SB‐269970, a selective 5‐HT7 antagonist, reverses working memory deficits in rats by normalizing glutamate neurotransmission

Abstract

5‐HT7 antagonists have been shown to have efficacy in animal models of cognition. However, the mechanism by which these procognitive effects occur is not well understood. The goal of these studies was to evaluate the effects of SB‐269970, a selective 5‐HT7 antagonist, in translational models of cognition and establish whether it modulates glutamate neurotransmission. The effects of SB‐269970 (10 mg/kg, i.p.), were evaluated in the delayed non‐matching to position (DNMTP) task alone and in combination with MK‐801 (0.1 mg/kg, i.p.), a non‐competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine (0.06 mg/kg, i.p.), a non‐selective muscarinic antagonist. Also, the ability of SB‐269970 (10 mg/kg, i.p.) to modulate MK‐801 (0.1 mg/kg, i.p.)‐induced glutamate and dopamine cortical release was evaluated using microdialysis in freely moving rats. MK‐801 and scopolamine significantly reduced percentage correct responding in the DNMTP task without affecting number of trials. SB‐269970 significantly reversed the deficits induced by MK‐801, but not by scopolamine. SB‐269970 normalized MK‐801‐induced glutamate but not dopamine release in the cortex and these effects were similar to LY379268, a group II mGluR agonist. These results indicate that blockade of 5‐HT7 receptors selectively normalizes glutamatergic neurotransmission.