Serotonergic behavioral responses, effects on motor activity and core temperature, and binding properties of the novel putative anxiolytic amphetamine derivative (+/-)1-(2,5-dimethoxy-4-ethylthio-phenyl)-2-aminopropane (ALEPH-2), were examined in rodents in order to elucidate the mechanism underlying its anxiolytic-like effect. After peripheral administration in rats, ALEPH-2 induced some...
The present study was designed to characterize further the rewarding and aversive properties of 3,4-methylenedioxymethamphetamine (MDMA), the alpha-ethyl homologue of MDMA (MBDB), fenfluramine, and the selective serotonin releasing agent 5-methoxy-6-methyl-2-aminoindan (MMAI) using the conditioned place preference paradigm (CPP). Extracellular dopamine (DA) and its metabolite DOPAC were also...
The influence of several alpha 2-adrenergic agents on the discriminative stimulus (DS) properties of lysergic acid diethylamide (LSD) was studied in rats trained to discriminate 0.08 mg/kg (186 nmol/kg) of LSD from saline in a two-lever operant paradigm. Only yohimbine fully mimicked LSD with an ED50 of 2.05 mg/kg (5.24 mumol/kg). Yohimbine's 5-HT1A agonist properties may be responsible for...
3,4-Methylenedioxymethamphetamine (MDMA)-induced serotonergic neurotoxicity was assessed in the striatum, hippocampus and frontal cortex of rats by using [3H]paroxetine binding to label serotonin (5-HT) uptake sites and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels as markers of serotonergic function. NMDA (40 mg/kg) induced a significant decrease in both [3H]paroxetine binding Bmax and...
The effects of the MAO-B inhibitors, L-deprenyl and MDL-72974 on MDMA-induced serotonergic neurotoxicity in rats were examined. MDMA alone produced a significant decrease in the number of 5-HT uptake sites, measured as a decrease in the Bmax for binding of [3H]paroxetine, and in 5-HT and 5-HIAA levels in the striatum. L-Deprenyl and MDL-72974 attenuated this MDMA-induced decrease in...
The hallucinogenic effects of lysergic acid diethylamide (LSD) have been attributed primarily to actions at serotonin receptors. A number of studies conducted in the 1970s indicated that LSD also has activity at dopamine (DA) receptors. These latter studies are difficult to interpret, however, because they were completed before the recognition of two pharmacologically distinct DA receptor...
The effect of the R(-) and S(+) isomers of 3,4-methylenedioxyamphetamine (MDA) and its N-methyl analog 3,4-methylenedioxymethamphetamine (MDMA) on [3H]inositol monophosphate accumulation was studied in cells expressing either 5-HT2A or 5-HT2C receptors. The isomers of MDA produced a concentration dependent increase in phosphatidyl inositol (PI) hydrolysis at the 5-HT2A receptors, with the R(-)...
The behavioral effects of 5-methoxy-6-methyl-2-aminoindan (MMAI) were examined using the drug discrimination procedure and direct observation for classification of the characteristic syndrome induced by MMAI. The stimulus effects of MMAI were studied in 5 different groups of rats trained to discriminate MMAI (1.71 mg/kg; 8 microM/kg), MDMA (3,4-methylenedioxymethamphetamine; 1.75 mg/kg; 7.6...
Isopropyl (IPLA), N-methyl-N-isopropyl (MIPLA), N-ethyl-N-isopropyl (EIPLA), and N,N-diisopropyl (DIPLA) lysergamides were evaluated for lysergic acid diethylamide (LSD)-like activity. In rats trained to discriminate 0.08 mg/kg LSD tartrate from saline, each of the subject compounds completely substituted, with an ED50 two to three times larger than that of LSD except for DIPLA, which had an...
Treatment of rats with serotonin (5-HT) precursors tryptophan (TRP, 400 mg/kg) and 5-hydroxytryptophan (5-HTP, 50 mg/kg) was shown to attenuate MDMA (20 mg/kg) induced serotonergic neurotoxicity as measured by [3H]-paroxetine binding in the striatum, hippocampus, and frontal cortex of the rat brain. Hippocampal 5-HT and 5-HIAA levels were also indicative of the protective effects of TRP and...
p-Methylthioamphetamine (MTA), was compared to p-chloroamphetamine (PCA) in a number of pharmacological assays. MTA was about 2-fold more potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and about 7-fold and 10-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]dopamine and [3H]norepinephrine, respectively. In drug discrimination assays,...
The benzofuran analogues of the hallucinogens 5-methoxy-N,N-dimethyltryptamine and 5-methoxy-alpha-methyltryptamine were synthesized and evaluated for affinity at the serotonin 5-HT2 and 5-HT1A receptors in rat brain homogenate, labeled with [125I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([125I]DOI) and [3H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([3H]-8-OH-DPAT), respectively. At the...
To assess the potential involvement of metabolism of 3,4-methylenedioxymethamphetamine (MDMA) to the catechol alpha-methylepinine in producing serotonergic neurotoxicity, we attempted to correlate aspects of this reaction with the neurotoxicity profile of MDMA. In contrast to the stereoselectivity of S-(+)-MDMA in causing persistent declines in rat brain 5-hydroxyindole levels, no...
Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that...
Recent studies of 5-HT2 receptor binding have involved the use of radiolabeled agonists. This report describes the use of [125I]-2-(2,5-dimethoxy-4-iodophenyl)aminoethane ([125I]-2C-I) as a label for low-density 5-HT2 agonist binding sites. A nonhydrolyzable analog of GTP, GppNHp, was found to inhibit the high affinity binding of [125I]-2C-I. 5-HT and several 5-HT2 agonists and antagonists...
The 3,4-ethylidenedioxy and 3,4-isopropylidenedioxy analogues, EDA and IDA, respectively, of 3, 4-methylenedioxyamphetamine (MDA) were compared to MDA in drug-stimulated [3H]-serotonin overflow from prelabelled rat hippocampal slices, [3H]-dopamine overflow from prelabelled rat caudate slices, in their ability to displace the 5-HT2 agonist R-[125I]-DOI from rat brain cortical binding sites....
The possible neurotoxic effects of the alpha-ethyl homologue of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), were examined following a regimen of twice daily dosing for four days. The levels of norepinephrine, serotonin and its metabolite 5-HIAA were quantitated by standard HPLC-EC techniques. In addition, the number of 5-HT uptake sites was estimated by examining the binding of...
Telemetric recordings of field potentials from frontal cortex, hippocampus, striatum and reticular formation of freely moving rats were analysed before and after injection of the enantiomeric hallucinogenic amphetamine derivatives R-DOB [(-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane], R-DOM [(-)-1-(2,5-dimethoxy-4-methylphenyl)-2-amino-propane] and R-DOI...
The term entactogen has recently been introduced to describe a new pharmacological class of compounds best represented by 3,4-methylenedioxymethamphetamine, MDMA, and its alpha-ethyl homologue MBDB. The present study was designed to test the similarities of the discriminative stimulus properties produced by MDMA and MBDB, as well as to elaborate further the distinction between entactogens,...
3,4-Methylenedioxymethamphetamine (MDMA) is a recently popularized recreational drug, although some have advocated its psychotherapeutic potential. Since the pharmacology of MDMA is largely uncharacterized, the stereochemical profiles of MDMA and some of its homologs were derived on inhibition of synaptosomal uptake of [3H]monoamines and compared to those of amphetamine and the hallucinogenic...
The nature of the stereochemistry and aromatic ring substituents and their importance to biological activity for phenethylamine-type hallucinogens is presented. The possibility of a hydrophobic site to bind to the 4-substituent and its likely geometry is described. A brief discussion of the structure-activity relationships for tryptamines such as psilocin and DMT is also given, with comments...
The 360-MHz 1H NMR spectra of bufotenin and psilocin were obtained, both as the free bases in CDCl3 and as protonated salts in D2O. Coupling constants for the side-chain methylenes were derived using the LAOCN3 program. These time-averaged coupling constants indicate that the trans and gauche rotamers of both compounds have about equal energy in D2O. There is a slight excess of the trans...