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Dimebolin (Dimebon™), is a non-selective antihistamine approved in Russia for the treatment of allergy. Recently, this drug has been shown to be neuroprotective in cellular models of Alzheimer's disease and Huntington's disease, and to preserve cognitive function when chronically administered to AF64A lesioned rats. Interests in identifying the molecular targets of dimebolin have intensified with reports of efficacy in clinical trials with Alzheimer's patients. Dimebolin has been found to interact with a number of molecular targets including acetylcholinesterases, N-methyl-D-aspartate receptors, and voltage-gated calcium channels, with potencies in the range of 5–50 μM. In the present study, the action of dimebolin at the serotonin 5-HT6 receptor was investigated. Dimebolin binds with moderate affinity to both the human and rat recombinant 5-HT6 receptor (Ki = 26.0 ± 2.5 nM and 119.0 ± 14.0 nM respectively) as well as the native rat 5-HT6 receptor, and acts as an antagonist in functional cAMP assays. Furthermore, dimebolin occupies the 5-HT6 receptor in vivo as assessed by ex vivo autoradiography, with a dose-occupancy relationship similar to that of the selective 5-HT6 antagonist SB-399885. Finally, both SB-399885 and dimebolin produce an acute enhancement of short-term social recognition memory, although dimebolin is approximately 10-fold less potent than SB-399885. Taken together, these studies demonstrate that dimebolin antagonizes the 5-HT6 receptor with higher affinity than other targets characterized to date, and suggest that this activity may play a role in the acute cognition enhancing effects of this compound in preclinical models and in the clinic.