Cocaine and Amphetamine Attenuate the Discriminative Stimulus Effects of Naltrexone in Opioid-Dependent Rhesus Monkeys

Abstract

This study tested the hypothesis that stimulants (indirect dopamine agonists) attenuate the discriminative stimulus of naltrexone in monkeys chronically treated with L-␣-acetylmethadol (LAAM). Four rhesus monkeys (Macaca mulatta) received LAAM (1.0 mg/kg s.c.) twice daily and discriminated a withdrawalprecipitating dose of naltrexone (0.0178 mg/kg s.c.) from saline. Cocaine (0.1-1.78 mg/kg), amphetamine (0.32-1.78 mg/kg), haloperidol (0.01-0.1 mg/kg), sulpiride (1.0 -10.0 mg/kg), propranolol (0.32-3.2 mg/kg), clonidine (0.001-0.1 mg/kg), desipramine (0.32-3.2 mg/kg), and imipramine (1.0 -10.0 mg/kg) were given s.c. before cumulative doses of naltrexone. Cocaine and amphetamine antagonized the discriminative stimulus effects of naltrexone, each shifting the naltrexone dose-effect curve significantly (e.g., 100-fold) rightward or downward. In contrast, the dopamine antagonist haloperidol shifted the naltrexone dose-effect curve 5-fold leftward. Sulpiride, desipramine, clonidine, and propranolol had comparatively less effect on the naltrexone discriminative stimulus, whereas some doses of imipramine attenuated the naltrexone stimulus in a manner similar to that of cocaine and amphetamine. These results support the notion that multiple neurotransmitter systems are involved in the discriminative stimulus effects of opioid withdrawal. Furthermore, these data are consistent with reports that dopamine levels decrease during opioid withdrawal and provide evidence that enhancing dopamine or other monoamine levels may attenuate subjective effects of opioid withdrawal.

Mechanisms of Withdrawal-Associated Increases in Heroin Self-Administration: Pharmacologic Modulation of Heroin vs Food Choice in Heroin-Dependent Rhesus Monkeys

“…However, clonidine did not alter other withdrawal signs, including the discriminative stimulus effects of withdrawal in rats or rhesus monkeys (Gellert and Holtzman, 1979; France and Woods, 1989) or the subjective effects of withdrawal in humans (Jasinski et al, 1985; Walsh et al, 2003). In contrast to clonidine, amphetamine decreased the discriminative stimulus effects of opioid withdrawal but did not attenuate somatic withdrawal signs in rhesus monkeys (Sell and France, 2002; McMahon et al, 2004; Sell et al, 2005). The selective effect of amphetamine on the discriminative stimulus effects of opioid withdrawal was interpreted to suggest an ability of amphetamine to attenuate withdrawal-induced suppression of mesolimbic dopamine levels (Sell and France, 2002).…”

Cocaine and Other Indirect-Acting Monoamine Agonists Differentially Attenuate a Naltrexone Discriminative Stimulus in Morphine-Treated Rhesus Monkeys

“…Smaller doses of cocaine and amphetamine increase opioid withdrawal in rodents, whereas larger doses seem to decrease opioid withdrawal, perhaps because cocaine and amphetamine induce stereotypy and therefore prevent the normal expression of withdrawal (Herz et al, 1974). In contrast, cocaine and amphetamine attenuate a naltrexone discriminative stimulus in l-␣-acetylmethadol-treated monkeys without decreasing signs induced by naltrexone in the same monkeys (Sell and France, 2002; S. L. Sell and C. P. France, unpublished observations).…”

Medications Development for Opioid Abuse

“…Lastly, opioid withdrawal is also associated with decreases in activity of some neurobiological systems, and given the well-established importance of the mesolimbic dopamine system as a mediator of motivated behavior, withdrawal-associated decreases in mesolimbic dopamine release may play an especially important role in modulating drug self-administration and the allocation of choice between drug and nondrug reinforcers (He et al 2004). In accordance with a potential role for decreased dopamine in opioid withdrawal, the indirect dopamine agonists amphetamine and cocaine blocked the discriminative stimulus effects of opioid withdrawal in opioid-dependent rhesus monkeys (Sell and France 2002); however, amphetamine failed to reliably decrease withdrawal-associated increases in opioid choice (Negus and Rice 2009).…”