The novel adenosine A2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade.
Dopamine D2 and adenosine A(2A) receptors interact to regulate aspects of motor and motivational function, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of parkinsonism and depression. The present experiments were performed to characterize the effects of Lu AA47070, which is a phosphonooxymethylene prodrug of a potent and selective adenosine A(2A) receptor antagonist, for its ability to reverse the motor and motivational effects of D2 antagonism. In the first group of studies, Lu AA47070 (3.75-30 mg/kg IP) was assessed for its ability to reverse the effects of the D2 receptor antagonist pimozide (1.0 mg/kg IP) using several measures of motor impairment, including catalepsy, locomotion, and tremulous jaw movements, which is a rodent model of parkinsonian tremor. Lu AA47070 produced a significant reversal of the effects of pimozide on all three measures of parkinsonian motor impairment. In addition, Lu AA47070 was able to reverse the effects of a low dose of the D2 antagonist haloperidol on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. The ability of Lu AA47070 to reverse the effects of D2 receptor blockade suggests that this compound could have potential utility as a treatment for parkinsonism, and for some of the motivational symptoms of depression.
Dept. of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA.
Lyndsey E
LE
Collins
Thomas N
TN
Sager
Anette G
AG
Sams
Adam
A
Pennarola
Russell G
RG
Port
Mona
M
Shahriari
John D
JD
Salamone
D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D003863:Depression / Q000188:drug therapy; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000737:chemistry; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D006220:Haloperidol / Q000009:adverse effects / Q000037:antagonists & inhibitors; D008297:Male; D058990:Molecular Targeted Therapy; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D010755:Organophosphates / Q000008:administration & dosage / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy; D010868:Pimozide / Q000009:adverse effects / Q000037:antagonists & inhibitors; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014202:Tremor / Q000139:chemically induced / Q000517:prevention & control
D058917:Adenosine A2 Receptor Antagonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010755:Organophosphates; D011355:Prodrugs; D043705:Receptor, Adenosine A2A; D013844:Thiazoles; C559609:phosphoric acid mono-(2-(4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino)thiazol-3-ylmethyl) ester; D010868:Pimozide; D006220:Haloperidol