The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat.
OBJECTIVE
Given that adenosine A2A antagonists appear to be therapeutic in several animal models of Parkinson's disease (PD), we examined the extent to which caffeine and selective A2A and A1 antagonists could enhance contralateral forepaw stepping in the unilateral 6-OHDA-lesioned rat.


METHODS
Following unilateral injections of 12 microg 6-OHDA into the medial forebrain bundle (MFB), frequency of stepping with both front paws was counted separately as the paws were dragged anteriorally and laterally by a treadmill.


RESULTS
The MFB lesions decreased contralateral stepping by 74-83%, and 8 mg/kg 3,4-dihydroxy-L-phenylalanine (L-DOPA) increased contralateral stepping by 25-26%. Caffeine given systemically (15 mg/kg) or into the dorsal striatum or external globus pallidus (GPE; 20-40 microg) increased contralateral forepaw stepping by 14%, 27%, and 26%, respectively, and enhanced the effect of 8 mg/kg L-DOPA on stepping. The selective A(2A) antagonist SCH-58261 (2 mg/kg) also increased stepping by 13% and enhanced the therapeutic effect of L-DOPA, whereas the selective A(1) [corrected] antagonist 8-cyclopentyltheophylline (3-7 mg/kg) and A(1) agonist N(6)-cyclopentyladenosine (0.03-0.2 mg/kg) had no effect. None of these drugs appeared to produce dyskinesic effects.


CONCLUSIONS
In this well-validated animal model of the akinesic effects of PD, caffeine and a selective A2A, but not an A1, antagonist were able to provide both monotherapeutic and adjunctive therapeutic effects. These data are consistent with the hypothesis that A2A antagonists may be therapeutic in human PD patients and indicate that the dorsal striatum and GPE are critical sites of therapeutic action.
Kelsey
John E
JE
Program in Neuroscience, Bates College, Lewiston, ME 04240, USA. jkelsey@bates.edu
Langelier
Nicole A
NA
Oriel
Brad S
BS
Reedy
Catherine
C
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005917:Globus Pallidus / Q000378:metabolism; D007267:Injections; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D000697:Central Nervous System Stimulants; D002110:Caffeine; D007980:Levodopa; D016627:Oxidopamine
Neuroscience. 1999 Jan;88(2):617-28
10197780
Eur J Pharmacol. 2007 Jul 2;566(1-3):94-102
17445798
Pol J Pharmacol Pharm. 1976 Nov-Dec;28(6):571-8
1034921
Eur J Pharmacol. 2006 Sep 28;546(1-3):82-7
16925991
Neuroreport. 1998 Aug 24;9(12):2857-60
9760134
Eur J Neurosci. 1996 Jun;8(6):1176-81
8752587
Synapse. 2001 Mar 1;39(2):233-238
11169767
Synapse. 2007 Aug;61(8):606-14
17476684
Pol J Pharmacol. 1997 Sep-Oct;49(5):323-7
9566031
Neurology. 1999 May 12;52(8):1673-7
10331698
Brain Res. 2007 Feb 16;1133(1):110-4
17196564
Trends Neurosci. 2006 Nov;29(11):647-54
17030429
J Neurosci. 2006 Dec 27;26(52):13548-55
17192438
J Neurosci. 1995 May;15(5 Pt 2):3863-75
7751951
Eur J Neurosci. 1998 May;10(5):1878-84
9751157
Exp Neurol. 2004 Sep;189(1):182-8
15296848
Exp Neurol. 2006 Nov;202(1):255-7
16808917
JAMA. 2000 May 24-31;283(20):2674-9
10819950
Neurotox Res. 2001 Nov;3(6):545-56
15111244
Ann Neurol. 1998 Apr;43(4):507-13
9546333
J Neurochem. 2003 Mar;84(6):1398-410
12614340
Behav Pharmacol. 2005 Dec;16(8):621-6
16286813
J Neurochem. 1991 Sep;57(3):1062-7
1713612
J Pharmacol Sci. 2007 Mar;103(3):329-32
17341841
Psychopharmacology (Berl). 1999 Nov;147(1):90-5
10591873
Behav Pharmacol. 2005 Mar;16(2):63-77
15767841
Eur J Pharmacol. 1997 Feb 26;321(2):143-7
9063681
Neurobiol Dis. 2004 Jun;16(1):110-23
15207268
Pharmacol Ther. 2005 Mar;105(3):267-310
15737407
Brain Res Mol Brain Res. 1992 Jul;14(3):186-95
1279342
Neuroscience. 1994 Mar;59(2):389-99
8008198
Psychopharmacology (Berl). 2004 Sep;175(2):179-88
15007533
Brain Res. 1993 Jun 11;613(2):347-51
8186990
Eur J Pharmacol. 2000 Nov 24;408(3):249-55
11090641
Neurosci Lett. 1996 Nov 8;218(3):209-13
8945765
Synapse. 2001 Aug;41(2):160-71
11400182
J Neural Transm Park Dis Dement Sect. 1991;3(3):203-13
1835581
Med Biol. 1974 Feb;52(1):48-54
4157329
Neurosci Lett. 2006 Jan 23;393(1):31-5
16236444
Brain Res. 1991 Dec 24;568(1-2):205-14
1814568
Exp Neurol. 2003 Nov;184(1):285-94
14637099
Pol J Pharmacol. 2003 Mar-Apr;55(2):155-64
12926542
J Mol Neurosci. 2005;26(2-3):209-20
16012194
Eur J Pharmacol. 1982 Jul 30;81(4):673-6
6288418
Behav Brain Res. 2004 Jan 5;148(1-2):47-54
14684247
Exp Neurol. 2000 Apr;162(2):321-7
10739638
Ann Neurol. 2001 Jul;50(1):56-63
11456310
Psychopharmacology (Berl). 1991;103(1):78-82
1900945
Exp Neurol. 2006 Feb;197(2):284-90
16005456