibit greater selectivity for individual mAChR subtypes than previous mAChR orthosteric agonists. In preclinical studies, these novel ligands have shown promising efficacy in several models for the enhancement of cognition. In this chapter, we will review the muscarinic cholinergic circuitry and pharmacology of mAChR agonists and antagonists relevant to the modulation of different aspects of cognition in animals and clinical populations.

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Abbreviations

AC:

Adenylyl cyclase

ACh:

Acetylcholine

AChEIs:

Acetylcholinesterase inhibitors

AD:

Alzheimer’s disease

ADAS-cog:

Alzheimer’s Disease assessment scale-cognitive

AMG:

Amygdala

BQCA:

Benzylquinolone carboxylic acid

cAMP:

Cyclic adenosine monophosphate

cc:

Corpus callosum

CGI:

Clinical Global Impression scale

CNS:

Central nervous system

CP:

Caudate-putamen

CSF:

Cerebrospinal fluid

DA:

Dopamine

DBB:

Diagonal band of Broca

EC:

Entorhinal cortex

EEG:

Electrocephalogram

EPSC:

Excitatory postsynaptic current

GABA:

γ-aminobutyric acid

HPC:

Hippocampus

IP3:

Inositol triphosphate

KO:

Knockout

LDTg:

Laterodorsal tegmental nucleus

M1–M5:

Muscarinic receptor subtypes M1 through M5

mAChRs:

Muscarinic acetylcholine receptors

(m)PFC:

(Medial) prefrontal cortex

NAM:

Negative allosteric modulator

NAS:

Nucleus accumbens

NBM:

Nucleus basalis of Meynert

NMDA:

N-methyl-d-aspartate

OB:

Olfactory bulb

PAM:

Positive allosteric modulator

PANSS:

Positive and negative syndrome scale

PLC:

Phospholipase C

PPI:

Prepulse inhibition

PPTg:

Pedunculopontine tegmental nucleus

SN:

Substantia nigra

TBPB:

1-(1’-2-methylbenzyl)-1,4’-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one

THAL:

Thalamus

VTA:

Ventral tegmental area

WT:

Wildtype

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Authors and Affiliations

  1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, 37232, USA

    Michael Bubser, Nellie Byun, Michael R. Wood & Carrie K. Jones

  2. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA

    Michael Bubser, Nellie Byun, Michael R. Wood & Carrie K. Jones

  3. Department of Chemistry, Vanderbilt University, Nashville, TN, 37232, USA

    Michael R. Wood

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  1. Michael Bubser
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  2. Nellie Byun
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  4. Carrie K. Jones
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Correspondence to Carrie K. Jones .

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  1. UHN67, Department of Pulmonary and Critical Ca, Oregon Health & Science University, SW Sam Jackson Park Road 3181, Portland, 97239, Oregon, USA

    Allison D. Fryer

  2. , Department of Pharmacology, Monash Institute of Pharmaceutical Scien, Royal Parade 381, Parkville, 3052, Victoria, Australia

    Arthur Christopoulos

  3. , Department of Pharmacology, University of Washington, Seattle, 98195-7750, Washington, USA

    Neil M. Nathanson

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Bubser, M., Byun, N., Wood, M.R., Jones, C.K. (2012). Muscarinic Receptor Pharmacology and Circuitry for the Modulation of Cognition. In: Fryer, A., Christopoulos, A., Nathanson, N. (eds) Muscarinic Receptors. Handbook of Experimental Pharmacology, vol 208. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23274-9_7

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