Interactions of Cocaine with Dopamine Uptake Inhibitors or Dopamine Releasers in Rats Discriminating Cocaine

Li, Su Min; Campbell, Bettye L.; Katz, Jonathan L.

doi:10.1124/jpet.105.100594

Cited by 43 publications

(41 citation statements)

References 35 publications

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“…Once induced, the reinforcing effects of the selective s 1 R agonists were independent of dopaminergic mechanisms in this study as well as a previous study (Hiranita et al, 2013). The lack of substantive dopaminergic mediation of the effects of sR agonists is not surprising in light of behavioral studies showing a failure of the sR agonists, PRE-084 or DTG, to substitute for cocaine in rats trained to discriminate cocaine from saline injections (Hiranita et al, 2011b), a procedure in which a number of indirect dopaminergic agonists fully substitute for cocaine (Witkin et al, 1991;Li et al, 2006). Furthermore, administration of intravenous doses of PRE-084 that maintained self-administration behavior did not significantly stimulate dopamine levels in the nucleus accumbens shell in rats that had self-administered cocaine and PRE-084, or in rats that were not previously exposed to cocaine or PRE-084 (Hiranita et al, 2010(Hiranita et al, , 2013Garcés-Ramírez et al, 2011).…”

Section: Discussionmentioning

confidence: 77%

Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

Hiranita

Soto

Tanda

et al. 2013

J Pharmacol Exp Ther

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A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of s agonists mediated by their selective actions at s 1 receptors (s 1 Rs), which are intracellularly mobile chaperone proteins implicated in abuserelated effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was affected neither by the dopamine receptor antagonist (1)-butaclamol (10-100 mg/kg) nor by the opioid antagonist (2)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induces reinforcing effects of previously inactive s 1 R agonists. It is further suggested that induced s 1 R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment.

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Section: Discussionmentioning

confidence: 77%

Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

Hiranita

Soto

Tanda

et al. 2013

J Pharmacol Exp Ther

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“…Further, in this and previous studies (Hiranita et al, 2011b;Martin-Fardon et al, 2007), selfadministration of cocaine was insensitive to pretreatment with s 1 R antagonists, whereas the self-administration of the s 1 R agonist, PRE-084, in the present study was dosedependently blocked by s 1 R antagonists. A lack of substantive dopaminergic mediation of the effects of sR agonists is further supported by a failure of either PRE-084 or DTG to substitute for cocaine in rats trained to discriminate cocaine from saline injections (Hiranita et al, 2011a), a procedure in which a number of indirect dopaminergic agonists fully substitute for cocaine (Li et al, 2006;Witkin et al, 1991). Importantly, the cocaine-discrimination procedure involves regular cocaine injections, further indicating that administration of cocaine alone does not induce pharmacological responses to sR agonists similar to those of cocaine.…”

Section: Discussionmentioning

confidence: 99%

Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

Hiranita

Mereu

Soto

et al. 2012

Neuropsychopharmacol

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Sigma 1 receptors (s 1 Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective s 1 R agonists (PRE-084, ( þ )-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine selfadministration, responding was not maintained by either s 1 R agonist. In contrast, after subjects self-administered cocaine s 1 R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both s 1 R agonists, extinguished when injections were discontinued, and reconditioned when s 1 R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of s 1 R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the sR antagonist, BD1063, blocked PRE-084 selfadministration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive s 1 R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced s 1 R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.

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“…It has been previously reported that the discriminative effects of cocaine can be potentiated by DA uptake inhibitors, both "standard" inhibitors that did (Holtzman, 2001;Li et al, 2006) and those that did not (Tolliver et al, 1999;Katz et al, 2004) fully substitute for cocaine. The present compounds enhanced rather than antagonized the discriminative stimulus of cocaine.…”

Section: Discussionmentioning

confidence: 99%

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

Hong

Kopajtic

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3b-aryltropanes with 2b-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2a-enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2b-Ph 2 COCH 2 -3b-4-ClPh analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2b compounds increased locomotion, only the 2b-(4-ClPh)PhCOCH 2 -3b-4-Cl-Ph analog had cocaine-like efficacy. None of the 2a-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)-compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2b-and 2a-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine.

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Interactions of Cocaine with Dopamine Uptake Inhibitors or Dopamine Releasers in Rats Discriminating Cocaine

Cited by 43 publications

References 35 publications

Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

Stimulants as Specific Inducers of Dopamine-Independent σ Agonist Self-Administration in Rats

Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

2-Substituted 3 -Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations

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