Dataset Information

Dopaminergic mechanisms of reinstatement of MDMA-seeking behaviour in rats.

ABSTRACT: BACKGROUND AND PURPOSE: Animal models of drug-seeking suggest that exposure to cues associated with self-administered drugs and drug primes might precipitate relapse via activation of central dopaminergic substrates. EXPERIMENTAL APPROACH: The effects of priming injections of dopamine and 5-HT agonists on drug-seeking and effects of dopamine antagonists on methylenedioxymethamphetamine (MDMA)-produced potentiation of drug-seeking following extinguished MDMA self-administration were examined. KEY RESULTS: Drug-seeking was produced by exposure to a light stimulus that had been paired with self-administered MDMA infusions and this effect was potentiated by experimenter-administered injections of the dopamine D(2) -like receptor agonist, quinpirole, the indirect agonist, amphetamine and the uptake inhibitor, GBR 12909. Drug-seeking was not elicited by the dopamine D(1) -like receptor agonist, SKF 81297 or the non-selective agonist, apomorphine. The 5-HT receptor agonists DOI or mCPP also failed to elicit drug-seeking. The 5-HT uptake inhibitor, clomipramine, attenuated drug-seeking produced by the MDMA-associated stimulus but failed to alter the potentiated response produced by GBR 12909. The D(1) receptor antagonist, SCH 23390 or the D(2) receptor antagonist, eticlopride attenuated the potentiation of drug-seeking produced by MDMA. CONCLUSIONS AND IMPLICATIONS: These data provide evidence of dopaminergic mechanisms in drug-seeking following extinction of MDMA self-administration. Because tissue levels of 5-HT were significantly decreased following MDMA self-administration, we suggest that MDMA begins to preferentially activate dopaminergic substrates to potentiate the drug-seeking response.

SUBMITTER: Schenk S

PROVIDER: S-EPMC3081120 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dopaminergic mechanisms of reinstatement of MDMA-seeking behaviour in rats.

Schenk S S Gittings D D Colussi-Mas J J

British journal of pharmacology 20110401 8

<h4>Background and purpose</h4>Animal models of drug-seeking suggest that exposure to cues associated with self-administered drugs and drug primes might precipitate relapse via activation of central dopaminergic substrates.<h4>Experimental approach</h4>The effects of priming injections of dopamine and 5-HT agonists on drug-seeking and effects of dopamine antagonists on methylenedioxymethamphetamine (MDMA)-produced potentiation of drug-seeking following extinguished MDMA self-administration were ...[more]

PMID: 21198550

Similar Datasets

Project description:Background and purposeThe macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) is a multifunctional μ-opioid receptor and κ-opioid receptor agonist and κ-opioid receptor antagonist that produces antinociception and prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference (CPP). We hypothesized that an analogue of CJ-15,208, cyclo[Pro-Sar-Phe-d-Phe], would demonstrate multifunctional μ-opioid receptor and κ-opioid receptor ligand activity, producing potent antinociception with fewer liabilities than selective μ-opioid receptor agonists, while preventing both drug- and stress-induced reinstatement of morphine-induced CPP.Experimental approachThe opioid receptor agonist and antagonist activity of cyclo[Pro-Sar-Phe-d-Phe] was characterized after i.c.v. and i.p. administration to C57BL/6J or transgenic opioid receptor "knockout" mice using the 55°C warm-water tail-withdrawal assay. Liabilities of locomotor coordination, respiration and spontaneous ambulation, and direct rewarding or aversive properties were assessed. Finally, the ability of cyclo[Pro-Sar-Phe-d-Phe] to block morphine- and stress-induced reinstatement of extinguished CPP was determined.Key resultscyclo[Pro-Sar-Phe-d-Phe] demonstrated dose-dependent, short-lasting antinociception, with an ED50 (and 95% confidence interval) of 0.15 (0.05-0.21) nmol i.c.v. and 1.91 (0.40-3.54) mg·kg-1 i.p., mediated by μ- and κ-opioid receptors. The macrocyclic tetrapeptide also demonstrated potent dose-dependent κ-opioid receptor antagonist-like activity at 2.5, but not at 4.5, h after administration. cyclo[Pro-Sar-Phe-d-Phe] displayed reduced liabiities compared with morphine, attributed to its additional activity at κ-receptors. Pretreatment with cyclo[Pro-Sar-Phe-d-Phe] prevented stress- and drug-induced reinstatement of extinguished morphine-place preference responses in a time-dependent manner.Conclusions and implicationsThese data suggest that cyclo[Pro-Sar-Phe-d-Phe] is a promising lead compound for both the treatment of pain with reduced sideeffects and preventing both drug- and stress-induced relapse in morphine-abstinent subjects.

Dataset Information

Dopaminergic mechanisms of reinstatement of MDMA-seeking behaviour in rats.

Publications

Dopaminergic mechanisms of reinstatement of MDMA-seeking behaviour in rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets