Hippocampal Neurotoxicity of D9-Tetrahydrocannabinol
Guy Chiu-Kai Chan, Thomas R. Hinds, Soren Impey, and Daniel R. Storm
The Journal of Neuroscience, 1998, 18, (14), 5322–5332
Marijuana consumption elicits diverse physiological and psychological effects in humans, including memory loss. Here we report that D9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is toxic for hippocampal neurons. Treatment of cultured neurons or hippocampal slices with THC caused shrinkage of neuronal cell bodies and nuclei as well as genomic DNA strand breaks, hallmarks of neuronal apoptosis. Neuron death induced by THC was inhibited by nonsteroidal anti-inflammatory drugs, including indomethacin and aspirin, as well as vitamin E and other antioxidants. Furthermore, treatment of neurons with THC stimulated a significant increase in the release of arachidonic acid. We hypothesize that THC neurotoxicity is attributable to activation of the prostanoid synthesis pathway and generation of free radicals by cyclooxygenase. These data suggest that some of the memory deficits caused by cannabinoids may be caused by THC neurotoxicity.
Key words : THC; cannabinoid receptors; CB1; cell death; hippocampal neurons; arachidonic acid; reactive oxygen species; SR141716A
Marijuana has a long history of consumption in human societies and is the most commonly used illicit drug today. Although marijuana is legalized in some states of the United States for therapeutic usage, its clinical use is controversial. One established therapeutic application of D-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is the treatment of nausea and vomiting associated with chemotherapy (Jaffe, 1990). Other uses of marijuana include appetite stimulation in cancer patients and abatement of pain (Abood and Martin, 1992; Voth and Schwartz, 1997). The effects of the drug in humans include hallucination, compromised cognition, memory loss, and immunosuppression (Abel, 1970; Reisine and Brownstein, 1994).
Human marijuana research is limited, and the retrospective nature of these studies compromise their interpretation. Nevertheless, marijuana usage disrupts short-term memory, working memory, and attentional skills (Fletcher et al., 1996), and induces deficits in mathematical skills, verbal expression, and memory retrieval (Block and Ghoneim, 1993). Long-lasting cannabis dependent short-term memory deficits (Schwartz et al., 1989) and residual neuropsychological effects (Pope and Yurgelun-Todd,
1996) persist even after abstinence.
Administration of cannabis extracts to rodents also causes long-lasting memory defects. For example, a 6 month oral administration of THC reduces maze learning with a residual learning defect that persists (Fehr et al., 1976; Stiglick and Kalant, 1982b, 1983; Stiglick et al., 1984). Radial arm learning paradigm showed similar impairments (Stiglick and Kalant, 1982a). Collectively, studies indicate that chronic exposure to THC impairs cognition and memory (Carlini et al., 1970; Abel, 1971).
The effects of THC are mediated primarily through cannabinoid CB1 receptor in the brain (Matsuda et al., 1990) or CB2 receptor in peripheral tissues (Munro et al., 1993). Cannabinoid receptors couple to several regulatory pathways, including the cAMP signal transduction system (Howlett, 1995). Because cannabinoid receptors inhibit adenylyl cyclases (Howlett and Fleming, 1984) and cAMP regulates synaptic plasticity (Frey et al., 1993; Chavez Noriega and Stevens, 1994; Weisskopf et al., 1994; Impey et al., 1996), cannabinoids could inhibit synaptic function. For example, Schaffer collateral long-term potentiation in the hippocampus is depressed by THC (Nowicky et al., 1987; Collins et al., 1994). Alternatively, memory loss may be attributable to cannabinoid neurotoxicity.
Chronic cannabinoid administration to rats causes distinct morphological changes in the hippocampus indicative of neurotoxicity (Scallet, 1991). THC exposure for 3 months decreases the mean volume of neurons and their nuclei, the synaptic density, and the dendritic length of CA3 pyramidal neurons (Scallet et al., 1987). Exposure to THC also decreases neuronal density in rat hippocampus (Landfield et al., 1988). Although animal studies suggest that chronic exposure to THC may be toxic for hippocampal neurons, mechanisms for THC neurotoxicity have not been defined.
To determine whether THC is toxic for hippocampal neurons and to explore possible mechanisms, we examined its influence on the viability and morphology of cultured rat hippocampal neurons and hippocampal slices. Our data indicate that THC induces cell death in neurons that may be attributable to activation of the phospholipase A2–cyclooxygenase pathway.