Chronic treatment with Delta(9)-tetrahydrocannabinol impairs spatial memory and reduces zif268 expression in the mouse forebrain.

Few studies have investigated the effects of chronic cannabinoid exposure on memory performance and whether tolerance occurs to cannabinoid-induced memory impairment. Here, we studied the effects of repeated exposure to Delta-tetrahydrocannabinol (THC: 1 mg/kg) on spatial memory and zif268 expression in mice. One group of animals was not pretreated with THC, whereas another group was injected with 13 daily injections of THC before memory testing in the Morris water maze. Both groups were administered with THC throughout the memory-testing phase of the experiment. THC decreased spatial memory and reversal learning, even in animals that received the THC pretreatment and were tolerant to the locomotor suppressant effects of the drug. Zif268 immunoreactivity was reduced in the CA3 of the hippocampus and in the prefrontal cortex only in non-pretreated animals, indicating that although tolerance to the effects of THC on neuronal activity was evident, cannabinoid-induced memory impairment in these animals persisted even after 24 days of exposure. This study shows that after extended administration of THC, its spatial memory-impairing effects are resistant to tolerance.