The cholinergic system, sigma-1 receptors and cognition

Aren van Waarde*, Nisha K. Ramakrishnan, Anna A. Rybczynska, Philip H. Elsinga, Kiichi Ishiwata, Ingrid M. Nijholt, Paul G. M. Luiten, Rudi A. Dierckx

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

62 Citations (Scopus)
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Abstract

This article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of beta-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescent-accelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress. (C) 2010 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)543-554
Number of pages12
JournalBehavioral Brain Research
Volume221
Issue number2
DOIs
Publication statusPublished - 10-Aug-2011

Keywords

  • Acetylcholine
  • Cholinergic system
  • Cognition
  • Sigma-1 receptors
  • Memory
  • Anti-amnesic effects
  • Sigma-1 agonists
  • Neurodegenerative disease
  • METHYL-D-ASPARTATE
  • LONG-TERM POTENTIATION
  • INDUCED NEURITE OUTGROWTH
  • RAT HIPPOCAMPAL SLICES
  • AMINOTETRAHYDROFURAN DERIVATIVE ANAVEX1-41
  • EXTRACELLULAR ACETYLCHOLINE LEVEL
  • PASSIVE-AVOIDANCE PERFORMANCE
  • SPONTANEOUS GLUTAMATE RELEASE
  • POSITRON-EMISSION-TOMOGRAPHY
  • INDUCED LEARNING IMPAIRMENT

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