Serotonin antagonists fail to alter MDMA self-administration in rats

This vehicle-controlled rat study (n=61) investigated the role of serotonergic agonists in preventing relapse into drug-seeking behavior, in response to re-exposure to a single dose of MDMA or cocaine (10 mg/0.3kg), or a conditioned light-cue associated with their drug-intake prior to extinction. Results indicate that 5-HT1A and 5-HT2A agonists prevent relapse into cocaine self-administration, but neither of the 5-HT1A, 5-HT1B, or 5-HT2A agonists could alter the maintenance of MDMA self-administration. However, the 5-HT1A agonists prevented relapse into drug-seeking behavior elicited by exposure to cues that had been associated with self-administered MDMA.

Abstract

Introduction: Acute exposure to ±3,4-methylenedioxymethamphetamine (MDMA) preferentially increases release of serotonin (5-HT), and a role of 5-HT in many of the behavioral effects of acute exposure to MDMA has been demonstrated. A role of 5-HT in MDMA self-administration in rats has not, however, been adequately determined. Therefore, the present study measured the effect of pharmacological manipulation of some 5-HT receptor subtypes on self-administration of MDMA.

Methods: Rats received extensive experience with self-administered MDMA prior to tests with 5-HT ligands. Doses of the 5-HT1A antagonist, WAY 100635 (0.1–1.0 mg/kg), 5-HT1B antagonist, GR 127935 (1.0–3.0 mg/kg), and the 5-HT2A antagonist, ketanserin (1.0–3.0 mg/kg) that have previously been shown to decrease self-administration of other psychostimulants and that decreased MDMA-produced hyperactivity in the present study did not alter MDMA self-administration.

Results: Experimenter-administered injections of MDMA (10.0 mg/kg, ip) reinstated extinguished drug-taking behavior, but this also was not decreased by any of the antagonists. In contrast, both WAY 100635 and ketanserin, but not GR 127935, decreased cocaine-produced drug seeking in rats that had been trained to self-administered cocaine. The 5-HT1A agonist, 8-OH-DPAT (0.1–1.0 mg/kg), but not the 5-HT1B/1A agonist, RU 24969 (0.3–3.0 mg/kg), decreased drug-seeking produced by the reintroduction of a light stimulus that had been paired with self-administered MDMA infusions.

Discussion: These findings suggest a limited role of activation of 5-HT1A, 5-HT1B or 5-HT₂ receptor mechanisms in MDMA self-administration or in MDMA-produced drug-seeking following extinction. The data suggest, however, that 5-HT1A agonists inhibit cue-induced drug-seeking following extinction of MDMA self-administration and might, therefore, be useful adjuncts to therapies to limit relapse to MDMA use. “

Authors: Susan Schenk, Jason Foote, Dane Aronsen, Natasha Bukholt, Quenten Highgate, Ross Van de Wetering & Jeremy Webster

Summary

  1. Introduction

MDMA, an amphetamine analogue, is being used recreationally by young people across the globe. Several studies have documented a dependence syndrome in some users, based on DSM IV criteria.

Ecstasy users develop an SUD because of the pharmacology of MDMA, which preferentially increases synaptic serotonin (5-HT) and produces smaller increases in synaptic dopamine (DA). However, selective 5-HTuptake inhibitors are not abused and fenfluramine did not maintain self-administration in rats trained to self-administer amphetamine.

Ecstasy users have decreased density of 5-HT transporters, and MDMA increases DA preferentially in the shell of the nucleus accumbens in rats. This neurochemical effect becomes sensitized following repeated exposure, and cross-sensitization to hyperlocomotion produced by amphetamine or the DA D2/3 agonist, quinpirole, is also shown.

MDMA’s acute effects have been attributed to both 5-HT and DA mechanisms, but its reinforcing effects have often been attributed to DAergic effects. This study optimized conditions for observing decreases in MDMA self-administration and reinstatement of drug-seeking following administration of some 5-HT agonists and antagonists.

2.1. Animals

Male Sprague-Dawley rats were housed 4 to a cage in hanging polycarbonate cages until weights of 300 g were achieved (2 – 3 months). They were then placed in isolation for 7 days before experimental procedures commenced.

2.2. Apparatus

Self-administration testing was conducted in standard operant chambers equipped with two levers. MDMA was delivered over a period of 12 s and a light was illuminated above the active lever.

2.3.1. Surgery

A catheter was inserted into the jugular vein and a 22 ga stainless steel tubing was threaded subcutaneously and mounted on the scalp using four jeweler’s screws embedded in dental acrylic. Daily Carprofen injections were administered for two days following surgery to prevent blood coagulation and infection.

2.3.2. Acquisition of self-administration

Every session began with an infusion of MDMA or cocaine paired with the illumination of a stimulus light.

Initial training consisted of daily 2 h sessions during which lever presses were reinforced with MDMA infusions (1.0 mg/kg). After a total of 90.0 infusions had been self-administered, rats were tested for 5-HT ligand effects on MDMA-self-administration and reinstatement of drug-seeking.

2.3.3. Self-administration tests

MDMA self-administration was tested in separate groups of rats with the 5-HT1A antagonist, WAY 100635, the 5-HT1B antagonist, GR 127935, or the 5-HT2A antagonist, ketanserin. The effects of each drug were determined in a recurring series of 2 h daily tests.

2.3.4. Reinstatement of extinguished drug-taking behavior

A recurring series of drug-seeking tests was conducted in rats, consisting of baseline, extinction and reinstatement phases. To determine whether 5-HT antagonists would decrease the potentiated drug-seeking response produced by MDMA, separate groups of rats were tested with each of the antagonists.

To determine whether the antagonists would decrease cocaine-produced cocaine-seeking, groups of rats were tested with cocaine self-administration and WAY 100635, GR 127935, orketanserin.

2.3.5. Locomotor activity testing

To ensure that the doses used in the MDMA self-administration and drug-seeking experiments were behaviorally relevant, effects on MDMA-produced hyperactivity were measured before and after administration of WAY 100635, GR 127935 and ketanserin.

2.4. Statistical analysis

The effects of the various antagonists on responding maintained by MDMA were measured using 2-way repeated measures ANOVAs.

2.5. Materials

All antagonists were obtained from Tocris Bioscience, NZ, and were administered 30 min, 15 min, and immediately prior to the test. MDMA and cocaine were obtained from ESR.

  1. Results

In 2 h tests, MDMA-maintained responding was high whereas inactive lever responding was low. Separate 2-way repeated measures ANOVA revealed significant main effects of lever but no significant effect of drug dose.

MDMA reinstated extinguished responding following extinction of self-administration. Pretreatment with antagonists had no effect on reinstatement of drug-seeking.

The antagonists decreased the drug seeking responses produced following extinction of cocaine self-administration. There was no effect of GR 127935 Dose or an interaction between Lever and WAY 100635 Dose.

During extinction, neither the light stimulus nor MDMA infusions reinforced lever pressing, but during the drug-seeking test, responses were reinforced by the presentation of the light stimulus.

The highest dose of the antagonists used in the self-administration experiments decreased the response to MDMA. The effects were dependent on time and dose, and were significant from 35 min following the MDMA injection.

  1. Discussion

Results show that 5-HT1A, 5-HT1B, and 5-HT2A receptor antagonists failed to alter the maintenance of MDMA self-administration.

The 5-HT1A, 5-HT1B, and 5-HT2A antagonists used in this study failed to decrease the potentiated drug-seeking response produced by a priming injection of MDMA.

The failure to observe effects of serotonin antagonists on MDMA-produced drug-seeking might be due to differences in the elimination half-life of the drugs. However, the short elimination half-life of WAY 100635 makes this unlikely, since other drugs with short elimination half-lives attenuated MDMA-produced drug-seeking.

We suggest that a decrease in MDMA-produced 5-HT and an increase in MDMA-produced DA is due to extensive self-administration experience, which is a prerequisite for both MDMA self-administration and drug-seeking following extinction of responding.

Results from other laboratories indicate more modest MDMA self-administration, although Dalley’s laboratory indicated self-administration that was comparable to rates achieved during the same protocol of amphetamine self-administration. The basis for the differences across laboratories is not understood, but might reflect procedural variables.

Some laboratories conduct MDMA self-administration for long periods of time, whereas others conduct it for shorter periods. The impact of these differences is not currently known.

In our previous study, 5-HT2 agonists and mCPP failed to alter drug-seeking, and the uptake inhibitor clomipramine decreased drug-seeking following extinction of MDMA self-administration. In the present study, 8-OH-DPAT but not RU 24969 decreased drug-seeking produced by reintroduction of the light stimulus that had been paired with MDMA infusions.

DAergic mechanisms of MDMA self-administration and drug-seeking have been demonstrated. 5-HT1 agonists may decrease DA overflow produced by psychostimulants, whereas DA antagonists are generally ineffective in altering psychostimulant-produced increases in DA.

Other studies have indicated a role of some 5-HT receptor mechanisms in drug self-administration, including a decrease in cocaine self-administration by 5-HT1B antagonists, a decrease in amphetamine self-administration by 8 OHDPAT, and a decrease in drug-seeking by WAY 100635 and ketanserin.

Drug-self-administration procedures are widely used to determine neurobiological mechanisms underpinning compulsive drug-taking. The present findings do not support the idea that 5-HT1A, 5-HT1B or 5-HT2A antagonists would be effective therapeutic interventions for MDMA dependence.

Study details

Topics studied
Addiction

Study characteristics
Animal Study

Participants
61