Cross-tolerance between delta9-tetrahydrocannabinol and ethanol: the role of drug disposition

Acute challenge doses of delta9-tetrahydrocannabinol (THC), 10.1 mg/kg, administered intragastrically by gavage (IG), or ethanol, 1.24 g/kg, IP, reduced the rotarod performance of female rats by 50%. Daily treatment of the animals with THC, 10.1 mg/kg, IG, or ethanol, 4 g/kg, IG, resulted in tolerance development to the impairing effects of the challenge doses of each drug on rotarod performance. THC-tolerant animals were cross-tolerant to the challenge dose of ethanol, but ethanol-tolerant rats did not show complete cross-tolerance to the challenge dose of THC. THC-tolerant animals initially had higher blood levels of 14C-THC than controls after IG drug administration. Following IV injection, the rates of 14C-THC disappearance were equivalent in the latter groups. 14C-THC disappearance was not altered in ethanol-tolerant animals. The rates of ethanol disappearance were not significantly modified in THC- or ethanol-tolerant animals. In conclusion, THC-tolerant female rats demonstrated cross-tolerance to ethanol as shown previously for males. Furthermore, the development of tolerance and cross-tolerance was not a function of changes in drug disappearance.