Cocaine-like discriminative stimulus effects of heroin in squirrel monkeys: role of active metabolites and opioid receptor mechanisms

Rowlett, James K.; Spealman, Roger D.; Platt, Donna M.

doi:10.1007/s002130000427

Cited by 9 publications

(8 citation statements)

References 22 publications

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“…In this experiment, receptor theory would predict that increasing naltrexone fixed-dose pretreatments would produce parallel rightward shifts in the fentanyl dose-effect function. The present results were consistent with this hypothesis, and the naltrexone pA 2 values reported in this study were consistent with previous naltrexone studies in monkeys (Rowlett et al, 2000;Bowen et al, 2002; Gerak and France, 2007). Overall, these results provide an empirical foundation to interpret the antinociceptive effects of fixedproportion fentanyl and naltrexone mixtures.…”

Section: Discussionsupporting

confidence: 93%

Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys

Cornelissen

Obeng

Rice

et al. 2018

J Pharmacol Exp Ther

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Receptor theory predicts that fixed-proportion mixtures of a competitive, reversible agonist (e.g., fentanyl) and antagonist (e.g., naltrexone) at a common receptor [e.g., mu-opioid receptors (MORs)] will result in antagonist proportion-dependent decreases in apparent efficacy of the agonist/antagonist mixtures and downward shifts in mixture dose-effect functions. The present study tested this hypothesis by evaluating behavioral effects of fixed-proportion fentanyl/naltrexone mixtures in a warm-water tail-withdrawal procedure in rhesus monkeys ( = 4). Fentanyl (0.001-0.056 mg/kg) alone, naltrexone (0.032-1.0 mg/kg, i.m.) alone, and fixed-proportion mixtures of fentanyl/naltrexone (1:0.025, 1:0.074, and 1:0.22) were administered in a cumulative-dosing procedure, and the proportions were based on published fentanyl and naltrexone values at MOR in monkey brain. Fentanyl alone produced dose-dependent antinociception at both 50 and 54°C thermal intensities. Up to the largest dose tested, naltrexone alone did not alter nociception. Consistent with receptor theory predictions, naltrexone produced a proportion-dependent decrease in the effectiveness of fentanyl/naltrexone mixtures to produce antinociception. The maximum effects of fentanyl, naltrexone, and each mixture were also used to generate an efficacy-effect scale for antinociception at each temperature, and this scale was evaluated for its utility in quantifying 1) efficacy requirements for antinociception at 50 and 54°C and 2) relative efficacy of six MOR agonists that vary in their efficacies to produce agonist-stimuated GTPS binding in vitro (from lowest to highest efficacy: 17-cyclopropylmethyl-3,14-dihyroxy-4,5-epoxy-6-[(3'-isoquinolyl)acetamindo]morphine, nalbuphine, buprenorphine, oxycodone, morphine, and methadone). These results suggest that fixed-proportion agonist/antagonist mixtures may offer a useful strategy to manipulate apparent drug efficacy for basic research or therapeutic purposes.

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Section: Discussionsupporting

confidence: 93%

Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys

Cornelissen

Obeng

Rice

et al. 2018

J Pharmacol Exp Ther

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“…The findings of the present study confirm that heroin has full or partial cocainelike DS effects in a sizeable proportion of subjects trained to discriminate cocaine, an observation consistent with other studies (e.g., Mello et al, 1995;Negus et al, 1998;Rowlett et al, 2000. These results suggest that although heroin and cocaine are pharmacologically distinct, they can share interoceptive effects in cocaine-trained monkeys.…”

Section: Discussionsupporting

confidence: 93%

“…For example, in drug discrimination procedures, which provide information relevant to understanding a drug's interoceptive effects, stimulants and opioids often engender shared discriminative stimulus (DS) effects. In this regard, various opioid agonists have been shown to engender partial or full substitution for cocaine in the majority of monkeys trained to discriminate cocaine from vehicle (Mello et al, 1995;Negus et al, 1998;Rowlett et al, 2000Rowlett et al, , 2001. Because shared DS effects of drugs often correspond closely with overlapping mechanisms of action, these findings suggest commonalities in the neuropharmacological mechanisms underlying transduction of the DS effects of stimulants and opioids.…”

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confidence: 99%

Cocaine-Like Discriminative Stimulus Effects of Heroin: Modulation by Selective Monoamine Transport Inhibitors

Rowlett¹

2004

J Pharmacol Exp Ther

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In previous studies, heroin was shown to engender cocaine-like discriminative stimulus (DS) effects; however, the mechanisms underlying the cocaine-like effects of heroin are unknown. The present study evaluated the extent to which the shared DS effects of heroin and cocaine involve common monoaminergic mechanisms of action. In squirrel monkeys discriminating cocaine (0.3 mg/kg) from saline, heroin engendered full or partial substitution for cocaine in three of four monkeys. Pretreatment with the selective dopamine transport inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909) dose dependently enhanced the cocaine-like DS effects of heroin in these three monkeys as well as the DS effects of cocaine in all subjects. Neither talsupram, a noradrenergic transport inhibitor, nor prazosin, a noradrenergic antagonist selective for ␣-1 receptors, systematically altered the cocainelike DS effects of heroin at doses that enhanced (talsupram) or attenuated (prazosin) the DS effects of cocaine. Pretreatment with the serotonin uptake inhibitor citalopram similarly failed to alter the cocaine-like DS effects of heroin at doses that attenuated the DS effects of cocaine. Altogether, these findings suggest that heroin shares DS effects with cocaine in a subset of monkeys, and these cocaine-like effects are mediated at least in part by enhanced dopaminergic activity. Unlike the DS effects of cocaine itself, however, the cocaine-like DS effects of heroin do not appear to involve either noradrenergic or serotonergic mechanisms.

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“…This is evidenced by the finding that stimulant drugs and opiates do not necessarily substitute for each other in drug discrimination tasks (Dykstra et al, 1992) and, when they do, they do so asymmetrically. Hence, opiates can substitute for the µ-opiate receptor-dependent component of the discriminative properties of cocaine (Rowlett et al, 2000) and can potentiate the discriminative properties of cocaine (Suzuki et al, 1995). Cocaine, by contrast, does not substitute for, and does not influence, the discriminative properties of opiates.…”

Section: Discussionmentioning

confidence: 99%

“…However, this role of the AIC may be restricted to stimulant drugs having distinctive peripheral and anxiogenic effects (Mitchell et al, 1996). Opiates do not fully substitute for stimulant drugs in drug discrimination tasks (Negus et al, 1998;Rowlett et al, 2000;Rowlett et al, 2004), suggesting differences in the peripheral versus central nature of the reinforcing effects of these different classes of drug. Whether the AIC influences the loss of control over intake of opiates that lack the acute peripheral effects of stimulants after they have been self-administered has been investigated in the present study.…”

Section: Introductionmentioning

confidence: 99%

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse

Joshi

Puaud

Fouyssac

et al. 2020

Preprint

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word count: 233 AbstractThe anterior insular cortex (AIC) has been implicated in addictive behaviour, including the loss of control over drug intake, craving and the propensity to relapse. Evidence suggests that the influence of the AIC on drug-related behaviours is complex since in rats exposed to extended access to cocaine self-administration, the AIC was shown to exert a statedependent, bidirectional influence on the development and expression of loss of control over drug intake, facilitating the latter but impairing the former. However, it is unclear whether this influence of the AIC is confined to stimulant drugs that have marked peripheral sympathomimetic and anxiogenic effects or whether it extends to other addictive drugs, such as opiates, that lack overt acute aversive peripheral effects. Thus, we investigated in outbred rats the effects of bilateral excitotoxic lesions of AIC, induced both prior to or after long-term exposure to extended access heroin self-administration, on the development and maintenance of escalated heroin intake and the subsequent vulnerability to relapse following abstinence. Compared to sham-surgeries, pre-exposure AIC lesions had no effect on the development of loss of control over heroin intake, but lesions made after a history of escalated heroin intake potentiated escalation and also enhanced responding at relapse. These data show that the AIC inhibits or limits the loss of control over heroin intake and propensity to relapse, in marked contrast to its influence on the loss of control over cocaine intake.

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Cocaine-like discriminative stimulus effects of heroin in squirrel monkeys: role of active metabolites and opioid receptor mechanisms

Abstract: These results suggest that heroin and its deacetylated metabolites engendered cocaine-like DS effects in a similar fashion. Furthermore, the cocaine-like DS effects of these opioids were modulated by a predominantly mu-opioid receptor mechanism.

Cited by 9 publications

References 22 publications

Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys

Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys

Cocaine-Like Discriminative Stimulus Effects of Heroin: Modulation by Selective Monoamine Transport Inhibitors

The anterior insular cortex in the rat exerts an inhibitory influence over the loss of control of heroin intake and subsequent propensity to relapse

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