Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation.
Alexander F. Hoffman, Murat Oz, Ruiqin Yang, Aron H Lichtman, Carl R. Lupica
Learning & memory (Cold Spring Harbor, N.Y.) 2007 preprint DOI: 10.1101/lm.439007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study |
|---|---|
| Population | Rats |
| Interventions | Delta(9)-THC AM251 |
| Dose | Delta(9)-THC 10 mg/kg i.p. q.d.; AM251 2 mg/kg |
| Duration | 1, 3, or 7 days of treatment, with recordings 1 day after final injection; additional experiments assessed LTP at 3 and 14 days after withdrawal |
| Topics | Cannabis |
| Key findings | Seven days of daily Delta(9)-THC injections completely blocked hippocampal LTP, with the blockade persisting for at least three days after withdrawal and full recovery not observed by 14 days. AM251 given before each injection prevented the blockade, and AM251 alone increased LTP. |
Abstract
Memory deficits produced by marijuana arise partly via interaction of the psychoactive component, Delta(9)-tetrahydrocannabinol (Delta(9)-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 Delta(9)-THC for hippocampal function are poorly understood. Rats were injected with Delta(9)-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, Delta(9)-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 Delta(9)-THC-treated animals. Delta(9)-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 Delta(9)-THC injection, and full reversal of the LTP deficit was not observed up to 14 d following Delta(9)-THC withdrawal. The cannabinoid antagonist AM251 (2 mg/kg), administered before each Delta(9)-THC injection prevented the blockade of LTP, and 7-d treatment with AM251 alone significantly increased the level of LTP. Chronic Delta(9)-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 Delta(9)-THC exposure for synaptic plasticity in the hippocampus that may help explain memory impairments in humans following chronic marijuana use.