Effects of High-Dose Methadone Maintenance on Cocaine Place Conditioning, Cocaine Self-Administration, and Mu-Opioid Receptor mRNA Expression in the Rat Brain

Abstract

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

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.…”

“…The same dose of cocaine has been used in previous experiments employing Sprague-Dawley male rats to investigate the effect of methadone maintenance on cocaine self-administration on a continuous schedule of reinforcement and on cocaine-seeking behavior (Leri et al, 2006).…”

“…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

“…However, in the present study, we found that amygdalar MOP-r mRNA levels were not affected by either chronic heroin or heroin withdrawal (data not shown). Therefore, further time-course studies are necessary before alternative explanations, such as indirect amygdalar activation due to extra-amygdalar opioid action can be ruled out (eg, in the nucleus accumbens core during opiate or cocaine withdrawal) (Yao et al, 2005;Leri et al, 2006;Zhou et al, 2006).…”