Differential effects of adenosine antagonists in two models of parkinsonian tremor.
Adenosine A(1) and A(2A) receptors are colocalized with dopamine D(1) and D(2) receptors on striatal projection neurons and adenosine antagonists have been proposed as adjunctive therapies to l-DOPA treatment in Parkinson patients. We present here two studies examining the effects of selective and non-selective adenosine antagonists in two rodent models of parkinsonian tremor. Tremulous jaw movements (TJMs) were induced by either the dopamine antagonist pimozide (1.0 mg/kg) or the acetylcholine agonist tacrine (5.0 mg/kg), and were quantified by a trained observer who was blind to the treatment conditions. Animals were treated concomitantly with either caffeine (10.0 mg/kg non-selective adenosine antagonist), 8-cyclopentyltheophylline (CPT; 10.0 mg/kg; selective A(1) antagonist) or SCH58261 (8.0 mg/kg; selective A(2A) antagonist). Caffeine, CPT and SCH58261 all significantly reduced pimozide-induced TJM activity. Surprisingly administration of adenosine antagonists did not reduce tacrine-induced TJMs, and in the case of SCH58261 significantly increased TJMs compared to tacrine alone. These results indicate that antagonism at A(1) receptors may be more important for the reduction of tremor than previously supposed. Furthermore they indicate that dopamine antagonist-induced tremor models and acetylcholine agonist-induced tremor models are not entirely similar, and caution should be taken when using these models to evaluate novel therapeutics.
Trevitt
J
J
California State University-Fullerton, Fullerton, CA 92834, USA. jtrevitt@fullerton.edu
Kawa
K
K
Jalali
A
A
Larsen
C
C
D000241:Adenosine / Q000037:antagonists & inhibitors*; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000627:therapeutic use; D018679:Cholinergic Agonists; D004195:Disease Models, Animal; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004357:Drug Synergism; D007568:Jaw / Q000187:drug effects; D008297:Male; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010868:Pimozide; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013619:Tacrine; D013806:Theophylline / Q000031:analogs & derivatives / Q000627:therapeutic use; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy*; D014230:Triazoles / Q000627:therapeutic use
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D018679:Cholinergic Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines; D014230:Triazoles; D010868:Pimozide; C053907:8-cyclopentyl-1,3-dimethylxanthine; D002110:Caffeine; D013619:Tacrine; D013806:Theophylline; D000241:Adenosine