Opposing actions of chronic Δ9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation

Alexander F. Hoffman, Murat Oz, Ruiqin Yang, Aron H. Lichtman, Carl R. Lupica

Research output: Contribution to journalArticlepeer-review

128 Citations (Scopus)


Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, Δ9-tetrahydrocannabinol (Δ9-THC), with cannabinoid receptors in the hippocampus. Although cannabinoids acutely reduce glutamate release and block hippocampal long-term potentiation (LTP), a potential substrate for learning and memory, the consequences of prolonged exposure to Δ9-THC for hippocampal function are poorly understood. Rats were injected with Δ9-THC (10 mg/kg, i.p., q.d.) for 1, 3, or 7 d, and electrophysiological recordings were performed in hippocampal slices 1d after the final injection. At this time, Δ9-THC was undetectable in hippocampus using liquid chromatography-mass spectrometry (LC-MS). Hippocampal LTP generated using high-frequency (HFS) or theta burst stimulation was not observed in brain slices from the 7-d Δ9-THC-treated animals. Δ9-THC also blocked HFS-LTP after 3 d, but not 1 d of treatment. The complete blockade of LTP persisted for 3 d after the last Δ9-THC injection, and full reversal of the LTP deficit was not observed up to 14 d following Δ9-THC withdrawal. The cannabinoid antagonist AM251 (2 mg/kg), administered before each Δ9-THC injection prevented the blockade of LTP, and 7-d treatment with AM251 alone significantly increased the level of LTP. Chronic Δ9-THC also produced tolerance to the inhibition of synaptic GABA, but not glutamate release by the agonist WIN55,212-2. These data define consequences of repeated Δ9-THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.

Original languageEnglish
Pages (from-to)63-74
Number of pages12
JournalLearning and Memory
Issue number1
Publication statusPublished - Jan 2007
Externally publishedYes

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience


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