Robert Oberlender

Drug discrimination studies with MDMA and amphetamine

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, hallucinogens and stimulants. Two groups of rats were trained to discriminate saline from either racemic MDMA hydrochloride (1.75 mg/kg) or S-(+)-amphetamine sulfate (1.0 mg/kg) in a two-lever drug discrimination task. The (±)-MDMA cue completely generalized to S-(+)-MDMA, S-(+)-amphetamine, (±)-MDA, S-(+)-MBDB, (±)-MBDB, R-(-)-MDMA, and R-(-)-MBDB, but not to LSD or DOM. The S-(+)-amphetamine cue generalized to (±)-methamphetamine, but not to racemic MDMA or MBDB, nor to their optical isomers. The S-(+)-isomers of both MDMA and MBDB were more potent than the R-(-)-isomers. The results indicate that MDMA and MBDB may share a component of their discriminative stimulus properties which is different from both stimulants and hallucinogens. Although MDA and MDMA have been shown to be amphetamine-like, the lack of stimulant effects for MBDB suggests that amphetamine-like stimulant activity is not necessary for a compound to share discriminative stimulus properties with MDMA.

Structure-Activity Relationships of MDMA and Related Compounds: A New Class of Psychoactive Drugs?a

It has been hypothesized that MDMA and substances that possess a psychopharmacological effect similar to MDMA are members of a novel pharmacological class named entactogens [1–3]. In this chapter evidence will be presented to support this, through a discussion of the data acquired in efforts directed toward testing this hypothesis. Although these studies are far from complete, the results gathered thus far, together with those from other laboratories, support the view that the pharmacology of entactogens is clearly different from other known classes of compounds.

Behavioral, biochemical and neurotoxicological actions of the α-ethyl homologue of p-chloroamphetamine

The present set of experiments was designed to examine the effects of extension of the alpha-methyl of p-chloroamphetamine (PCA) to an alpha-ethyl. Therefore, the alpha-ethyl homologue of PCA, 1-(4-chlorophenyl)-2-aminobutane (CAB), was compared to PCA in a number of pharmacological assays. CAB was 2-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and 5-fold less potent at inhibiting uptake of [3H]dopamine ([3H]DA). In drug discrimination assays, CAB was approximately 3-fold less potent than PCA in animals trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or its alpha-ethyl homologue, S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-(+)-MBDB), from saline. Monitoring with in vivo microdialysis, 10 mg/kg of PCA caused a large increase in extracellular DA and a significant decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. In contrast, 11 mg/kg CAB caused no increase and 22 mg/kg CAB caused only a slight increase in extracellular DA. Both doses of CAB caused a decrease in extracellular DOPAC. The potential 5-HT neurotoxicity of CAB was examined by measuring monoamine and metabolite levels and [3H]paroxetine binding at one week following acute doses. A 10 mg/kg dose of PCA caused an 80% decrease in cortical and hippocampal serotonergic markers, while an equimolar dose of CAB decreased only hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels. However, 22 mg/kg of CAB produced a 20-40% decrease in all serotonergic markers. Thus, extension of the alpha-alkyl significantly decreases the dopaminergic effects of PCA. The similar decrease in relative 5-HT neurotoxicity and the decreased ability to alter dopaminergic systems in vivo and in vitro supports the involvement of DA in the neurotoxicity of PCA.

5-iodo-2-aminoindan, a nonneurotoxic analogue of p-iodoamphetamine

A rigid analogue, 5-iodo-2-aminoindan (5-IAI), of the serotonin neurotoxic halogenated amphetamine p-iodoamphetamine (PIA) was pharmacologically evaluated for production of serotonin neurotoxicity. A comparison was also made between 5-IAI and PIA in the two-lever drug discrimination paradigm in rats trained to discriminate saline from 3,4-methylenedioxymethamphetamine (MDMA) or saline from the alpha-ethyl homologue of MDMA, MBDB. PIA and 5-IAI were both behaviorally active, and fully substituted in both groups of animals, but were considerably less potent than p-chloroamphetamine (PCA). PIA had about twice the potency of PCA as an inhibitor of [3H]-5-HT uptake in rat brain cortical synaptosomes, while 5-IAI was only about 75% as potent as PCA in this assay. A single 40 mg/kg dose of PIA resulted in a 40% reduction of 5-HT and 5-HIAA levels and in the number of 5-HT uptake sites in rat cortex at one week sacrifice. The same dose of 5-IAI with one week sacrifice led to about a 15% decrease in 5-HIAA levels and number of 5-HT uptake sites, but only the latter was statistically significant. In rat hippocampus, PIA gave significant decreases in all serotonin markers examined, while 5-IAI slightly but significantly decreased only 5-HT levels. Neither compound produced any change in catecholamine or catecholamine metabolite levels. The results confirm earlier reports of the selective serotonin neurotoxicity of PIA, which is less severe than that of PCA, and also demonstrate that its rigid analogue 5-IAI does not appear to cause significant serotonin deficits in the rat.

STRUCTURAL VARIATION AND (+)-AMPHETAMINE-LIKE DISCRIMINATIVE STIMULUS PROPERTIES

Rats were trained to discriminate (+)-amphetamine sulfate (5.43 mumol/kg, 1 mg/kg) from saline in a food-reinforced, two-lever drug discrimination paradigm. Side chain variations of the amphetamine molecular structure were analyzed for their effects on the discriminative stimulus properties of this prototype central nervous system stimulant. Partial generalization was observed for the alpha-ethyl homologue of (+)-amphetamine, (+)-AEPEA, and for 2-aminoindan (AI), while 5,6-methylenedioxy-2-aminoindan (MDAI) elicited only saline-appropriate responding. By contrast, 2-amino-1,2-dihydronaphthalene (ADN) and 2-aminotetralin (AT) completely substituted for (+)-amphetamine. Relative to the training drug, ADN was 1/4 as potent and AT was 1/8 as potent. The S-(-)-isomer of ADN was found to be responsible for the (+)-amphetamine-like discriminative properties of the racemate. The results suggest that constraining or extending the alpha-alkyl substituent of (+)-amphetamine has a deleterious effect on the ability of the resulting analogue to adopt the active conformation of (+)-amphetamine, thereby diminishing its characteristic discriminative stimulus properties.

Studies of dioxole ring substituted 3,4-methylenedioxyamphetamine (MDA) analogues

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. They were also compared in the two-lever drug discrimination assay in rats, utilizing d-LSD tartrate (0.08 mg/kg) or MDMA.HCl (1.75 mg/kg) as the training stimulus. MDA and EDA were nearly equipotent in inducing release of both [3H]-monoamine transmitters, while IDA was considerably less potent. Pretreatment of hippocampal slices with the 5-HT-uptake inhibitor fluoxetine (3.2 microM) blocked the [3H]-5-HT overflow induced by MDA. In the drug discrimination experiments, complete substitution occurred with all three drugs in both LSD- and MDMA-trained rats. The ED50 values indicated that MDA had about twice the potency of EDA, and five times the potency of IDA in MDMA-trained rats. In the LSD-trained animals, MDA was about three times more potent than EDA and about seven times more potent than IDA. The KI values for displacement of R-[125I]-DOI generally parallel the results of the LSD transfer tests.

Unreliability of the rat stomach fundus as a predictor of hallucinogenic activity in substituted phenethylamines

A series of three isomeric 2,4,5-substituted monoethoxy dimethoxy phenylisopropylamines were compared for their contractile effect in the rat fundus as potential antagonists to the effect of serotonin in the fundus. The three isomers were also evaluated for their discriminative stimulus properties in rats that had been trained to discriminate injections of saline from LSD tartrate (0.08 mg/kg). The drug discrimination studies revealed that the 2,5-dimethoxy-4-ethoxy substitution was most potent in rats, consistent with the reported clinical activity of this isomer in man. By contrast, of the three isomers examined, this was the weakest in eliciting a contraction in the fundus. None of the compounds antagonized serotonin induced contractions, and it was not possible to determine pA2 values. Questions are raised about the determination of pA2 values for partial agonists and it is concluded that the fundus is not a reliable model for prediction of hallucinogenic activity of phenethylamines.