Methadone Maintenance Reduces Heroin- and Cocaine-Induced Relapse without Affecting Stress-Induced Relapse in a Rodent Model of Poly-Drug Use

Abstract

Although it is well established that methadone can be an effective treatment for opiate addiction, it is not clear how methadone maintenance affects cocaine use and cravings in individuals who self-administer both opiates and cocaine. In our attempt to explore the effect of methadone maintenance on the effects of cocaine, we first assessed the locomotor stimulatory effects of cocaine in rats maintained on methadone (0, 10, 20, or 30 mg/kg/day, via osmotic minipumps). Chronic methadone elevated baseline locomotion in a dose-dependent manner and did not reduce the direct stimulatory effects of cocaine (5 mg/kg). We then investigated the effects of the highest methadone maintenance dose (30 mg/kg/day) on heroin and cocaine seeking in extinction, and when it was precipitated by exposure to heroin, cocaine, or foot-shock stress in rats trained to self-administer both drugs in the same experimental context (heroin 0.05 mg/kg/inf; cocaine 0.5 mg/kg/inf, eight 3-h sessions each). In tests of reinstatement, rats responded selectively on the appropriate drug-associated lever after priming injections of heroin (0.25 mg/kg) or cocaine (20 mg/kg). Methadone maintenance blocked both cocaine-and heroin-induced reinstatement, but not stress-induced reinstatement, which was not lever selective. These results suggest that although methadone maintenance may not reduce the direct stimulatory effects of cocaine, it has the potential to reduce both spontaneous and cocaine-primed cocaine-seeking behavior.

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

“…In fact, during cocaine self-administration on a PR (Experiment 2), it was found that rats maintained on 30 mg/kg/day methadone failed to adjust to the increased work requirement to obtain drug infusions and, as a result, obtained significantly less cocaine than control animals. These results are consistent with previous findings from our laboratories showing that rats maintained on doses of methadone above 20 mg/kg/day do not respond for cocaine-conditioned cues, do not approach a cocaine-conditioned environment, and do not show reinstatement of cocaine seeking after priming injections of cocaine (Leri et al, 2004(Leri et al, , 2005(Leri et al, , 2006. It is important to note that methadone-induced blockade of cocaine seeking observed in our experiments is not an artifact of impaired sensory-motor functioning.…”

“…It is important to note that methadone-induced blockade of cocaine seeking observed in our experiments is not an artifact of impaired sensory-motor functioning. In fact, rats tested in Experiment 2 displayed normal locomotor activity and those tested in our previous experiments showed no reduction of cocaine self-administration on a continuous schedule of reinforcement, and showed significant reinstatement of heroin and cocaine seeking after exposure to foot-shock stress (Leri et al, 2004(Leri et al, , 2006. Interestingly, it was found that methadone maintenance did not attenuate the rise in extracellular dopamine levels in the ventral striatum induced by acute cocaine injections.…”

“…In the other experiments (except Experiment 3, see below), a single dose of 30 mg/kg/day was used because this methadone dose has been previously shown to (1) increase locomotor activity, (2) block cocaine-induced reinstatement of cocaine seeking, (3) block formation and expression of cocaine place conditioning, (4) not alter cocaine self-administration on a continuous schedule of reinforcement, and (5) not alter stress-induced reinstatement of cocaine seeking (Leri et al, 2004(Leri et al, , 2006.…”

“…In primates, methadone maintenance has been shown to suppress cocaine selfadministration on a variety of reinforcement schedules, but these effects have been attributed to impaired sensorymotor functions (Negus and Mello, 2004) such as impaired ability to initiate motor behavior toward the self-administration lever. In rats, high-dose methadone maintenance neither alters the stimulatory action of cocaine (Leri et al, 2004(Leri et al, , 2006 nor reduces the intravenous self-administration of cocaine on a continuous schedule of reinforcement (Leri et al, 2006). However, rats maintained on high-dose methadone show significant reductions in cocaine seeking as indexed by reduced reinstatement of operant responding after priming injections of cocaine (Leri et al, 2004), as well as reduced formation and expression of cocaine-induced place preference (Leri et al, 2006).…”

Involvement of Arginine Vasopressin and V1b Receptor in Heroin Withdrawal and Heroin Seeking Precipitated by Stress and by Heroin

“…In fact, it is well known that the effect of heroin primes on reinstatement is dependent on activation of muopioid receptor (MOP-r) (de Wit and Stewart, 1983;Shaham et al, 1996;Leri et al, 2004). In the paraventricular nucleus of the hypothalamus, AVP-producing parvocellular cells express MOP-rs, and activity of these cells is under tonic inhibition by endogenous opioids (Nikolarakis et al, 1987).…”