Δ⁹-Tetrahydrocannabinol discrimination: Effects of route of administration in rats

Cannabis users typically smoke or vape cannabis or ingest it in edibles, whereas cannabinoids are typically administered via injection in rodent research. The present study examined the effects of route of administration (ROA) of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. Adult female and male Long Evans rats were trained to discriminate intraperitoneal (i.p.) THC from vehicle in a drug discrimination procedure. Following acquisition, dose-effect curves were determined with THC using i.p., oral (p.o.), and subcutaneous (s.c.) injection in both sexes and aerosol exposure in males only, followed by a time course with one dose for each ROA. Both sexes acquired THC discrimination in a similar number of sessions, although baseline response rates were significantly lower in females than males. THC fully substituted for the 3 mg/kg i.p. training dose across all ROA. While potencies were similar for ROA involving first-pass metabolism (i.p. and p.o.), THC potency was lower with s.c. administration. During the time course analysis, aerosol administration had the shortest latency to onset of discriminative stimulus effects and the shortest duration of effect, whereas s.c. administration had the longest duration. The results of this examination of the effects of ROA on an abuse-related effect of THC provide an empirical foundation to facilitate choice of ROA for mechanistic investigation of THC's pharmacology. Further, animal models using translationally relevant ROA may facilitate more accurate predictions of their effects in humans.