Investigation of MDMA-related agents in rats trained to discriminate MDMA from saline

https://doi.org/10.1016/0091-3057(92)90405-5Get rights and content

Abstract

To determine whether metabolite-related analogs of N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce stimulus effects similar to those of the parent compound, and to determine the structural requirements associated with the MDMA stimulus, several MDMA analogs were examined in tests of stimulus generalization using rats trained to discriminate 1.5 mg/kg MDMA from saline. Although several of the analogs produced up to 50–60% MDMA-appropriate responding, none [with the exception of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA)] resulted in stimulus generalization. The partial generalization, coupled with the possible reduced ability of certain of the agents to penetrate the blood-brain barrier relative to MDMA, suggests that these agents are not behaviorally inactive. PMMA, although not a metabolite of MDMA, is closely related in chemical structure to MDMA and its metabolites; PMMA produces > 80% MDMA-appropriate responding and is approximately three times more potent (ED50 = 0.2 mg/kg) than MDMA itself (ED50 = 0.76 mg/kg). PMMA is a newer scheduled substance with an as yet unknown mechanism of action; however, on the basis of the stimulus generalization observed PMMA may share some behavioral and mechanistic similarity with MDMA. These results also indicate that an intact methylenedioxy ring, such as that found in MDMA but absent in PMMA, is not a prerequisite for MDMA-like activity and further support the notion that ring-opened MDMA metabolites may produce effects that contribute to the actions of MDMA.

References (21)

There are more references available in the full text version of this article.

Cited by (29)

  • In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation

    2020, Drug and Alcohol Dependence
    Citation Excerpt :

    Fifteen minutes prior to an errorless training session, rats were injected with 0.9 % physiological saline (ip; S) or the training drug of 1.5 mg/kg MDMA (ip; D) and placed into a darkened chamber for a total of eight 20 min sessions in the following order: S, S, S, D, D, D, S, D. The 15 min pre-session injection interval and 1.5 mg/kg MDMA training dose were chosen from previous drug discrimination studies with MDMA in rats (Kueh and Baker, 2007; Glennon and Higgs, 1992; Schechter, 1987). The house light illuminated and the levers extended into the operant chamber after the 15 min period.

  • Modulatory effects of low-dose MDMA on cocaine-induced locomotor activity and place conditioning in rats

    2012, Pharmacology Biochemistry and Behavior
    Citation Excerpt :

    The current findings indicate that low MDMA doses (1.5, 3.0 mg/kg) have little to no effect on locomotor activity and fail to establish conditioned place preference in adult male Sprague–Dawley rats following three conditioning trials. Although locomotor activity during MDMA conditioning trials was not significantly different from activity levels following saline injections, it should be noted that MDMA is behaviorally active at these low doses in rodents as indicated by numerous reports that rats can be trained to discriminate them from vehicle (Glennon and Higgs, 1992; Baker et al., 1997; Fantegrossi et al., 2009). While MDMA alone failed to establish CPP, the concurrent administration of 20 mg/kg cocaine and 3.0 mg/kg MDMA showed a non significant trend towards establishing a CPP compared to either of these substances alone.

  • Neural and Cardiac Toxicities Associated With 3,4-Methylenedioxymethamphetamine (MDMA)

    2009, International Review of Neurobiology
    Citation Excerpt :

    Nash et al. (1988) showed that i.p. injections of 1–3 mg/kg of MDMA stimulate prolactin and corticosterone secretion in rats, and similar oral doses increase plasma prolactin and cortisol in human drug users (Harris et al., 2002; Mas et al., 1999). The dose of MDMA discriminated by rats and humans is identical: 1.5 mg/kg, i.p., for rats (Glennon and Higgs, 1992; Oberlender and Nichols, 1988; Schechter, 1988) and 1.5 mg/kg, p.o., for humans (Johanson et al., 2005). A few studies have shown that rats will self-administer MDMA at doses ranging from 0.25 to 1.0 mg/kg i.v., indicating these doses possess reinforcing efficacy (Ratzenboeck et al., 2001; Schenk et al., 2003).

  • Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges

    2008, Neuroscience
    Citation Excerpt :

    We sought to minimize this obstacle by designing an MDMA dosing regimen in rats based on threshold pharmacological doses. To this end, a typical dose of MDMA used for discrimination training in rats is 1.5 mg/kg i.p. (Schechter, 1988; Glennon and Higgs, 1992). Interestingly, human subjects discriminate this same dose administered orally in an experimental setting (Johanson et al., 2006), and recreational doses are in the range of 1–3 mg/kg (Cole et al., 2002; Schifano et al., 2006).

  • N-Methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) and N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) produce non-identical discriminative stimuli in rats

    2007, Pharmacology Biochemistry and Behavior
    Citation Excerpt :

    Comparative studies in humans have not been reported, but in drug discrimination studies using rats, MDMA and PMMA produce what appear to be similar discriminative stimulus effects. That is, stimulus generalization occurs between MDMA and PMMA regardless of which of the two is used as training drug (Glennon and Higgs, 1992; Glennon et al., 1997). Moreover, for both agents, the S(+)-optical isomer is the more potent, the α-methyl group can be homologated to an α-ethyl group with retention of action, and the preferred side chain conformation of both agents appears to be mimicked by an aminotetralin structure (Glennon et al., 1997; Young et al., 1999).

View all citing articles on Scopus
View full text