Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation.
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.
Hoffman
Alexander F
AF
United States Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Cellular Neurobiology Branch, Electrophysiology Research Unit, Baltimore, Maryland 21224, USA.
Oz
Murat
M
Yang
Ruiqin
R
Lichtman
Aron H
AH
Lupica
Carl R
CR
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D013759:Dronabinol / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D004558:Electric Stimulation; D004594:Electrophysiology; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000187:drug effects; D009435:Synaptic Transmission; D013826:Theta Rhythm; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D048588:Benzoxazines; D002186:Cannabinoids; D005971:Glutamates; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; C103505:AM 251; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol