Choice between Heroin and Food in Nondependent and Heroin-Dependent Rhesus Monkeys: Effects of Naloxone, Buprenorphine, and Methadone

Abstract

Several medications are approved for treatment of opiate abuse, but determinants of their clinical effectiveness are not completely understood. States of opiate dependence or withdrawal may constitute one important set of determinants. To test this hypothesis, the effects of naloxone, buprenorphine, and methadone were assessed on choice between heroin and food in nondependent rhesus monkeys and in heroin-dependent monkeys undergoing withdrawal. A choice procedure was used to permit dissociation of medication effects on the relative reinforcing properties of heroin from nonselective effects on response rates. In nondependent monkeys, increasing unit doses of heroin (0 -0.1 mg/kg/injection) maintained dose-dependent increases in heroin choice. Chronic 5-day treatment with naloxone (0.01-0.32 mg/kg/h) or buprenorphine (0.01-0.1 mg/kg/day) produced dose-dependent rightward shifts in heroin choice dose-effect curves, whereas chronic methadone (0.1-0.56 mg/kg/h) had little effect on heroin choice up to doses that suppressed responding. In heroin-dependent monkeys, opiate withdrawal produced overt abstinence signs as well as increases in heroin choice, manifested as leftward shifts in heroin choice dose-effect curves. The withdrawal-associated increases in heroin choice suggest that opiate withdrawal increased the relative reinforcing efficacy of heroin in comparison with food, an effect that may be related to relapse in humans. Methadone prevented withdrawal-associated increases in heroin choice, whereas buprenorphine was less effective. These findings suggest that agonist medications such as methadone may derive their clinical utility from their ability to attenuate withdrawal-associated increases in opiate reinforcement. Moreover, this procedure may be useful for exploring mechanisms underlying withdrawal-associated increases in opiate reinforcement and for testing candidate medications.

Supply of a Nondrug Substitute Reduces Escalated Heroin Consumption

“…This general conclusion appears, however, to conflict with previous research in opioid-dependent monkeys showing that opioid withdrawal decreased the ability of food to substitute for heroin (Negus, 2006) or morphine (Spragg, 1940;Griffiths et al, 1975). For instance, Negus (2006) recently demonstrated using a discrete-trials choice procedure in monkeys that withdrawal from prolonged access to heroin self-administration is associated with an increased preference for heroin that was temporarily correlated with the emergence of physical signs of opioid withdrawal.…”

“…For instance, Negus (2006) recently demonstrated using a discrete-trials choice procedure in monkeys that withdrawal from prolonged access to heroin self-administration is associated with an increased preference for heroin that was temporarily correlated with the emergence of physical signs of opioid withdrawal. In the present study, no attempt was made to measure physical signs of opioid withdrawal in LgA rats.…”

Effects of d-Amphetamine and Buprenorphine Combinations on Speedball (Cocaine+Heroin) Self-Administration by Rhesus Monkeys

“…Buprenorphine consistently reduces cocaine self-administration in both clinical and preclinical studies . Buprenorphine also reduces heroin and speedball self-administration in both clinical and preclinical studies Mello and Negus, 1998;Montoya et al, 2004;Negus, 2006). Taken together, these clinical and preclinical data suggest that this speedball selfadministration model in non-human primates is useful for evaluation of new pharmacotherapies for drug abuse treatment (Mello, 2005).…”

High-Dose Methadone Maintenance in Rats: Effects on Cocaine Self-Administration and Behavioral Side Effects

“…Loss of sex drive is a side effect commonly reported by patients on methadone maintenance (Daniell, 2002b;Fischer et al, 2002), but it is not clear whether sexual dysfunctions result from a dose-dependent pharmacological effect of methadone (Daniell, 2002a;de la Rosa and Hennessey, 1996) or from preexisting hypogonadism induced by heroin addiction (Mirin et al, 1980). Another side effect reported by some methadone-maintained patients is general anhedonia (Fischer et al, 2002), and in primates chronic exposure to methadone reduces operant responding for palatable food (Negus, 2006;Negus and Mello, 2004). However, because acute methadone can have rate-suppressing effects on operant behavior (Macenski et al, 1994;McMillan et al, 1980;Thompson, 1987, 1989), its effect on consumption of palatable food needs to be examined using a test that does not involve operant responding.…”