Abstract
It is firmly established that the hippocampus, a brain region implicated in spatial learning, episodic memory, and consolidation, contains a high concentration of CB1 receptors. Moreover, systemic and intrahippocampal administration of cannabinoid agonists have been shown to impair hippocampal-dependent memory tasks. However, the degree to which CB1 receptors in the hippocampus play a specific functional role in the memory disruptive effects of marijuana or its primary psychoactive constituent Δ9-tetrahydrocannabinol (Δ9-THC) is unknown. This study was designed to determine whether hippocampal CB1 receptors play a functional role in the memory disruptive effects of systemically administered cannabinoids, using the radial arm maze, a well characterized rodent model of working memory. Male Sprague–Dawley rats were implanted with bilateral cannulae aimed at the CA1 region of the dorsal hippocampus. The CB1 receptor antagonist, rimonabant, was delivered into the hippocampus before to a systemic injection of either Δ9-THC or the potent cannabinoid analog, CP-55,940. Strikingly, intrahippocampal administration of rimonabant completely attenuated the memory disruptive effects of both cannabinoids in the radial arm maze task, but did not affect other pharmacological properties of cannabinoids, as assessed in the tetrad assay (that is, hypomotility, analgesia, catalepsy, and hypothermia). Infusions of rimonabant just dorsal or ventral to the hippocampus did not prevent Δ9-THC-induced memory impairment, indicating that its effects on mnemonic function were regionally selective. These findings provide compelling evidence in support of the view that hippocampal CB1 receptors play a necessary role in the memory disruptive effects of marijuana.
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Acknowledgements
We thank Dr. Carl Lupica for his insightful comments and suggestions on an earlier version of this paper. This research was supported by the National Institute on Drug Abuse (R01DA 015683, R01DA003672, and T23DA07027).
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None of the authors report any conflicts of interest with the work presented in this paper. This research has been supported solely by the National Institutes of Health (NIH). AHL declares that over the past 3 years that he has received compensation from Pfizer, Ironwood Pharmaceuticals, and Allergan. In addition, AHL has received funding from Pfizer and Ironwood for contracts unrelated to the research presented in this paper. AJP declares full-time employment at Abbott, since completing his postdoctoral fellowship and contributions to this paper. LEW declares no financial support or compensation has been received from any individual or corporate entity over the past 3 years.
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Wise, L., Thorpe, A. & Lichtman, A. Hippocampal CB1 Receptors Mediate the Memory Impairing Effects of Δ9-Tetrahydrocannabinol. Neuropsychopharmacol 34, 2072–2080 (2009). https://doi.org/10.1038/npp.2009.31
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DOI: https://doi.org/10.1038/npp.2009.31
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