Contribution of nicotinic receptors to the function of synapses in the central nervous system: the action of choline as a selective agonist of alpha 7 receptors.
The alpha 7-nicotinic receptor (nAChR)-selective agonist choline and nAChR-subtype-selective antagonists led to the discovery that activation of both alpha 7 and alpha 4 beta 2 nAChRs located in CA1 interneurons in slices taken from the rat hippocampus facilitates the tetrodotoxin (TTX)-sensitive release of gamma-aminobutyric acid (GABA). Experiments carried out in cultured hippocampal neurons not only confirmed that preterminal alpha 7 and alpha 4 beta 2 nAChRs modulate the TTX-sensitive release of GABA, but also demonstrated that evoked release of GABA is reduced by rapid exposure of the neurons to acetylcholine (ACh, 10 microM-1 mM) in the presence of the muscarinic receptor antagonist atropine (1 microM). This effect of ACh, which is fully reversible and concentration-dependent, is partially blocked by superfusion of the cultured neurons with external solution containing either the alpha 7-nAChR-selective antagonist methyllycaconitine (MLA, 1 nM) or the alpha 4 beta 2-nAChR-selective antagonist dihydro-beta-erythroidine (DH beta E, 100 nM). A complete blockade of ACh-induced reduction of evoked release of GABA was achieved only when the neurons were perfused with external solution containing both MLA and DH beta E, suggesting that activation of both alpha 7 and alpha 4 beta 2 nAChRs modulates the evoked release of GABA from hippocampal neurons. Such mechanisms may account for the apparent involvement of nAChRs in the psychological effects of tobacco smoking, in brain disorders (e.g., schizophrenia and epilepsy), and in physiological processes, including cognition and nociception.
Albuquerque
E X
EX
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA.
Pereira
E F
EF
Braga
M F
MF
Alkondon
M
M
D000818:Animals; D002478:Cells, Cultured; D002794:Choline / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D002794:Choline