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

Rowlett, James K.

doi:10.1124/jpet.104.065631

Cited by 15 publications

(12 citation statements)

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“…The latter results are in agreement and consistent with a previous report that prazosin produced partial antagonism of a cocaine stimulus and that prazosin antagonized fully the cocaineenhancing stimulus effects of PRO in rats (Kleven and Koek 1998). On the other hand, prazosin has been reported to produce either no antagonism (at all) of the stimulus effect of cocaine in rats (Kleven et al 1999) or full antagonism (or a shift of the dose response) of the stimulus effect of cocaine in pigeons (Johanson and Barrett (1993) and squirrel monkeys (Rowlett et al 2004;Spealman 1995). Taken together, the latter results raise the likely possibility of a species (and/or other methodological) difference(s) in the behavioral evaluation of the interactive effects between prazosin and cocaine.…”

Section: Discussionsupporting

confidence: 81%

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Young

Glennon

2008

Psychopharmacology

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Rationale Racemic propranolol (PRO), a β-adrenoceptor antagonist, has been evaluated as a test agent but not as a discriminative stimulus. Its S(−) stereoisomer is thought to subserve the effects of (±)PRO. Materials and methods Rats were trained to discriminate S(−)PRO (5 mg/kg) from saline in a two-lever foodreinforced operant conditioning task. Results The S(−)PRO stimulus was shown to be centrally mediated, dose-related, time dependent, and stereoselective: S(−)PRO (ED 50 =2.2 mg/kg) was twice as potent as (±)PRO and approximately four times as potent as R(+)PRO. The S(−)PRO stimulus generalized fully to the β-adrenoceptor agent pindolol, the α 1 -adrenoceptor agonist methoxamine, cocaine, and the serotonergic agents TFMPP and RU 24969; partial generalization occurred to (−)ephedrine and nisoxetine but not to fenfluramine or 5-OMe DMT. The S(−)PRO stimulus was blocked completely (and competitively) when prazosin, an α 1 -adrenoceptor antagonist, was given in combination with the training dose of S(−)PRO. Moreover, prazosin exerted antagonism of the S(−)PRO-like effect of (±)PRO or R(+)PRO but produced only partial antagonism of the S(−)PRO-like effect of cocaine. In a second study, rats were trained to discriminate 8 mg/kg of cocaine from saline. The cocaine stimulus generalized to S(−)PRO, (±)PRO, and R(+)PRO. Prazosin partially attenuated the stimulus effect of cocaine (8 mg/kg) but completely blocked the cocaine-like effects of (±), S(−), and R(+)PRO. Conclusions PRO and cocaine exhibited cross-substitution, but their stimulus effects were antagonized differentially by prazosin. PRO (and its optical isomers) can exert a stimulus effect that is based, at least in part, on increased α 1 -adrenoceptor activity. PRO might be better characterized as an adrenoceptor partial agonist.

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Section: Discussionsupporting

confidence: 81%

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Young

Glennon

2008

Psychopharmacology

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“…The ␦ opioid agonist SNC 80 also substituted partially for cocaine but not for heroin. These findings are consistent with other studies (Negus et al, 1998b;Rowlett and Spealman, 1998;Kantak et al, 1999;Rowlett et al, 2004) demonstrating that heroin and other opioid agonists can share DS effects with cocaine, despite being pharmacologically distinct.…”

Section: Discussionsupporting

confidence: 82%

Asymmetric Generalization and Interaction Profiles in Rhesus Monkeys Discriminating Intravenous Cocaine or Intravenous Heroin from Vehicle

Platt

Rowlett²,

Spealman³

2010

The Journal of Pharmacology and Experimental Therapeutics

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Many polydrug abusers combine cocaine with heroin in the form of a "speedball." This study investigated the discriminative stimulus (DS) effects of speedballs in rhesus monkeys trained to discriminate either intravenous cocaine or intravenous heroin from vehicle. Initial substitution tests revealed an asymmetry in the generalization profile of dopamine and opioid agonists such that agonists partially substituted for cocaine, but direct and indirect dopamine agonists did not substitute for heroin. Subsequent speedball tests in which drug mixtures were administered by coinjecting the component drugs while keeping the dose-ratio constant revealed an additional asymmetry. In cocaine-trained monkeys, coadministration of cocaine and heroin produced leftward shifts in the cocaine dose-response function. Heroin's cocaine-enhancing effects were mimicked by the agonists fentanyl and methadone and less consistently by thereversed by the antagonist naltrexone and the ␦ antagonist naltrindole. In heroin-trained monkeys, coadministration of cocaine and heroin attenuated the DS effects of heroin. Cocaine's heroin-attenuating effects were mimicked by the D1-like agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine (SKF 81297) and the D2-like agonist R-(Ϫ)-propylnorapomorphine and reversed by the D1-like antagonist (6aS-trans)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H- (SCH 39166) and the D2-like antagonist raclopride. Attenuation of the effects of heroin was accompanied by decreases in response rate. These results suggest that heroin enhances the DS effects of cocaine via , and to a lesser extent ␦, receptor mechanisms; whereas cocaine-induced inhibition of the DS effects of heroin probably was due at least in part to masking of the heroin DS presumably via stimulation of both D1-and D2-like receptors.Many polydrug abusers take cocaine combined with heroin by self-administering the drugs together in the form of "speedballs." Between 30 and 80% of heroin abusers also use cocaine (Kosten et al., 1986), and cocaine abuse has been reported with high frequency in heroin-dependent individuals maintained on methadone (Levin et al., 1996). Likewise, Lauzon et al. (1994) found that 50% of intravenous cocaine users reported using heroin regularly.Speedball abusers often report that the combined use of cocaine and heroin produces a more pleasurable subjective experience than either drug alone and that the combination may ameliorate perceived undesirable effects of the individual drugs (Kosten et al., 1986). These self-reports have been largely confirmed in laboratory studies with human volunteers (Foltin and Fischman, 1992;Foltin et al., 1995;Preston et al., 1996;Walsh et al., 1996). In the studies by Foltin and Fischman (1992) and Walsh et al. (1996), for example, the subjective effects of cocaine combined with the heroin-like opioids morphine and hydromorphone were greater than those induced by the individual drugs on measures of "drug liking" and "high." Similarly, ratings of "magnitude of drug e...

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“…Moreover, cocaine and heroin have been shown to share abuse-related effects (e.g., discriminative stimulus effects), and these shared effects probably involve DA and not serotonergic or noradrenergic systems (Rowlett et al, 2004). Cocaine binds to recognition sites associated with the DA transporter, resulting in inhibition of DA transport and, as a consequence of vesicular release of DA, accumulation of this neurotransmitter in the synapse.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Heroin and Cocaine Self-Administration by Dopamine D1- and D2-Like Receptor Agonists in Rhesus Monkeys

Rowlett

Platt²,

Yao³

et al. 2007

The Journal of Pharmacology and Experimental Therapeutics

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Cocaine-heroin combinations ("speedballs") are commonly self-administered by polydrug abusers. Speedball self-administration may reflect in part an enhancement of the reinforcing effects of the drug combination compared with either drug alone. The present study investigated the degree to which the dopamine receptor system plays a role in cocaine-induced enhancement of heroin self-administration. In rhesus monkeys trained under a progressive ratio schedule of i.v. drug injection, combining heroin with cocaine shifted the heroin dose-response function leftward, and isobolographic analysis indicated that the combined effects were dose-additive. Likewise, combining heroin with the D1-like receptor agonists 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine HCl (SKF 81297) and 6-chloro-N-allyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine (SKF 82958) resulted in a leftward shift in the heroin dose-response function that was dose-additive. In contrast, combining heroin with the D2-like agonists R-(Ϫ)-propylnorapomorphine (NPA) and quinpirole shifted the heroin dose-response function to the right. Isobolographic analysis of the combined effects of heroin with NPA and quinpirole revealed infra-additive interactions in both cases. When combined with cocaine instead of heroin, both the D1-like receptor agonist SKF 81297 and the D2-like receptor agonist NPA enhanced cocaine self-administration. The combinations of SKF 81297 with cocaine were dose additive; however, the NPA-cocaine interaction was infra-additive. Together, the results suggest that D1-and D2-like receptor mechanisms may play qualitatively different roles in the combined self-administration of heroin and cocaine. In particular, stimulation of D1-like receptors enhances self-administration of heroin or cocaine individually, similar to the effects of combining cocaine with heroin, whereas stimulation of D2-like receptors seems to play primarily an inhibitory role.Many polydrug abusers self-administer combinations of heroin and cocaine in the form of "speedballs". Research efforts focused on understanding speedball abuse have yet to reveal clear pharmacological mechanisms underlying this form of polydrug abuse. Preclinical investigations have implicated brain dopamine (DA) and opioid systems as important in modulating the abuse-related effects of stimulants and opioids when used individually (Di Chiara and North, 1992;Koob, 1992), and speedballs may engender their effects by an interaction of these two neurotransmitter systems (for review, see Leri et al., 2003).Although cocaine acts generally at monoamine systems (i.e., DA, serotonin, and norepinephrine systems), considerable evidence suggests that the abuse-related effects of cocaine itself are due primarily to its action at DA systems (for review, see Woolverton and Johnson, 1992;Platt et al., 2002). Moreover, cocaine and heroin have been shown to share abuse-related effects (e.g., discriminative stimulus effects), and these shared effects probably involve DA and not ...

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

Cited by 15 publications

References 23 publications

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Asymmetric Generalization and Interaction Profiles in Rhesus Monkeys Discriminating Intravenous Cocaine or Intravenous Heroin from Vehicle

Modulation of Heroin and Cocaine Self-Administration by Dopamine D1- and D2-Like Receptor Agonists in Rhesus Monkeys

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