Adenosine A(2A) receptor antagonists are potential antidepressants: evidence based on pharmacology and A(2A) receptor knockout mice

1 Adenosine, an ubiquitous neuromodulator, and its analogues have been show n to produce 'depressant' effects in animal models believed to be relevant to depressive disorders, while adenosine receptor antagonists have been fou nd to reverse adenosine-mediated 'depressant' effect. 2 We have designed studies to assess whether adenosine A(2A) receptor antag onists, or genetic inactivation of the receptor would be effective in estab lished screening procedures, such as tail suspension and forced swim tests, which are predictive of clinical antidepressant activity. 3 Adenosine A(2A) receptor knockout mice were found to be less sensitive to 'depressant' challenges than their wildtype littermates. Consistently, the adenosine A(2A) receptor blockers SCH 58261 (1-10 mg kg(1), i.p.) and KW 6 002 (0.1-10 mg kg(-1), p.o.) reduced the total immobility time in the tail suspension test. 4 The efficacy of adenosine A(2A) receptor antagonists in reducing immobili ty time in the tail suspension test was confirmed and extended in two group s 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 immobil ity time, while SCH 58261 at 10 mg kg(-1) reduced immobility of mice that w ere selectively bred for their spontaneous 'helplessness' in this assay. 5 Additional experiments were carried out using the forced swim test. SCH 5 8261 at 10 mg kg(-1) reduced the immobility time by 61%, while KW 6002 decr eased the total immobility time at the doses of 1 and 10 mg kg(1) by 75 and 79%, respectively. 6 Administration of the dopamine D-2 receptor antagonist haloperidol (50-20 0 mug kg(-1) i.p.) prevented the antidepressant-like effects elicited by SC H 58261 (10 mg kg(-1) i.p.) in forced swim test whereas it left unaltered i ts stimulant motor effects. 7 In conclusion, these data support the hypothesis that AIA receptor antago nists prolong escape-directed behaviour in two screening tests for antidepr essants. Altogether the results support the hypothesis that blockade of the adenosine A,A receptor might be an interesting target for the development of effective antidepressant agents.