The cholinergic system, sigma-1 receptors and cognition.
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 β-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.
van Waarde
Aren
A
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. a.van.waarde@ngmb.umcg.nl
Ramakrishnan
Nisha K
NK
Rybczynska
Anna A
AA
Elsinga
Philip H
PH
Ishiwata
Kiichi
K
Nijholt
Ingrid M
IM
Luiten
Paul G M
PG
Dierckx
Rudi A
RA
D000109:Acetylcholine / Q000502:physiology; D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002799:Cholinergic Fibers / Q000502:physiology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D016202:N-Methylaspartate / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology / Q000627:therapeutic use*; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D000097605:Sigma-1 Receptor
D000109:Acetylcholine; D002118:Calcium; D018698:Glutamic Acid; D016202:N-Methylaspartate; D011619:Psychotropic Drugs; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor