title: Muscarinic receptor/G-protein coupling is reduced in the dorsomedial striatum of cognitively impaired aged rats.
abstract: Behavioral flexibility, the ability to modify responses due to changing task demands, is detrimentally affected by aging with a shift towards increased cognitive rigidity. The neurobiological basis of this cognitive deficit is not clear although striatal cholinergic neurotransmission has been implicated. To investigate the possible association between striatal acetylcholine signaling with age-related changes in behavioral flexibility, young, middle-aged, and aged F344 X Brown Norway F1 rats were assessed using an attentional set-shifting task that includes two tests of behavioral flexibility: reversal learning and an extra-dimensional shift. Rats were also assessed in the Morris water maze to compare potential fronto-striatal-dependent deficits with hippocampal-dependent deficits. Behaviorally characterized rats were then assessed for acetylcholine muscarinic signaling within the striatum using oxotremorine-M-stimulated [(35)S]GTPγS binding and [(3)H]AFDX-384 receptor binding autoradiography. The results showed that by old age, cognitive deficits were pronounced across cognitive domains, suggesting deterioration of both hippocampal and fronto-striatal regions. A significant decline in oxotremorine-M-stimulated [(35)S]GTPγS binding was limited to the dorsomedial striatum of aged rats when compared to young and middle-aged rats. There was no effect of age on striatal [(3)H]AFDX-384 receptor binding. These results suggest that a decrease in M2/M4 muscarinic receptor coupling is involved in the age-associated decline in behavioral flexibility.
authors.affiliation: Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Erasmo
authors.initials: E
authors.lastname: Nieves-Martinez
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haynes
authors.forename: Steven R
authors.initials: SR
authors.lastname: Childers
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Nicolle
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001288:Attention; D001345:Autoradiography; D003072:Cognition Disorders / Q000473:pathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005508:Food Deprivation / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007554:Isotopes / Q000493:pharmacokinetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D010276:Parasympatholytics / Q000493:pharmacokinetics; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D043588:Receptor, Muscarinic M4 / Q000378:metabolism*; D012193:Reversal Learning / Q000502:physiology; D012718:Set, Psychology
chemical_list: D007554:Isotopes; D010276:Parasympatholytics; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; C065959:AFDX 384; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010890:Pirenzepine; D019204:GTP-Binding Proteins
references.citation: Front Syst Neurosci. 2011 Mar 03;5:11
references.pmid: 21427783
references.citation: Brain Res. 1994 Sep 26;658(1-2):87-92
references.pmid: 7834359
references.citation: Neuroscience. 1991;40(1):159-67
references.pmid: 2052149
references.citation: Neuroscience. 1995 Jul;67(2):277-92
references.pmid: 7675169
references.citation: Eur Neuropsychopharmacol. 2005 Mar;15(2):163-75
references.pmid: 15695061
references.citation: Neurobiol Learn Mem. 2011 Sep;96(2):95-120
references.pmid: 21704718
references.citation: Curr Opin Neurobiol. 2010 Apr;20(2):199-204
references.pmid: 20167474
references.citation: Neurobiol Aging. 2007 Apr;28(4):619-26
references.pmid: 16600436
references.citation: Neurobiol Aging. 2002 Jul-Aug;23(4):555-64
references.pmid: 12009505
references.citation: Brain Res. 1992 Apr 3;576(2):327-31
references.pmid: 1515926
references.citation: Neurobiol Aging. 1996 Nov-Dec;17(6):877-83
references.pmid: 9363799
references.citation: J Neurosci. 2003 Jan 15;23(2):676-81
references.pmid: 12533627
references.citation: J Pharmacol Exp Ther. 1991 Nov;259(2):601-7
references.pmid: 1941609
references.citation: Br J Pharmacol. 1988 Feb;93(2):437-45
references.pmid: 3359114
references.citation: J Neurosci. 2008 Oct 22;28(43):10972-82
references.pmid: 18945905
references.citation: J Neurosci. 2000 Jun 1;20(11):4320-4
references.pmid: 10818167
references.citation: Neurobiol Learn Mem. 2009 Jan;91(1):13-22
references.pmid: 18845266
references.citation: Front Integr Neurosci. 2009 Mar 09;3:4
references.pmid: 19404412
references.citation: J Neurosci. 1991 Oct;11(10):3218-26
references.pmid: 1941081
references.citation: Neurobiol Learn Mem. 2008 Feb;89(2):114-24
references.pmid: 17709264
references.citation: Eur J Neurosci. 2003 Dec;18(12):3335-42
references.pmid: 14686906
references.citation: Behav Neurosci. 2002 Feb;116(1):105-15
references.pmid: 11898801
references.citation: Exp Gerontol. 1998 May;33(3):249-65
references.pmid: 9615923
references.citation: Ann N Y Acad Sci. 2007 Dec;1121:355-75
references.pmid: 17698989
references.citation: J Pharmacol Exp Ther. 1998 Feb;284(2):707-13
references.pmid: 9454818
references.citation: J Neurosci. 2008 Oct 29;28(44):11124-30
references.pmid: 18971455
references.citation: Behav Neurosci. 1993 Aug;107(4):618-26
references.pmid: 8397866
references.citation: Ann N Y Acad Sci. 1993 Sep 24;695:42-5
references.pmid: 8239310
references.citation: J Chem Neuroanat. 2005 Oct;30(2-3):119-28
references.pmid: 16095872
references.citation: J Neurosci. 1994 May;14(5 Pt 2):3351-63
references.pmid: 8182478
references.citation: Biochem Biophys Res Commun. 1995 Aug 24;213(3):869-74
references.pmid: 7654249
references.citation: Age (Dordr). 2012 Oct;34(5):1051-73
references.pmid: 21710198
references.citation: Int J Dev Neurosci. 1990;8(6):689-708
references.pmid: 2288244
references.citation: J Neurochem. 1995 Jun;64(6):2755-64
references.pmid: 7760056
references.citation: Learn Mem. 2003 Jan-Feb;10(1):64-73
references.pmid: 12551965
references.citation: Behav Brain Res. 2003 Nov 30;146(1-2):97-103
references.pmid: 14643463
references.citation: Jpn J Pharmacol. 1991 Dec;57(4):483-93
references.pmid: 1666417
references.citation: Eur J Pharmacol. 1988 Oct 26;156(1):133-42
references.pmid: 3208836
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7242-6
references.pmid: 7638174
references.citation: Exp Gerontol. 2004 Feb;39(2):217-23
references.pmid: 15036415
references.citation: Behav Brain Res. 2008 Feb 11;187(1):100-8
references.pmid: 17920704
references.citation: Behav Neurosci. 2006 Apr;120(2):298-306
references.pmid: 16719694
references.citation: Mol Pharmacol. 1987 Jul;32(1):100-8
references.pmid: 3600611
references.citation: Trends Pharmacol Sci. 1988 Feb;Suppl:54-60
references.pmid: 3074538
references.citation: Behav Brain Res. 2007 May 16;179(2):219-28
references.pmid: 17337305
references.citation: Neurosci Biobehav Rev. 2010 Apr;34(5):670-7
references.pmid: 20026186
references.citation: Life Sci. 2001 Feb 16;68(13):1545-55
references.pmid: 11253171
references.citation: Biochim Biophys Acta. 1994 Apr 20;1191(1):59-64
references.pmid: 7512384