Behavioral, thermal and neurochemical effects of acute and chronic 3,4-methylenedioxymethamphetamine (“Ecstasy”) self-administration

Abstract

Abstract3,4-methylenedioxymethamphetamine (MDMA) is a popular methamphetamine derivative associated with young adults and all-night dance parties. However, the enduring effects of MDMA at voluntary intake levels have not been extensively investigated. In this study, MDMA-influenced behaviors and core temperatures were assessed over the course of 20 daily MDMA selfadministration sessions in rats. In vivo microdialysis techniques were used in a subsequent MDMA challenge test session to determine extracellular nucleus accumbens dopamine (NAcc DA) and serotonin (5-HT) levels in MDMA-experienced and naïve animals before and after a selfadministered MDMA injection (3.0 mg/kg, i.v.). During self-administration sessions, gradual and significant increases in MDMA intake and MDMA-stimulated locomotor activity were observed across sessions. Core temperature significantly decreased during initial MDMA sessions, but was unaltered by the last 10 sessions. In the MDMA challenge test, MDMA-naïve rats showed significantly higher NAcc 5-HT responses compared to MDMA-experienced rats, though MDMA experience did not affect the magnitude of NAcc DA response. The overall findings suggest that changes in MDMA-induced responses over the course of increasing levels of drug exposure may reflect the development of tolerance to a number of MDMA effects.

Rats preexposed to MDMA display attenuated responses to its aversive effects in the absence of persistent monoamine depletions

“…This interpretation of our findings is supported by previous research showing tolerance to many of the effects of MDMA, including behavioral tolerance to its reinforcing effects (Fantegrossi et al 2004), MDMA-induced cognitive impairments (Frederick et al 1995) and hyperactivity (Callaway and Geyer 1992;Brennan and Schenk 2006), as well as physiological tolerance to MDMA-induced serotonin syndrome (Marston et al 1999;Shankaran and Gudelsky 1999;Piper et al 2005) and temperature dysregulation (Shankaran and Gudelsky 1999;Piper et al 2005;Piper et al 2006). However, it is important to note that sensitization to many of these effects has also been observed following repeated MDMA exposure (see Spanos and Yamamoto 1989;Dafters 1995;Kalivas et al 1998;Reveron et al 2010). The presence of tolerance or sensitization is likely to depend on a variety of factors, including variations in study parameters and complex interactions between multiple drug responses.…”

Effects of Repeated 3,4-Methylenedioxymethamphetamine Administration on Neurotransmitter Efflux and Sensory-Evoked Discharge in the Ventral Posterior Medial Thalamus

“…Such mitigating actions could explain the blunting of electrophysiological effects in repetitively treated rats and some aspects of tolerance to drug effects reported by human recreational users. In general, this effect is consistent with evidence of tolerance to various MDMA effects after repeated drug administration in humans (Parrott, 2005), nonhuman primates (Frederick et al, 1995;Fantegrossi, 2008), and rats (Callaway and Geyer, 1992;Marston et al, 1999;Baumann et al, 2008;Reveron et al, 2010).…”

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

“…Effects of MDMA selfadministration on these same measures in rats are, however, lacking. One study failed to observe a change in dialysate levels of MDMAstimulated DA overflow following relatively small amounts of selfadministered MDMA (Reveron et al, 2010) whereas another showed increased DA overflow following more extensive MDMA selfadministration (Colussi-Mas et al, 2010). Another study reported MDMA-produced changes in dialysate levels of DA and 5HT as well as in MDMA-produced hyperactivity, but comparisons to effects of MDMA from saline self-administering rats was not provided so that an indication of changes due specifically to MDMA self-administration was not possible (Feduccia and Duvauchelle, 2008).…”

“…Modest levels of MDMA self-administration have been reported to produce sensitised locomotor responses (Reveron et al, 2010), but effects of more extensive exposures have not been reported. Accordingly, in this study we measured MDMA-produced horizontal and vertical activities following a regimen of MDMA self-administration that we have previously shown decreased tissue levels of 5HT when measured following 5, but not 14, days of abstinence (Do and Schenk, 2013).…”