Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys.
Δ(9)-tetrahydrocannabinol (Δ(9)-THC) modifies dopamine efflux. However, the extent to which cannabinoid and dopamine drugs modify each others behavioral effects has not been fully established. This study examined dopamine releasers andor transport inhibitors alone and in combination with cannabinoids in two drug discrimination assays. Experimentally and pharmacologically experienced rhesus monkeys (n 5) discriminated Δ(9)-THC (0.1 mgkg i.v.) from vehicle while responding under a fixed ratio 5 schedule of stimulus-shock termination. A separate group (n 6) of monkeys responded under the same schedule, received daily Δ(9)-THC (1 mgkg12 h s.c.), and discriminated the cannabinoid antagonist rimonabant (1 mgkg i.v.), i.e., cannabinoid withdrawal, from vehicle. A sign of withdrawal sign (head shaking) was examined in monkeys receiving Δ(9)-THC daily. Rimonabant antagonized the Δ(9)-THC discriminative stimulus and a dose of Δ(9)-THC greater than the daily treatment attenuated the rimonabant discriminative stimulus. In monkeys discriminating Δ(9)-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 Δ(9)-THC. In Δ(9)-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 Δ(9)-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 Δ(9)-THC or rimonabant discriminations. The dopamine transporter ligands and haloperidol attenuated head shaking, whereas imipramine and desipramine did not. Dopamine release andor inhibition of dopamine transport blocks detection of Δ(9)-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.