Central excitatory properties of Δ9-tetrahydrocannabinol and its metabolites in iron-induced epileptic rats

The effects of δ⁹-tetrahydrocannabinol (Δ⁹-THC), two of its metabolites, 8β-hydroxy-Δ⁹-THC and 11-hydroxy-Δ⁹-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. Δ⁹-Tetrahydrocannabinol produced depression of the spontaneously firing epileptic focus, excitatory behavior, generalized after-discharge-like bursts of epileptiform polyspikes and frank convulsions. The pharmacological profiles of the two metabolites differed from that of the parent compound: 11-Hydroxy-Δ⁹-THC did not precipitate convulsions, but it did elicit all the other effects of Δ⁹-THC; the 8β-hydroxy derivative, on the other hand, exerted only two Δ⁹-THC-like effects; that is, it evoked polyspike bursts and convulsions. In contrast, cannabidiol, even in large doses (100 mg/kg) was devoid of all the effects of Δ⁹-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to Δ⁹-THC in the following ways: focal depression was partially blocked, polyspike activity was enhanced and convulsions abolished. Phenytoin pretreatment elicited similar effects, but it failed to block the Δ⁹-THC-induced convulsions. In general, the cannabinoids exhibit a wide spectrum of CNS effects ranging from focal depression to convulsions; specifically, however, the pharmacological profile of each agent can differ markedly; for example, the convulsant properties of Δ⁹-THC are not a universal characteristic of this class of drugs.