Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats

CB1 is the most abundant metabotropic receptor of the brain, being found in areas classically involved in learning and memory and present at higher density at presynaptic terminals. Different sets of evidence support the idea that endogenous ligands (endocannabinoids) to the CB1 receptors act as modulators of neurotransmission. In hippocampus, endocannabinoids seem to act as retrograde messengers mediating down-regulation of GABA release. Previous reports have described a cognitive impairment effect of cannabinoid agonists, or facilitation by antagonists. The scope of the present study is to investigate the effect of intrahippocampal administration of the CB1-selective antagonist, AM251, in two behavioral tasks. One hundred and twelve male Wistar rats with bilateral cannulae implanted in the CA1 region of the dorsal hippocampus were trained in a step-down inhibitory avoidance task (IA, footshock, 0.5 mA) or an open field habituation task (OF). Immediately, after training, animals received an infusion of 0.55, 5.5, and 55.5 ng/side of AM251 (Tocris), or its vehicle (DMSO/saline), via these cannulae. Our results show that AM251 disrupted memory consolidation of the IA task, but not the OF task, an effect that seems to be purely mnemonic since the drug showed no motor performance effects. Only the intermediate dose (5.5 ng/side) of AM251 was effective in IA and the absence of effect with the larger dose may be the consequence of non-specific binding. The fact that OF was not affected raises the possibility that this endogenous system requires some degree of aversiveness to be recruited. We propose that increased levels of endogenous cannabinoids in the hippocampus, following a training session, contribute to facilitate memory consolidation, a process that may have been disrupted with AM251. (C) 2004 Elsevier Inc. All rights reserved.