Positive modulation of α7 nAChR responses in rat hippocampal interneurons to full agonists and the α7-selective partial agonists, 4OH-GTS-21 and S 24795

NEUROPHARMACOLOGY

卷:56

Article

Lopez-Hernandez, Gretchen Y.¹  Thinschmidt, Jeffrey S.¹  Morain, Philippe²  Trocme-Thibierge, Caryn²  Kem, William R.¹  Soti, Ferenc¹  Papke, Roger L.¹ 

[1] Univ Florida, Dept Therapeut & Pharmacol, Coll Med, Gainesville, FL 32610 USA

[2] Inst Rech Int Servier, F-92415 Courbevoie, France

关键词: Brain slices;    Patch-clamp;    nAChRs;    Partial agonists;    Full agonists;    Hippocampus;    Positive allosteric modulators;   

DOI  :  10.1016/j.neuropharm.2009.01.011

来源: Elsevier

【 摘 要 】

One approach for the identification of therapeutic agents for Alzheimer's disease has focused on the research of alpha 7 nAChR-selective agonists such as the partial agonists 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21) and, more recently, 2-[2-(4-bromophenyl)-2-oxoethyl]-1-methyl pyridinium (S 24795). An alternative approach for targeting alpha 7 nAChR has been the development of positive modulators for this receptor. In this study we examined the interactions between full or partial agonists and positive modulators of alpha 7 nAChRs in situ in brain tissue. Three positive modulators were used, 5-hydroxyindole (5-HI), 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596), and genistein. Whole-cell recordings were performed in stratum radiatum interneurons from rat brain slices. Hippocampal interneurons were stimulated by ACh, choline, S 24795, or 4OH-GTS-21, before and after bath perfusion with the positive modulators. 5-HI was not effective at potentiating 200 mu M 4OH-GTS-21-evoked responses, however 5-HI induced a sustained potentiation of responses evoked by 30 mu M 4OH-GTS-21. When I mM ACh and 200 mu M 4OH-GTS-21 were applied alternately alpha 7-mediated responses to both agonists were reduced, suggesting that high concentration of 4OH-GTS-21 produces residual inhibition or desensitization and that 5-HI is not effective at overcoming receptor desensitization. Similar results were obtained with 0 receptors expressed in Xenopus oocytes. Interestingly, responses evoked by S 24795 were potentiated by 5-HI but not by genistein. Additionally, PNU-120596 was able to potentiate alpha 7-mediated responses, regardless of the nature of the agonist. We demonstrated that the potentiation of alpha 7 nAChR response would depend on the nature and the effective concentration of the agonist involved and its particular interaction with the positive modulator. (C) 2009 Elsevier Ltd. Ail rights reserved.

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