Adenosine A2A receptor antagonists are potential antidepressants: evidence based on pharmacology and A2A receptor knockout mice.
1. Adenosine, an ubiquitous neuromodulator, and its analogues have been shown to produce 'depressant' effects in animal models believed to be relevant to depressive disorders, while adenosine receptor antagonists have been found to reverse adenosine-mediated 'depressant' effect. 2. We have designed studies to assess whether adenosine A2A receptor antagonists, or genetic inactivation of the receptor would be effective in established screening procedures, such as tail suspension and forced swim tests, which are predictive of clinical antidepressant activity. 3. Adenosine A2A receptor knockout mice were found to be less sensitive to 'depressant' challenges than their wildtype littermates. Consistently, the adenosine A2A receptor blockers SCH 58261 (1 - 10 mg kg(-1), i.p.) and KW 6002 (0.1 - 10 mg kg(-1), p.o.) reduced the total immobility time in the tail suspension test. 4. The efficacy of adenosine A2A receptor antagonists in reducing immobility time in the tail suspension test was confirmed and extended in two groups of mice. Specifically, SCH 58261 (1 - 10 mg kg(-1)) and ZM 241385 (15 - 60 mg kg(-1)) were effective in mice previously screened for having high immobility time, while SCH 58261 at 10 mg kg(-1) reduced immobility of mice that were selectively bred for their spontaneous 'helplessness' in this assay. 5. Additional experiments were carried out using the forced swim test. SCH 58261 at 10 mg kg(-1) reduced the immobility time by 61%, while KW 6002 decreased the total immobility time at the doses of 1 and 10 mg kg(-1) by 75 and 79%, respectively. 6. Administration of the dopamine D2 receptor antagonist haloperidol (50 - 200 microg kg(-1) i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10 mg kg(-1) i.p.) in forced swim test whereas it left unaltered its stimulant motor effects. 7. In conclusion, these data support the hypothesis that A2A receptor antagonists prolong escape-directed behaviour in two screening tests for antidepressants. Altogether the results support the hypothesis that blockade of the adenosine A2A receptor might be an interesting target for the development of effective antidepressant agents.
El Yacoubi
M
M
UMR 6036 CNRS, IFRMP 23, U.F.R. de Médecine & Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.
Ledent
C
C
Parmentier
M
M
Bertorelli
R
R
Ongini
E
E
Costentin
J
J
Vaugeois
J M
JM
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001763:Blepharoptosis / Q000139:chemically induced / Q000517:prevention & control; D004195:Disease Models, Animal; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007103:Immobilization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2 / Q000502:physiology; D018047:Receptors, Purinergic P1 / Q000235:genetics; D012110:Reserpine / Q000008:administration & dosage; D013550:Swimming; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D000928:Antidepressive Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; D014230:Triazoles; C111599:istradefylline; D012110:Reserpine; D006220:Haloperidol