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Adenosine A_2A receptors and depression

From the UMR 6036 CNRS, IFRMP 23, U.F.R. de Médecine & Pharmacie, Rouen, France.

Address correspondence and reprint requests to Dr. Jean-Marie Vaugeois, UMR 6036 CNRS, IFRMP 23, U.F.R. de Médecine & Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex 1, France; e-mail: jean-marie.vaugeois{at}univ-rouen.fr

Adenosine and its analogues have been shown to induce "behavioral despair" in animal models believed to be relevant to depression. Recent data have shown that selective adenosine A_2A receptor antagonists (e.g., SCH 58261, ZM241385, and KW6002) or genetic inactivation of the receptor was effective in reversing signs of behavioral despair in the tail suspension and forced swim tests, two screening procedures predictive of antidepressant activity. A_2A antagonists were active in the tail suspension test using either mice previously screened for having high immobility scores or mice that were selectively bred for their spontaneous "helplessness" in this test. At stimulant doses, caffeine, a nonselective A₁/A_2A receptor antagonist, was effective in the forced swim test. The authors have hypothesized that the antidepressant-like effect of selective A_2A antagonists is linked to an interaction with dopaminergic transmission, possibly in the frontal cortex. In support of this idea, administration of the dopamine D₂ receptor antagonist haloperidol prevented antidepressant-like effects elicited by SCH 58261 in the forced swim test (putatively involving cortex), whereas it had no effect on stimulant motor effects of SCH 58261 (putatively linked to ventral striatum). The interaction profile of caffeine with haloperidol differed markedly from that of SCH 58261 in the forced swim and motor activity tests. Therefore, a clear-cut antidepressant-like effect could not be ascribed to caffeine. In conclusion, available data support the proposition that a selective blockade of the adenosine A_2A receptor may be an interesting target for the development of effective antidepressant agents.

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