Methamphetamine effects in zebrafish (Danio rerio) depend on behavioral endpoint, dose and test session duration.

Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have been limited studies on the effects of methamphetamine in adult zebrafish and the parameters of exposure (dose, test session length) have not been well-documented. Behavior following drug exposure is generally measured during relatively short sessions (6-10 min is common) in a novel tank environment.

Behavioral metabolomics: how behavioral data can guide metabolomics research on neuropsychiatric disorders.

Introduction: Metabolomics produces vast quantities of data but determining which metabolites are the most relevant to the disease or disorder of interest can be challenging.

Objectives: This study sought to demonstrate how behavioral models of psychiatric disorders can be combined with metabolomics research to overcome this limitation.

Methods: We designed a preclinical, untargeted metabolomics procedure, that focuses on the determination of central metabolites relevant to substance use disorders that are (a) associated with changes in behavior produced by acute drug exposure and (b) impacted by repeated drug exposure.

Repeated eticlopride administration increases dopamine D receptor expression and restores behavioral flexibility disrupted by methamphetamine exposure to male rats.

Repeated methamphetamine exposure impairs reversal learning in laboratory animals and downregulates dopamine D receptor expression. In the present study, we tested the possibility that repeated exposure to the dopamine D antagonist, eticlopride, would increase D receptor expression, improve behavioral flexibility and restore behavioral flexibility that was disrupted by exposure to methamphetamine in rats. Male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D antagonist, eticlopride (0.

The role of extracellular serotonin and MDMA in the sensitizing effects of MDMA.

MDMA is a non-selective monoamine releasing stimulant with potent serotonergic effects - a pharmacological effect not typically associated with drugs of misuse or efficacious reinforcers. Nonetheless, MDMA is misused by humans and self-administered by laboratory animals. We have previously shown that repeated exposure to MDMA sensitized both the locomotor activating and reinforcing effects of MDMA in rats.

Methylenedioxymethamphetamine (MDMA): Serotonergic and dopaminergic mechanisms related to its use and misuse.

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 that is misused.

Regional changes in ∆FosB expression in rat brain following MDMA self-administration predict increased sensitivity to effects of locally infused MDMA.

Repeated 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 of achieving this objective.

Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions.

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 patients to address the underlying psychopathology of the disorder.

Comparison of the effects of abstinence on MDMA and cocaine self-administration in rats.

Rationale: 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.

Dopamine and serotonin antagonists fail to alter the discriminative stimulus properties of ±methylenedioxymethamphetamine.

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).

Repeated MDMA administration increases MDMA-produced locomotor activity and facilitates the acquisition of MDMA self-administration: role of dopamine D receptor mechanisms.

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 self-administration and investigated the role of dopamine D receptor mechanisms.

Methods: Rats received the selective D antagonist, eticlopride (0.

Generalization of serotonin and dopamine ligands to the discriminative stimulus effects of different doses of ±3,4-methylenedioxymethamphetamine.

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.

Serotonin antagonists fail to alter MDMA self-administration in rats.

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.

AMPA Receptors as Therapeutic Targets for Neurological Disorders.

Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors.

MDMA self-administration fails to alter the behavioral response to 5-HT(1A) and 5-HT(1B) agonists.

Rationale: 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 several of the behaviors that have been shown to be impacted in ecstasy users and in animals exposed to MDMA.

Repeated administration of the 5-HT₁B/₁A agonist, RU 24969, facilitates the acquisition of MDMA self-administration: role of 5-HT₁A and 5-HT₁B receptor mechanisms.

Rationale: 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 acquisition of self-administration has not been determined.

Objectives: This study was designed to determine the effect of pharmacological manipulation of 5-HT1A and 5-HT1B receptor mechanisms on the acquisition of MDMA self-administration.

Contribution of Impulsivity and Serotonin Receptor Neuroadaptations to the Development of an MDMA ('Ecstasy') Substance Use Disorder.

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 misuse in susceptible subjects. Data from both the human and laboratory animal literature are synthesized to support the idea that (1) MDMA becomes a less efficacious serotonin releaser and a more efficacious dopamine releaser with the development of behaviour consistent with an SUD and (2) that upregulated serotonin receptor mechanisms contribute to the development of the MDMA SUD via dysregulated inhibitory control associated with the trait of impulsivity.

Persistent sensitisation to the locomotor activating effects of MDMA following MDMA self-administration in rats.

Effects of MDMA exposure on MDMA-produced hyperactivity are dependent on the exposure regimen; high-dose exposure produced tolerance whereas repeated, intermittent exposure produced sensitised responses. In the present study we measured the impact of MDMA self-administration on MDMA-produced hyperactivity. Rats self-administered a total of 165mg/kg MDMA during daily 2h sessions.

RU 24969-produced adipsia and hyperlocomotion: differential role of 5HT 1A and 5HT 1B receptor mechanisms.

RU 24969 is a widely used, but non-selective, 5-HT1B/1A agonist that decreases fluid consumption and increases forward locomotion. The mechanism underlying these behavioural responses is not, however, well understood. Accordingly, effects of the selective 5-HT1A and 5-HT1B antagonists, WAY 100635, and GR 127935, respectively, on these two responses to RU 24969 were determined.

A 3-lever discrimination procedure reveals differences in the subjective effects of low and high doses of MDMA.

Drug discrimination studies have suggested that the subjective effects of low doses of (±)3,4-methylenedioxymethamphetamine (MDMA) are readily differentiated from those of d-amphetamine (AMPH) and that the discriminative stimulus properties are mediated by serotonergic and dopaminergic mechanisms, respectively. Previous studies, however, have primarily examined responses to doses that do not produce substantial increases in extracellular dopamine. The present study determined whether doses of MDMA that produce increases in synaptic dopamine would also produce subjective effects that were more like AMPH and were sensitive to pharmacological manipulation of D1-like receptors.

Acquisition of MDMA self-administration: pharmacokinetic factors and MDMA-induced serotonin release.

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 self-administration.

Effects of repeated exposure to MDMA on 5HT1a autoreceptor function: behavioral and neurochemical responses to 8-OHDPAT.

A consistent effect of repeated exposure to 3,4 methylenedioxymethamphetamine (MDMA) is a decrease in the tissue levels of serotonin (5-HT). A variety of behavioural and neurochemical tests were conducted to determine whether the tissue deficits were accompanied by an increased sensitivity of the 5-HT1a autoreceptor. Tests were conducted 2 weeks following MDMA exposure (four injections of 10.

Contribution of impulsivity and novelty-seeking to the acquisition and maintenance of MDMA self-administration.

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 as premature responding on the five-choice serial reaction time task (5-CSRTT), and novelty-seeking, measured as the locomotor response in a novel environment, were measured prior to self-administration.

Repeated exposure to MDMA and amphetamine: sensitization, cross-sensitization, and response to dopamine D₁- and D₂-like agonists.

Rationale: Acute exposure to (±) 3, 4-methylenedioxymethamphetamine (MDMA) produces hyperlocomotion that is preferentially expressed in the periphery of closed chambers. Following repeated administration, however, a sensitized hyperlocomotor response is preferentially expressed in the center of an activity box, so that the response resembles the more generalized activity that is produced by D-amphetamine (AMPH).

Objectives: The present study was designed to determine whether common neuroadaptations underlie the acute and sensitized responses to MDMA and AMPH.

A single injection of a novel κ opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats.

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 exposure on cocaine-induced hyperactivity and cocaine sensitization in rats.

Self-administered MDMA produces dose- and time-dependent serotonin deficits in the rat brain.

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.