Cerebral and cerebellar neurochemical changes and behavioral manifestations in rats chronically exposed to marijuana smoke.

Groups of male and female Fischer rats were exposed to marijuana cigarette smoke via an automatic smoking machine. Inhaled Δ⁹-tetrahydrocannabinol doses of 0.7, 2, and 4 mg/kg were relevant to man and were given for 12, 18, 27, 57, and 87 days. Another group of rats treated for 87 days was studied after a recovery of 20 days. Control animals inhaled smoke produced by placebo cigarettes. In the first week of exposure, 20% of lower-dosed rats were hyperactive and 50% at the high dose were prostrate or ataxic upon removal from the inhalator. Behavioral aberrations ameliorated within a few hours except for the depression exhibited by males at the high dose. Tolerance to CNS inhibition developed in 1–2 weeks. CNS stimulation, as manifested by hypersensitivity and hyperactivity, progressively involved more animals, primarily females, in all groups during Days 27–57. Tolerance to CNS stimulation developed thereafter. Fighting was displayed by 90% of females and 50% of males at 4 mg/kg by weeks 6–7. Neurotoxicity was expressed by involuntary vertical jumping, predominantly among high-dosed males in weeks 3 and 8. Normal behavior was displayed after cessation of treatment. At necropsy, homogenates of cerebrum and cerebellum were prepared and were analyzed for protein, RNA and acetylcholinesterase (AChE) activity. Cerebral AChE activity in females increased 33–71% after 12 exposures, decreased 10–23% after 57 exposures and rose 12% after 87 exposures. Cerebellar enzyme activity initially increased 15–35% in animals of both sexes during the subchronic phase but declined in females after 27 exposures. The extent of change in enzyme activity was generally reduced with continued treatment. Cerebellar RNA increased approximately 20% in rats of both sexes, but at different time intervals during the subchronic phase, and remained elevated in females at 87 days. Neurochemical changes were sex related and coincided with behavioral manifestations, and some changes extended into the recovery period. Inhalation findings were similar to those obtained earlier by the oral route; however, females demonstrated a greater facility to adapt to the cumulative toxic effects of marijuana smoke.