Differential effects of μ-, δ- and κ-opioid receptor agonists on the discriminative stimulus properties of cocaine in rats

We investigated whether chronic exposure to heroin alters responses to cocaine in ways that might explain the use of cocaine by opioid addicts. To this end, the effects of cocaine (5 and 20 mg/kg) were assessed on locomotor activity of rats chronically exposed to heroin (0.0, 3.5, 7.0, and 14.0 mg/kg/day, over 14 days, via osmotic mini-pumps), or withdrawn from heroin (1 day, acute withdrawal, and 14 days, protracted withdrawal). Chronic heroin exposure, in itself, dose dependently increased locomotion and acute cocaine administration further elevated locomotor activity in a dose-dependent and additive manner. During acute withdrawal, there was a dosedependent decrease in locomotion that was reversed by cocaine in a dose-dependent manner. During protracted withdrawal, spontaneous locomotion normalized, but rats previously exposed to heroin displayed cross-sensitization to cocaine as indicated by small, but significant, enhanced locomotor response to 5 mg/kg of cocaine, and enhanced intravenous self-administration of low doses of cocaine (0.13 mg/kg/infusion). In a separate study, we measured extracellular dopamine (DA) in the nucleus accumbens (Acb) using in vivo microdialysis before and after acute withdrawal from heroin. During chronic exposure to heroin, basal extracellular DA was elevated dose dependently, whereas in acute withdrawal, levels were not different from those in vehicle-treated rats. In response to cocaine, however, DA activity in the Acb was significantly lower in rats withdrawn from the highest dose of heroin.

Section: Effects Of Cocaine During Chronic Exposure To Heroin and Dursupporting

confidence: 78%

Effects of Cocaine in Rats Exposed to Heroin

Leri

Flores

Rajabi

et al. 2003

“…In both the heroin study and the present study with methadone, we have consistently observed that chronic exposure to opiate drugs elevates locomotor activity in a dose-dependent manner and that the stimulatory effects of cocaine summate with those of the opiate drugs. It should not be surprising to find an additive effect of cocaine on locomotion induced by chronic opiate exposure in light of the known synergistic interactions between dopaminergic agonists (cocaine and amphetamine) and mu agonists on 6-hydroxydopamine-induced rotation behavior (Kimmel and Holtzman, 1997), drug reinforcement (Bilsky et al, 1992;Duvauchelle et al, 1998;Mattox et al, 1997;Ranaldi and Munn, 1998;Rowlett et al, 1997;Wang et al, 2001), drug discrimination (Green-Jordan et al, 2001;Bergman, 1992, 1994;Suzuki et al, 1997), elevation of dopamine concentration in the ventral striatum (Gerasimov and Dewey, 1999;Hemby et al, 1999), analgesia (Gatch et al, 1995;Kauppila et al, 1992;Misra et al, 1987;Nott, 1968;Shimada et al, 1988;Sierra et al, 1992), and drug toxicity (Blumberg and Ikeda, 1978;Leander and Lucot, 1977;Plunkett et al, 1989). It is surprising, however, that although chronic methadone maintenance did not reduce cocaineinduced stimulation of locomotion, it did reduce cocaineinduced reinstatement of cocaine seeking.…”

Section: Discussionmentioning

confidence: 99%

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

Leri

Tremblay

Sorge

et al. 2004

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.

“…However, the k agonists U50 488 and EKC did not consistently alter cocaine discrimination performance in rhesus monkeys (Negus and Mello, 1999). In rats, both attenuation of cocaine discrimination (Kantak et al, 1999;Mori et al, 2002) and no effect have been reported (Broadbent et al, 1995;Suzuki et al, 1997;Woolfolk and Holtzman, 1997).…”

Section: Introductionmentioning

confidence: 85%

Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys

Bowen

Negus

Zong

et al. 2002

k-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed k/m receptor activity is unclear. The effects of three mixed k/m agonists (MCL-101, (À)cyclorphan, and Mr2034) and one k-selective agonist (enadoline) on cocaine selfadministration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all k agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose-effect curve (0.001-0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (À)cyclorphan (0.0032-0.032 mg/kg/h) and MCL-101 (0.0032-0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration doseeffect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (À)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed k/m agonists produced fewer side effects (some salivation) than the k-selective agonist (sedation, salivation, emesis). However, none of these k agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, k and mixed k/m-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed k/m agonists appear to offer some advantages over selective k agonists as potential treatments for cocaine abuse.