Behavioral and biochemical effects of chronic ? 9-tetrahydrocannabinol in rats

Abstract

In an attempt to identify the possible role of brain biogenic amines and adrenocorticotrophic hormone (ACTH) release in the behavioral and physiological effects of Δ 9-tetrahydrocannabinol (THC), the time course of drug action was studied. THC (20 mg/kg) was administered daily for 1, 4, 21, or 42 days to Sprague-Dawley rats that were examined for changes in body temperature, food and water intake, rearing and walking activity, compulsive motor routines, and mouse killing. Four hours after the last THC administration the animals were killed and concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in telencephalon, striatum, diencephalon, mesencephalon, and cerebellum, corticosterone in blood plasma, and epinephrine in the adrenal glands were determined. After initial THC administrations a marked hypothermia, anorexia, adipsia, and depression in locomotion were observed, all of which disappeared within 1 week of treatment. The reduced growth rate and decreased rearing activity persisted throughout the 42-day THC treatment. Compulsive motor routines and mouse killing were induced in a significant proportion of rats treated with THC for more than 3 weeks. Level of 5-HT was increased by 16–37% in all brain regions of rats given THC for 21–42 days. Plasma corticosterone was greatly increased after a single THC injection and remained elevated, to a lesser degree, for 42 days. Adrenal epinephrine was decreased after a single THC administration and increased after 42 days. None of the currently investigated biochemical changes correlated with the marked behavioral and physiological changes after initial THC administration to which tolerance develops. The syndrome of compulsive motor routines after prolonged THC treatment might be mediated by elevated brain 5-HT activity.