Adenosine A2A antagonism reverses levodopa-induced motor alterations in hemiparkinsonian rats.
To evaluate the possible involvement of adenosine A(2A) receptor-mediated mechanisms in levodopa-induced motor fluctuations, we investigated the effects of CSC (8-(3-chlorostryryl) caffeine), a selective adenosine A(2A) receptor antagonist, on levodopa-induced motor alterations in rats with unilateral 6-OHDA lesion. Acute and chronic administration of CSC was studied to evaluate the possible reversion or prevention of these levodopa effects. In a first set of experiments, rats were treated with levodopa (25 mg/kg with benserazide, twice daily, i.p.) for 22 days and on day 23 CSC (5 mg/kg, i.p.) was administered immediately before levodopa. In a second set of experiments, rats were treated daily for 22 days with levodopa and CSC (5 mg/kg/day, i.p.). The duration of the rotational behavior induced by chronic levodopa decreased after 22 days (P < 0.05). Acute administration of CSC on day 23 reversed levodopa-induced shortening in motor response duration (P < 0.01). Chronic CSC administration did not prevent the shortening in response duration induced by levodopa. Our results demonstrate that the adenosine A(2A) receptor antagonist CSC reverses but does not prevent levodopa-induced motor alterations in parkinsonian rats. These results suggest a role for adenosine A(2A) receptor-mediated mechanisms in the pathophysiology of levodopa-induced motor response complications. These findings suggest that the antagonism of adenosine A(2A) receptors might confer clinical benefit to parkinsonian patients under levodopa therapy suffering from motor complication syndrome.
Bové
J
J
Laboratori de Neurologia Experimental, Fundació Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, Spain.
Marin
C
C
Bonastre
M
M
Tolosa
E
E
D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000502:physiology*
D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine; D007980:Levodopa