Differential regulation of adenosine A(1) and A(2A) receptors in serotonintransporter and monoamine oxidase A-deficient mice

The serotonin (5HT) transporter (5HTT) removes 5HT from the synaptic cleft and is thus critical to the control of serotonergic neurotransmission. Mice with a targeted inactivation of the 5HTT represent a novel and unique tool to study serotonergic system functioning. Because the release of 5HT is re gulated by adenosine, we investigated 5HTT-deficient mice for possible adap tive changes of adenosine A(1) and A(2A) receptors. A(1) and A(2A) receptor s were studied by means of quantitative autoradiography using the radioliga nds [H-3]8-cyclopentyl-1,3-dipropylxanthine and [H-3]CGS 21680, respectivel y. A comparison of 5HTT knockout versus control mice revealed upregulation of A(1) receptors in the dorsal raphe nucleus (DRN, +21%), but not in any o f the serotonergic projection areas, and downregulation of A(2A) receptors in basal ganglia. The adaptive changes of A(1) and A(2A) receptors in 5HTT- deficient mice are likely to represent a compensatory neuroprotective effec t mediated by the adenosinergic modulatory system. For comparison, these re ceptors were also studied in monoamine oxidase A (MAOA) knockout mice and i n 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed ada ptive changes of adenosine A(1) and A(2A) receptors similar to 5HTT knockou t mice, while investigation of MAOA-deficient mice revealed an upregulation of A(2A) receptors, which may relate to a role of both MAOA and adenosine A(2A) receptors in anxiety. (C) 2000 Elsevier Science B.V. All rights reser ved.