RationaleAfter decades of social stigma, hallucinogens have reappeared in the clinical literature demonstrating unique benefits in medicine. The precise behavioral pharmacology of these compounds remains unclear, however.ObjectivesTwo commonly studied hallucinogens, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD), were investigated both in vivo and...
The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the...
AbstractBackgroundPreconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA.MethodsMale Dark Agouti...
“Ecstasy” [3,4-methylenedioxymetamphetamine (MDMA)] is of considerable interest in light of its prosocial properties and risks associated with widespread recreational use. Recently, it was found to bind trace amine-1 receptors (TA 1 Rs), which modulate dopaminergic transmission. Accordingly, using mice genetically deprived of TA 1 R ( TA 1 -KO ), we explored their significance to the actions of...
ABSTRACT Many adolescents often take ethanol (EtOH) in combination with 3,4‐methylenedioxymethylamphetamine (MDMA). In the present work, we used a mouse model to study the effect of repeated pre‐exposure during adolescence to EtOH (2 g/kg), MDMA (10 or 20 mg/kg) or EtOH + MDMA on the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm. Pre‐exposure to...
3,4-Methylenedioxymethamphetamine (MDMA)'s O-demethylenated metabolite, 3,4-dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol-thioether metabolites (e.g., 5-N-acetylcystein-S-yl-HHMA) that mediate MDMA neurotoxicity. To further test this hypothesis, HHMA formation was blocked with dextromethorphan (DXM), which competitively...
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 serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive...
A series of C1, C2, C3 and N6 analogs of nantenine (2) was synthesized and evaluated in 5-HT(2A) and α(1A) receptor functional assays. Alkyl substitution of the C1 and N6 methyl groups of nantenine provided selective 5-HT(2A) and α(1A) antagonists, respectively. The C2 alkyloxy analogs studied were generally selective for α(1A) versus 5-HT(2A). The C3 bromo analog 15 is one of the most potent...
Objectives Ecstasy is a recreational drug whose active ingredient, 3,4-methylenedioxymethamphetamine (MDMA), acts predominantly on the serotonergic system. Although MDMA is known to be neurotoxic in animals, the long-term effects of recreational Ecstasy use in humans remain controversial but one commonly reported consequence is mild cognitive impairment particularly affecting verbal episodic...
Abstract Background: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) misuse is associated with hyponatremia particularly in women. Hyponatremia is possibly due to inappropriate secretion of plasma arginine vasopressin (AVP). Objective: To assess whether MDMA increases plasma AVP and copeptin in healthy male and female subjects and whether effects depend on MDMA-induced release of serotonin...
The behavioral and neurochemical adaptations related to chronic 3,4-methylenedioxymethamphetamine (MDMA) treatment are largely unknown. In this study, we assessed whether repeated administration of MDMA would induce (a) context-dependent locomotor sensitization in mice and (b) changes in serotonin 5-HT(2A) and dopamine D₂ receptor functionality as measured by [³⁵S]GTPγS binding. Mice were...
Biochemical JournalJune 15, 2011Zoë Barclay, Louise Dickson, Derek N Robertson et al.
The 5-HT2AR (5-hydroxytryptamine-2A receptor) is a GPCR (G-protein-coupled receptor) that is implicated in the actions of hallucinogens and represents a major target of atypical antipsychotic agents. In addition to its classical signalling though PLC (phospholipase C), the receptor can activate several other pathways, including ARF (ADP-ribosylation factor)-dependent activation of PLD...
We found evidence that MDMA but not hallucinogen use is associated with changes in the cerebral presynaptic serotonergic transmitter system. Because hallucinogenic drugs primarily have serotonin(2A) receptor agonistic actions, we conclude that the negative association between MDMA use and cerebral SERT binding is mediated through a direct presynaptic MDMA effect rather than by the serotonin(2A)...
A number of published studies have questioned the serotonin neurotoxic potential of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and related drugs (fenfluramine, p-chloroamphetamine) based upon results from Western blot studies using a custom synthesized serotonin transporter (SERT) antibody that found no reduction in the abundance of a 50kDa protein after substituted amphetamine...
Halpern et al. 1 presented some interesting findings from a study of abstinent ecstasy users in Salt Lake City, USA. Their ecstasy group reported comparatively slight use of all psychoactive drugs, both legal and illicit, and were therefore different from the typical user who often takes a range of other drugs. Their control group comprised similar-aged occasional rave attendees, who had never...
The serotonin (5-HT) 2A receptor is implicated in numerous psychiatric disorders, making it an important, clinically relevant target. Despite the availability of transgenic mouse lines, the native mouse 5-HT(2A) receptor is not well-characterized. The goals of the current study were to determine 5-HT(2A) and 5-HT(2C) receptor densities in mouse cortex, establish a pharmacological profile of the...
BACKGROUND AND PURPOSE: The designer drug 1-(4-methylphenyl)-2-methylaminopropan-1-one (4-methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5-HT in the nucleus accumbens of awake rats and compare...