Differential regulation of adenosine A 1 and A 2A receptors in serotonin transporter and monoamine oxidase A-deficient mice

Abstract

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 1 and A 2A receptors. A 1 and A 2A receptors were studied by means of quantitative autoradiography using the radioligands [ 3H]8-cyclopentyl-1,3-dipropylxanthine and [ 3H]CGS 21680, respectively. 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 of 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 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 1 and A 2A receptors similar to 5HTT knockout 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.