Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release.
The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5-HT6 receptor antagonists led us to study the relationship between 5-HT6 receptors and cholinergic neurotransmission. A selective cholinergic lesion, induced by injection of the immunotoxin 192-IgG-Saporin into the nucleus basalis magnocellularis, failed to alter the density of 5-HT6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5-HT6 receptors are not located on cholinergic neurons. The 5-HT6 receptor antagonist SB-357134 (0.001-1 microM) induced a concentration-dependant K+-evoked [3H]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB-357134, up to 1 microM, stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 microM) blocked the SB-357134-induced K+-stimulated [3H]ACh release, and simultaneous administration of MK-801 (1 microM) and SB-357134 (0.05 microM) elicited an increase in K+-evoked ACh release. In the striatum, SB-357134, 1 microM, decreased dopamine release, and the increase in K+-evoked [3H]ACh release induced by 5-HT6 receptor blockade was reversed by the D1 receptor antagonist, SCH23390 (1 microM). In both the frontal cortex and striatum, bicuculline, 1 microM, showed no effect on SB-357134-evoked [3H]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5-HT6 receptor functions.
Marcos
Beatriz
B
Department of Pharmacology, School of Medicine, University of Navarra, Pamplona, Spain.
Gil-Bea
Francisco J
FJ
Hirst
Warren D
WD
García-Alloza
Mónica
M
Ramírez
María J
MJ
D000109:Acetylcholine / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001921:Brain / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018678:Cholinergic Agents / Q000008:administration & dosage; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000922:Immunotoxins / Q000008:administration & dosage; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D009699:N-Glycosyl Hydrolases; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000145:classification / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013449:Sulfonamides / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism; D000096926:Benzenesulfonamides
D000109:Acetylcholine; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D000922:Immunotoxins; D009699:N-Glycosyl Hydrolases; D018377:Neurotransmitter Agents; D010879:Piperazines; D011188:Potassium; D011985:Receptors, Serotonin; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013449:Sulfonamides; D014316:Tritium; C085696:192 IgG-saporin; C422502:N-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide; D000096926:Benzenesulfonamides; C097216:serotonin 6 receptor