Benzodiazepine-like behavioral effects following withdrawal from chronic delta-9-tetrahydrocannabinol administration in rats.
Chronic exposure to cannabis extract or delta-9-tetrahydrocannabinol (THC) has been reported to produce hippocampal neuropathology in rats, as well as classical "hippocampal" behavioral deficits. In an attempt to replicate and extend these findings, male rats were exposed to THC for 13 consecutive weeks, beginning in early adolescence. Drugs were administered five consecutive days a week (Monday through Friday). There were five dose levels: vehicle control, 5, 10, or 20 mg/kg, p.o., and 20 mg/kg THC four days a week (Monday-Thursday), followed by 60 mg/kg on Friday. Following THC exposure, all animals were withdrawn from drugs for seven weeks prior to behavioral testing. Three behavioral tasks previously shown to be sensitive to hippocampal damage were assessed. These were habituation of open-field activity, 24-hr passive avoidance response retention, and complex maze performance. A fourth task, emergence latency, was also included because it has been determined to be sensitive to "anxiety" levels. To facilitate interpretation of the complex maze data, two additional experiments are also reported. One experiment tested rats exposed to trimethyltin (TMT, a potent hippocampal neurotoxicant) on the complex maze. The second assessed the affects of chronic/acute benzodiazepine (BZ) exposure upon maze performance. Test results did not suggest that chronic THC exposure produced behavioral deficits resembling those seen following hippocampal damage. Habituation rates in an activity monitor were identical for all exposure groups, and there was no passive avoidance retention deficit. Further, while TMT caused pronounced abnormalities in the complex maze, chronic THC exposure at the two highest dose levels significantly improved maze performance, similar to BZ effects on this task. Chronic THC also appeared to reduce freezing on the emergence task, another anxiolytic-like effect. These results support other reports of persistent long-term behavioral effects of chronic THC exposure. However, they suggest that some behavioral effects may more closely resemble the effects of minor tranquilizers rather than hippocampal damage.
Holson
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Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Ali
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Scallet
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Slikker
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Paule
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines; D001835:Body Weight / Q000187:drug effects; D013759:Dronabinol / Q000009:adverse effects*; D005260:Female; D007858:Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000523:psychology*; D014298:Trimethyltin Compounds / Q000633:toxicity
D014151:Anti-Anxiety Agents; D014298:Trimethyltin Compounds; D001569:Benzodiazepines; D013759:Dronabinol