Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys

Rationale δ⁹-tetrahydrocannabinol (δ⁹- THC) modifies dopamine efflux. However, the extent to which cannabinoid and dopamine drugs modify each other's behavioral effects has not been fully established. Objectives This study examined dopamine releasers and/or transport inhibitors alone and in combination with cannabinoids in two drug discrimination assays. Methods Experimentally and pharmacologically experienced rhesus monkeys (n05) discriminated δ⁹-THC (0.1 mg/kg i.v.) from vehicle while responding under a fixed ratio 5 schedule of stimulus-shock termination. A separate group (n06) of monkeys responded under the same schedule, received daily δ⁹-THC (1 mg/kg/12 hs.c.), and discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.), i.e., cannabinoid withdrawal, from vehicle. A sign of withdrawal sign (head shaking) was examined in monkeys receiving δ⁹-THC daily. Results Rimonabant antagonized the δ⁹-THC discriminative stimulus and a dose of δ⁹-THC greater than the daily treatment attenuated the rimonabant discriminative stimulus. In monkeys discriminating δ⁹-THC, the dopamine transporter ligands cocaine, amphetamine, bupropion, RTI 113, and RTI 177 produced a maximum of 2% responding on the drug lever and blocked the discriminative stimulus effects of δ⁹- THC. In δ⁹-THC treated monkeys discriminating rimonabant, the dopamine transporter ligands partially substituted for and increased the potency of rimonabant to produce discriminative stimulus effects. The dopamine antagonist haloperidol enhanced the δ⁹-THC discriminative stimulus without significantly modifying the rimonabant discriminative stimulus. Imipramine and desipramine, which have low affinity for dopamine transporters, were less effective in modifying either the δ⁹-THC or rimonabant discriminations. The dopamine transporter ligands and haloperidol attenuated head shaking, whereas imipramine and desipramine did not. Conclusions Dopamine release and/or inhibition of dopamine transport blocks detection of δ⁹-THC and is potentially the mechanism by which some therapeutics (e.g., bupropion) reduce the subjective effects of marijuana and enhance the subjective effects of marijuana withdrawal.