AbstractFor more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB1 receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though a CB1 receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogenous cannabinoid system. Several groups have reported that CB1 receptor antagonists enhance memory duration in a variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB1 receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB1 receptor antagonists elicit a variety of effects, including enhancement of long‐term potentiation (LTP), while disrupting long‐term depression (LTD) and interfering with transient forms of plasticity, including depolarization‐induced suppression of inhibition (DSI) and depolarization‐induced suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB1 receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB1 receptors may strengthen memory duration, but interferes with extinction of learned behaviors that are associated with traumatic or aversive memories. Drug Dev Res 70:555–565, 2009. © 2009 Wiley‐Liss, Inc.