Metabolomics produces vast quantities of data but determining which metabolites are the most relevant to the disease or disorder of interest can be challenging. This study sought to demonstrate how behavioral models of psychiatric disorders can be combined with metabolomics research to overcome this limitation. We designed a preclinical, untargeted metabolomics procedure, that focuses on the...
Abstract Methylenedioxymethamphetamine (MDMA) is an amphetamine analogue that preferentially stimulates the release of serotonin (5HT) and results in relatively small increases in synaptic dopamine (DA). The ratio of drug‐stimulated increases in synaptic DA, relative to 5HT, predicts the abuse liability; drugs with higher DA:5HT ratios are more likely to be abused. Nonetheless, MDMA is a drug...
AbstractRepeated exposure to drugs produces a plethora of persistent brain changes, some of which underlie the development of drug addiction. An important objective of addiction research is to identify the brain changes that might mediate the transition from drug use to drug misuse. The persistent accumulation of the transcription factor, ∆FosB, following repeated drug exposure provides a means...
Most studies on discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) have been conducted using a relatively low dose (1.5 mg/kg), and those studies have invariably implicated serotonergic mechanisms. In contrast, dopaminergic mechanisms mediate the discriminative stimulus effects of amphetamine (AMPH). Some studies have suggested that the discriminative stimulus effects...
3,4-Methylenedioxymethamphetamine (MDMA) preferentially increases synaptic serotonin (5HT). This response was attenuated following repeated exposure but there was recovery as a result of abstinence. Effects of abstinence on self-administration of many drugs have been documented but the impact on MDMA self-administration is unknown. This study compared the effects of abstinence on MDMA and...
Abstract Background For a number of mental health disorders, including posttraumatic stress disorders (PTSD), there are not many available treatment options. Recently, there has been renewed interest in the potential of methylenedioxymethamphetamine (MDMA) to restore function for patients with these disorders. The primary hypothesis is that MDMA, via prosocial effects, increases the ability of...
Studies that have attributed the discriminative stimulus effects of ±3,4-methylenedioxymethamphetamine (MDMA) to serotonergic mechanisms typically use a relatively low training dose of 1.5 mg/kg. The role of serotonin in the discriminative stimulus effects of higher doses of MDMA is, however, unknown. Separate groups of rats were trained to discriminate MDMA (1.5 or 3.0 mg/kg) from saline using...
Rationale: Repeated exposure to ±3, 4-methylenedioxymethamphetamine (MDMA) produces sensitization to MDMA-produced hyperactivity, but the mechanisms underlying the development of this sensitized response or the relationship to the reinforcing effects of MDMA is unknown. Objectives: This study determined the effect of a sensitizing regimen of MDMA exposure on the acquisition of MDMA...
As is the case with other drugs of abuse, a proportion of ecstasy users develop symptoms consistent with a substance use disorder (SUD). In this paper, we propose that the pharmacology of MDMA, the primary psychoactive component of ecstasy tablets, changes markedly with repeated exposure and that neuroadaptations in dopamine and serotonin brain systems underlie the shift from MDMA use to MDMA...
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...
3,4 Methylenedioxymethamphetamine (MDMA) preferentially stimulates the release of serotonin (5-HT) that subsequently produces behavioral responses by activation of post-synaptic receptor mechanisms. The 5-HT1A and 5-HT1B receptors are both well localized to regulate dopamine (DA) release, and have been implicated in modulating the reinforcing effects of many drugs of abuse, but a role in...
Regular use of the street drug, ecstasy, produces a number of cognitive and behavioral deficits. One possible mechanism for these deficits is functional changes in serotonin (5-HT) receptors as a consequence of prolonged 3,4 methylenedioxymethamphetamine (MDMA)-produced 5-HT release. Of particular interest are the 5-HT(1A) and 5-HT(1B) receptor subtypes since they have been implicated in...
Abstract The current study aimed to elucidate the role of pharmacokinetic ( PK ) parameters and neurotransmitter efflux in explaining variability in (±) 3, 4‐methylenedioxymethamphetamine ( MDMA ) self‐administration in rats. PK profiles of MDMA and its major metabolites were determined after the administration of 1.0 mg/kg MDMA (iv) prior to, and following, the acquisition of MDMA...
It has been suggested that the response to novelty and impulsivity predict the latency to acquisition and maintenance of drug self-administration, respectively. The aim of this study was to examine the relationship between these two traits and (1) the latency to acquisition and (2) maintenance (drug-seeking) of 3,4-methylenedioxymethamphetamine (MDMA) self -administration. Impulsivity, measured...
Kappa opioid receptor (KOPr) activation antagonizes many cocaine-related behaviors but adverse side-effects such as sedation, dysphoria, and depression limit their therapeutic use. Recently, salvinorin A (Sal A), a naturally occurring KOPr agonist, has been shown to attenuate cocaine-induced drug seeking in a model of relapse in rats. The present study evaluated the effects of acute Sal A...
The present study provides a profile of acqui- sition and maintenance of self-administration of +/-3,4- methylenedioxymethamphetamine (MDMA) obtained from a large cohort of rats tested during a 2 year period. Of the 128 rats, 49% self-administered 1.0 mg/kg/infusion MDMA to an initial criterion within a 25 day cut-off period. The number of test sessions required to meet this initial criterion...
ABSTRACT 3,4‐Methylenedioxymethamphetamine (MDMA) use and abuse have been increasing worldwide. Of concern, exposure to high doses of MDMA decreases several markers of serotonin (5HT) neurotransmission and produces deficits in tissue levels of 5HT. Studies in laboratory animals have been conducted primarily following large doses (20.0–80.0 mg/kg) of experimenter‐administered MDMA, but it is...
The present study was undertaken to examine effects of self-administered MDMA on novel object exploration (NOR) memory. Self-administration was conducted during daily 2 h tests that continued until a total of 165 mg/kg was self-administered (range = 13-41 days for individual rats). Control rats were placed in the self-administration boxes during daily sessions but did not receive any drug. One...
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...
In laboratory animals, exposure to priming injections of 3,4-methylenedioxymethamphetamine (MDMA) produced drug seeking following extinction of MDMA self-administration. This study aimed to evaluate whether the magnitude of drug seeking was related to latency to acquisition of MDMA self-administration and increases in striatal dopamine, as measured by in-vivo microdialysis. Rats were given...
Our previous work indicated that pretreatment with the selective kappa-opioid receptor (KOPr) agonist, U69593, attenuated the ability of priming injections of cocaine to reinstate extinguished cocaine-seeking behavior. The present study expanded these initial tests to include other traditional KOPr agonists, U50488H, spiradoline (SPR), and salvinorin A (Sal A), an active constituent of the...
It has been suggested that activation of dopamine D1-like and D2-like receptors contribute equally to the maintenance of drug self-administration. This study compared the contribution of these receptor subtypes to 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (MA) self-administration. Effects of pretreatment with the D2-like receptor antagonist, eticlopride (0.0, 0.0125, 0.025 or...
The prevalence of 3,4-methylenedioxymethamphetamine (MDMA) use has increased globally and the pattern of consumption has changed considerably. Previously, a subculture of MDMA users was fairly restricted to the dance club scene. More recently, use has spread outside of this subculture and now many users consume MDMA frequently and in large amounts and some meet criteria for drug abuse and/or...
Exposure to self-administered drugs is sufficient to produce drug-seeking in animal models. In many cases priming injections of drugs that share discriminative stimulus properties with the self-administered drug also can lead to drug-seeking, suggesting that exposure might precipitate relapse. The present investigation examined the ability of MDMA or cocaine priming injections to reinstate...
Abstract 3,4‐Methylenedioxymethamphetamine (MDMA) self‐administration has been shown in animals with extensive drug histories, but only a small number of studies have examined high rates of responding maintained by MDMA in previously drug‐naïve animals. In the present study, influence of dose (0.25 or 1.0 mg/kg/infusion) on the acquisition of MDMA self‐administration was measured during daily...