Positive modulation of alpha7 nAChR responses in rat hippocampal interneurons to full agonists and the alpha7-selective partial agonists, 4OH-GTS-21 and S 24795.
One approach for the identification of therapeutic agents for Alzheimer's disease has focused on the research of alpha7 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 alpha7 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 alpha7 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 microM 4OH-GTS-21-evoked responses, however 5-HI induced a sustained potentiation of responses evoked by 30 microM 4OH-GTS-21. When 1 mM ACh and 200 microM 4OH-GTS-21 were applied alternately alpha7-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 alpha7 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 alpha7-mediated responses, regardless of the nature of the agonist. We demonstrated that the potentiation of alpha7 nAChR response would depend on the nature and the effective concentration of the agonist involved and its particular interaction with the positive modulator.
López-Hernández
Gretchen Y
GY
Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL 32610-0267, USA. gylopez@ufl.edu
Thinschmidt
Jeffrey S
JS
Morain
Philippe
P
Trocme-Thibierge
Caryn
C
Kem
William R
WR
Soti
Ferenc
F
Papke
Roger L
RL
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000691:Anabasine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005071:Evoked Potentials / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects*; D007555:Isoxazoles / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C116666:3-(4-hydroxy-2-methoxybenzylidene)anabaseine; D000316:Adrenergic alpha-Agonists; C579165:Chrna7 protein, rat; D018076:DNA, Complementary; D007211:Indoles; D007555:Isoxazoles; D018722:Nicotinic Agonists; D010671:Phenylurea Compounds; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; C524163:S 24795; D064569:alpha7 Nicotinic Acetylcholine Receptor; C026785:5-hydroxyindole; D000691:Anabasine
Brain Res. 2002 Sep 6;948(1-2):33-46
12383953
J Neurosci. 2005 Apr 6;25(14):3712-23
15814802
Mol Pharmacol. 2007 Sep;72(3):715-24
17565004
Neuropharmacology. 2005 May;48(6):869-80
15829257
J Biol Chem. 2007 Feb 23;282(8):5899-909
17189260
Mol Pharmacol. 1997 Jul;52(1):172-9
9224827
Brain Res. 1998 Nov 9;810(1-2):257-63
9813357
Br J Pharmacol. 2006 Nov;149(6):724-32
17016503
J Neurophysiol. 2003 Apr;89(4):1797-806
12611953
Psychopharmacology (Berl). 2008 Mar;196(4):555-64
18034231
Eur J Pharmacol. 2000 Mar 30;393(1-3):179-95
10771012
Psychopharmacology (Berl). 2008 Apr;197(3):499-508
18265960
Neurosci Lett. 2001 Oct 26;312(3):161-4
11602335
Neuroreport. 1999 Jun 3;10(8):1779-82
10501574
J Physiol. 2000 Jun 15;525 Pt 3:735-46
10856125
J Comp Neurol. 1994 Nov 15;349(3):325-42
7852628
Nat Rev Drug Discov. 2005 Aug;4(8):673-84
16056392
J Neurosci. 1998 Feb 15;18(4):1187-95
9454829
Neuropharmacology. 2004 Jun;46(7):1023-38
15081799
Mol Pharmacol. 1994 Mar;45(3):546-54
8145738
Neurobiol Aging. 1995 Sep-Oct;16(5):857-60
8532124
Brain Res. 2008 Apr 8;1203:51-60
18321476
Acta Physiol (Oxf). 2008 Feb;192(2):203-12
18005395
Biol Psychiatry. 2001 Feb 1;49(3):166-74
11230867
Biol Psychiatry. 1995 Jul 1;38(1):22-33
7548469
J Neurophysiol. 1995 Sep;74(3):1212-21
7500145
J Neurosci. 2005 Apr 27;25(17):4396-405
15858066
J Neurochem. 2000 Jan;74(1):237-43
10617125
J Neurosci. 2005 Oct 26;25(43):9836-49
16251431
Neuropharmacology. 2002 Sep;43(3):374-84
12243767
Mol Pharmacol. 2004 Jan;65(1):56-67
14722237
Neuroscience. 2007 Mar 2;145(1):314-22
17218065
Proc Natl Acad Sci U S A. 2007 May 8;104(19):8059-64
17470817
Neurosci Lett. 1996 Aug 9;213(3):201-4
8873149
Br J Pharmacol. 2002 Sep;137(1):49-61
12183330
J Neurophysiol. 2000 May;83(5):2682-90
10805668
J Physiol. 1999 May 1;516 ( Pt 3):739-56
10200422
Biophys J. 1995 Feb;68(2):516-24
7696505
Br J Pharmacol. 2003 Jan;138(1):245-53
12522096
Brain Res. 1995 Mar 20;674(2):252-9
7796104
J Biol Chem. 2003 Sep 5;278(36):34411-7
12821669
Parkinsonism Relat Disord. 2003 Jun;9(5):243-6
12781587
Brain Res. 1994 May 9;645(1-2):309-17
8062092
J Physiol. 1997 Nov 1;504 ( Pt 3):603-10
9401968
Neuropharmacology. 2007 Jul;53(1):134-44
17544457
Mol Pharmacol. 1995 Jan;47(1):164-71
7838125
J Physiol. 2006 Aug 1;574(Pt 3):699-710
16690715
J Neurosci. 1993 Feb;13(2):596-604
7678857
Biochem Pharmacol. 2007 Oct 15;74(8):1172-81
17706607
Mol Pharmacol. 1998 Feb;53(2):283-94
9463487