Differential regulation of adenosine A1 and A(2A) receptors in serotonin transporter 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 regulated by adenosine, we investigated 5HTT-deficient mice for possible adaptive changes of adenosine A and A receptors. A and A receptors were studied by means of quantitative autoradiography using the radioligands 1 2A 1 2A 3 3 [ H]8-cyclopentyl-1,3-dipropylxanthine and [ H]CGS 21680, respectively. A comparison of 5HTT knockout versus control mice revealed upregulation of A receptors in the dorsal raphe nucleus (DRN, 121%), but not in any of the serotonergic projection areas, and 1 downregulation of A receptors in basal ganglia. The adaptive changes of A and A receptors in 5HTT-deficient mice are likely to 2A 1 2A represent a compensatory neuroprotective effect mediated by the adenosinergic modulatory system. For comparison, these receptors were also studied in monoamine oxidase A (MAOA) knockout mice and in 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed adaptive changes of adenosine A and A receptors similar to 5HTT knockout mice, while investigation of 1 2A MAOA-deficient mice revealed an upregulation of A receptors, which may relate to a role of both MAOA and adenosine A receptors 2A 2A in anxiety.