Rapid tolerance to Δ 9-tetrahydrocannabinol and cross-tolerance between ethanol and Δ 9-tetrahydrocannabinol in mice

Abstract

Motor incoordination in the rota-rod test was used to assess the development of rapid tolerance to Δ 9-tetrahydrocannabinol and rapid cross-tolerance between ethanol and Δ 9-tetrahydrocannabinol in mice. Further, the influence of the cannabinoid receptor antagonist SR 141716A ( N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1 H-pyrazole-3-carboxyamide) on the motor impairment induced by both drugs was examined. Mice were injected on day 1 with equipotent doses of Δ 9-tetrahydrocannabinol (28 mg/kg, i.p.) and ethanol (2.25 g/kg, i.p.) and tested at 30, 60 and 90 min after the injections. On day 2, control groups received ethanol or Δ 9-tetrahydrocannabinol, some groups received the same treatment as the day before, while the remaining groups switched the treatment. All groups were tested to evaluate tolerance. The development of rapid tolerance to Δ 9-tetrahydrocannabinol was observed and pretreatment with ethanol resulted in rapid cross-tolerance to Δ 9-tetrahydrocannabinol. SR 141716A (2 mg/kg, i.p.) failed to block the development of rapid tolerance to both drugs, ethanol and Δ 9-tetrahydrocannabinol. These results suggest that Δ 9-tetrahydrocannabinol, similarly to ethanol, can induce rapid tolerance to motor incoordination in mice. They also support the use of the 2-day protocol as an effective procedure to reduce the length of drug exposure necessary to induce tolerance.