Time-course of the effects of chronic Δ9-tetrahydrocannabinol on behaviour, body temperature, brain amines and withdrawal-like behaviour in the rat

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Abstract
The effects of clomipramine HCl (15 mg kg−1 i.p.) on behaviour, body temperature and brain amines were investigated in rats that had been chronically treated twice daily with increasing doses of Δ9-tetrahydrocannabinol (Δ9-THC, 2–6 mg kg−1 i.v.). Δ9-THC produced a biphasic change in behaviour, stimulation followed by depression, and a pronounced hypothermia. Tolerance developed rapidly to these effects of Δ9-THC. Chronic treatment with Δ9-THC reduced the levels of homovanillic acid, 5-hydroxytryptamine and noradrenaline. The level of dopamine was not altered with chronic treatment and tolerance appeared to develop to the increased level of 5-hydroxyindoleacetic acid induced by Δ9-THC. Injection of clomipramine, 12–14 h after 2, 5 or 10 days of Δ9-THC treatment induced characteristic changes in the rats behaviour which consisted of writhes, backward kicking, wet shakes, jumps, ataxia and front paw and whole body tremor. The severity of the behavioural changes appeared to be dependent on the period of Δ9-THC administration and they were not accompanied by a change in body temperature or consistent changes in brain amines or metabolites. The results indicate that physical dependence on Δ9-THC may occur since clomipramine is able to precipitate changes in behaviour, indicative on an abstinence syndrome, in rats chronically treated with Δ9-THC. It is suggested that tryptaminergic mechanisms are altered during chronic Δ9-THC treatment and that clomipramine induces the behavioural changes by interacting with an altered tryptaminergic system.