Some effects of dopamine transporter and receptor ligands on discriminative stimulus, physiologic, and directly observable indices of opioid withdrawal in rhesus monkeys

Rationale: Some monoamine uptake inhibitors (e.g., cocaine) attenuate the subjective and discriminative stimulus effects of opioid withdrawal. Objective: This study examined a role for dopamine transporters and receptors as targets for drugs to modify the discriminative stimulus effects of opioid withdrawal and further examined a subset of these drugs for their capacity to modify some directly observable and physiologic indices of withdrawal. Materials and methods: Rhesus monkeys receiving 2 mg/kg/day of l-α-acetylmethadol discriminated the opioid antagonist naltrexone (0.0178 mg/kg s.c.). Results: The naltrexone discriminative stimulus was attenuated not only by the μ agonist morphine but also by the dopamine D₂-like receptor agonists bromocryptine and quinpirole. In contrast, the naltrexone discriminative stimulus was not consistently modified by the non-selective, D₁- and D₂-like agonist apomorphine or by uptake inhibitors with high selectivity for dopamine transporters (GBR 12909, RTI 113, and RTI 177). In the same monkeys, naltrexone dose dependently decreased body temperature, increased breathing frequency, and induced directly observable signs (grimacing, salivation, and unusual posture). Hypothermia, hyperventilation, and signs of withdrawal were significantly attenuated by morphine and not by quinpirole. Conclusions: Attenuation of opioid withdrawal by D₂-like receptor agonists that have lower efficacy than dopamine, and not by uptake inhibitors with selectivity for dopamine transporters, suggests that magnitude of receptor stimulation (e.g., efficacy) and selectivity at dopamine receptors are important factors in the modulation of opioid withdrawal. Attenuation of the naltrexone discriminative stimulus by drugs that inhibit both dopamine and serotonin uptake (e.g., cocaine) could result from an inhibitory effect of serotonin on dopamine. The role of dopamine in opioid withdrawal appears to be restricted to subjective (i.e., not somatic).