European Journal of Neuroscience
November 16, 2007
Susan Schenk, Lincoln S. Hely, Barbara Lake et al.
113 citations
MDMA self-administration was studied in previously drug-naïve rats. Acquisition varied widely, with about 60% of rats learning to self-administer MDMA over 15 days, a lower rate and slower onset than for cocaine. Responding depended on dose, and breakpoints under a progressive ratio schedule increased with dose. Rats that self-administered MDMA showed lower densities of serotonin transporter sites (SERT) across brain regions, comparable to reductions from experimenter-administered MDMA. The findings indicate MDMA has high abuse liability and that long-term self-administration may cause lasting deficits in serotonin neurotransmission.
Pharmacology, biochemistry, and behavior
December 1, 2009
Aashish S. Morani, Bronwyn Kivell, Thomas E. Prisinzano et al.
91 citations
Pretreatment with several kappa-opioid receptor agonists, including salvinorin A (Sal A), the active compound in Salvia divinorum, reduced cocaine-induced drug-seeking in rats. After learning to self-administer cocaine, rats underwent extinction and then received a cocaine priming injection. Cocaine-induced reinstatement of drug-seeking was attenuated by U69593, U50488H, spiradoline, and Sal A. Sal A did not affect sucrose-reinforced responding or cocaine-induced hyperactivity, suggesting its effects are specific to drug-seeking. These findings indicate that Sal A, like other kappa-opioid agonists, can suppress cocaine-seeking behavior.
Neuropsychobiology
January 1, 2009
Susan Schenk
71 citations
Use of MDMA has risen globally and shifted from a dance-club subculture to broader, more frequent, high-dose consumption, with some users meeting criteria for abuse or dependence. Because studying human users involves confounding factors, animal models—especially self-administration—are used for their predictive validity. Most studies in primates and rodents show only low daily self-administration of MDMA, though some subjects self-administer high levels, possibly depending on test sessions, prior training, or other variables. MDMA is generally a weaker reinforcer than other drugs of abuse. The review suggests that repeated MDMA exposure reduces serotonin release, and the resulting serotonin deficit enhances dopamine responses, which may drive the development and maintenance of MDMA self-administration.
British Journal of Pharmacology
December 30, 2010
Susan Schenk, David Gittings, Joyce Colussi‐mas
61 citations
In rats trained to self-administer MDMA (ecstasy), a light cue previously paired with the drug triggered drug-seeking behavior. This effect was amplified by priming injections of drugs that activate dopamine D2-like receptors (quinpirole, amphetamine, GBR 12909) but not by a D1-like receptor agonist (SKF 81297), the non-selective dopamine agonist apomorphine, or serotonin (5-HT) receptor agonists. A serotonin uptake inhibitor reduced cue-induced drug-seeking but did not block the potentiation caused by a dopamine uptake inhibitor. Blocking either D1 or D2 receptors attenuated the MDMA-enhanced drug-seeking. The findings suggest that after repeated MDMA use, dopamine pathways become more influential in driving relapse to drug-seeking, partly because MDMA reduces brain serotonin levels.
Addiction Biology
June 14, 2013
Sarah Bradbury, Judith Bird, Joyce Colussi‐mas et al.
59 citations
About half of rats fail to acquire MDMA self-administration, and the difference is not due to how the drug is metabolized. MDMA triggers greater release of serotonin than dopamine in the brain. Rats that did acquire self-administration showed lower serotonin overflow than those that did not. Destroying serotonin neurons with a toxin made more rats acquire MDMA self-administration and speeded acquisition of cocaine self-administration. These findings suggest that serotonin limits initial sensitivity to MDMA's rewarding effects and delays reliable self-administration.
Journal of Clinical Psychopharmacology
October 10, 2018
Susan Schenk, David Newcombe
53 citations
MDMA (ecstasy) shows some promise as an aid to psychotherapy for posttraumatic stress disorder (PTSD) by increasing prosocial feelings, possibly through oxytocin release and reduced fear conditioning. However, MDMA also carries risks of neurotoxicity and potential for misuse. The article weighs the pros and cons of using MDMA for PTSD, noting that while some evidence suggests it can help patients address underlying trauma, its significant adverse effects raise concerns. Alternative treatments based on MDMA's pharmacology but with fewer side effects are proposed. Further research into the mechanisms behind MDMA's beneficial effects may lead to safer treatment options.
The International Journal of Neuropsychopharmacology
March 25, 2010
Joyce Colussi‐mas, Richard J. Wise, Alex Howard et al.
51 citations
In rats that learned to self-administer MDMA, a later injection of the drug triggered renewed drug-seeking behavior. The strength of this drug seeking was greater in rats that had acquired self-administration more quickly and in those that showed larger MDMA-induced increases in dopamine in the dorsal striatum. Rats that never learned to self-administer MDMA or that received the drug passively did not show this effect. The findings suggest that individual differences in initial sensitivity to MDMA's reinforcing effects and in the drug's ability to elevate striatal dopamine influence the propensity to seek the drug after a period of abstinence.
Journal of Neurochemistry
March 12, 2021
Susan Schenk, Quenten Highgate
47 citations
MDMA, an amphetamine analogue, primarily stimulates serotonin release with smaller increases in synaptic dopamine. The ratio of dopamine to serotonin increase predicts abuse liability, with higher ratios indicating greater risk. Despite a lower ratio, MDMA is misused. Repeated exposure produces neuroadaptive changes in both serotonin and dopamine systems, explaining the development and maintenance of self-administration in animals and substance use disorder in humans. Research shows serotonin inhibits the acquisition of MDMA self-administration, while dopamine is critical for its maintenance. The paper describes circuitry and serotonin receptors that modulate dopamine activity and reviews limited research on MDMA's effects on these receptor mechanisms.
Addiction Biology
July 11, 2012
Judith Bird, Susan Schenk
39 citations
Impulsivity, but not novelty-seeking, predicts how strongly rats seek MDMA after withdrawal. Before self-administration, rats were tested for impulsivity (premature responding on a five-choice task) and novelty-seeking (locomotor activity in a novel environment). Impulsivity was positively correlated with the magnitude of drug-seeking triggered by MDMA, while novelty-seeking showed no significant link to either acquisition or drug-seeking. MDMA self-administration also caused transient deficits in attention and increased premature responses. The findings suggest impulsivity may be a risk factor for compulsive drug-seeking after MDMA withdrawal.
Journal of Drug and Alcohol Research
January 1, 2012
Susan Schenk, Joyce Colussi‐mas, Jennifer Do et al.
38 citations
About half of a large sample of rats learned to self-administer MDMA, taking an average of 16 daily sessions before meeting the initial criterion. When the dose was reduced, the rats increased their responding in a compensatory manner. Over an additional 14 days of self-administration, daily intake rose from 8.5 to 15.25 mg/kg. These results indicate that MDMA acts as a reliable reinforcer for roughly half of rats, and that acquiring self-administration requires more sessions than is typical for other abused drugs.
Addiction Biology
September 28, 2011
Jennifer Do, Susan Schenk
37 citations
MDMA use is rising worldwide, and high doses reduce serotonin (5HT) markers in the brain. This study examined whether self-administered MDMA causes lasting serotonin deficits in rats. Rats self-administered MDMA infusions until reaching total doses of either 165 or 315 mg/kg. Serotonin levels in the frontal cortex, striatum, and hippocampus were measured 2 or 10 weeks later. The lower dose did not significantly reduce serotonin in any brain region. The higher dose decreased serotonin by 30–35% in all three regions at 2 weeks, but levels recovered by 10 weeks. These dose- and time-dependent deficits suggest similar effects may occur in humans who use MDMA.
Behavioral Neuroscience
January 1, 2006
Evangeline Daniela, David Gittings, Susan Schenk
37 citations
Rats pressed a lever to receive intravenous MDMA, and their responding increased when the required number of presses rose from 1 to 5, decreased when saline replaced MDMA, and increased again when MDMA was restored. During training, each MDMA infusion was accompanied by a light. After an average of 19 daily sessions, omitting either the light or the drug caused responding to decline gradually over 15 days. Omitting both the light and the drug produced a dramatic and lasting decrease in responding. These results suggest that cues paired with MDMA acquire conditioned properties that may contribute to drug-taking behavior.
Behavioral Neuroscience
January 1, 2006
David N. Harper, Maree Hunt, Susan Schenk
26 citations
Acute MDMA exposure disrupts memory performance in rats, possibly by increasing confusion between events from previous and current trials. In a delayed matching-to-sample task, lengthening the intertrial interval from 5 to 15 seconds reduced this disruption, suggesting that separating current-trial to-be-remembered events from previous-trial events can attenuate MDMA's memory-impairing effects.
Addiction Biology
September 1, 2020
Ross Van de Wetering, Susan Schenk
9 citations
Repeated exposure to MDMA (ecstasy) causes long-lasting changes in the brain, particularly accumulation of the protein ΔFosB in several regions. In male rats, MDMA self-administration significantly increased ΔFosB in the nucleus accumbens core, parts of the caudate-putamen, several cortical areas, and the amygdala, but not in other striatal regions. Pretreatment with MDMA enhanced the drug's locomotor-activating effect only when injected into the nucleus accumbens or medial caudate-putamen, matching the ΔFosB pattern. These findings resemble those seen with other addictive drugs, suggesting common neuroplastic changes underlying addiction.
Metabolomics : Official journal of the Metabolomic Society
August 2, 2023
Ross Van de Wetering, Jan A Vorster, Sophie Geyrhofer et al.
4 citations
Combining behavioral models with metabolomics can help identify which metabolites are most relevant to substance use disorders. In a preclinical experiment, untargeted metabolomics was performed on 336 microdialysis samples from the medial striatum of 21 male Sprague-Dawley rats during an MDMA-induced behavioral sensitization study. Orthogonal partial least squares analysis, using behavioral data as the Y variable and relative concentrations of 737 detected features as X variables, revealed that MDMA and its derivatives, serotonin, and several dopamine/norepinephrine metabolites were the strongest predictors of acute MDMA-produced behavior. Repeated MDMA exposure significantly altered MDMA metabolism, which may contribute to increased abuse liability with repeated use. Including behavioral data guides metabolomics analysis and enhances relevance to the phenotype of interest.
Behavioural Pharmacology
June 1, 2019
Susan Schenk, Quenten Highgate
2 citations
Rats trained to recognize a high dose (3.0 mg/kg) of MDMA or amphetamine (0.5 mg/kg) were given drugs that block dopamine or serotonin receptors. Dopamine blockers reduced the rats' ability to recognize amphetamine but not MDMA. Serotonin blockers had no effect on either drug's recognition. The findings suggest that the high-dose MDMA stimulus involves both dopamine and serotonin systems, and either system alone is enough to maintain the drug's effects.