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


METHODS
Rhesus monkeys receiving 2 mg/kg/day of L: -alpha-acetylmethadol discriminated the opioid antagonist naltrexone (0.0178 mg/kg s.c.).


RESULTS
The naltrexone discriminative stimulus was attenuated not only by the mu agonist morphine but also by the dopamine D(2)-like receptor agonists bromocryptine and quinpirole. In contrast, the naltrexone discriminative stimulus was not consistently modified by the non-selective, D(1)- and D(2)-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 D(2)-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) indices [corrected]
McMahon
Lance R
LR
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Li
Jun-Xu
JX
Carroll
F Ivy
FI
France
Charles P
CP
D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000523:psychology*
D000701:Analgesics, Opioid; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D009292:Narcotic Antagonists; D011954:Receptors, Dopamine; D009271:Naltrexone