MDMA (3,4-Methylenedioxymethamphetamine)-Mediated Distortion of Somatosensory Signal Transmission and Neurotransmitter Efflux in the Ventral Posterior Medial Thalamus

Abstract

MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) is reported to enhance tactile sensory perception, an effect that is believed to contribute to its popularity as a recreational drug. To date, no literature exists that addresses the neurophysiological mechanisms underlying the effects of MDMA on somatosensation. However, MDMA interactions with the serotonin transporter protein (SERT) are well known. The rat trigeminal somatosensory system has been studied extensively and receives serotonergic afferents from the dorsal raphe nucleus. Given that these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that short-term lowdose MDMA administration (3 mg/kg i.p.) led to a significant increase in 5-hydroxytryptamine (5-HT) efflux in the ventral posterior medial (VPM) thalamus, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We further evaluated the potential for MDMA to modulate whisker-evoked discharge (WED) of individual neurons in this region. After surgically implanting stainless steel 8-wire multichannel electrode bundles, we recorded spike train activity from single cells of halothane-anesthetized rats while mechanically activating the whisker pathway. We found that short-term low-dose MDMA (3 mg/kg i.p.) increased the spontaneous firing rate but reduced the magnitude and duration of WED in individual VPM thalamic neurons. It is noteworthy that the time course of drug action on neuronal firing patterns was generally consistent with increased 5-HT efflux as shown from our microdialysis studies. Based on these results, we propose the working hypothesis that MDMA may "distort" rather than enhance tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat

“…From this comparison, the authors concluded that MDMA doses in rats must be 4-fold higher than human doses to achieve similar peak plasma MDMA concentrations and that MDMA pharmacokinetics are linear in rats. Because there are published findings contradicting both of these conclusions (Chu et al, 1996;Delaforge et al, 1999;Starr et al, 2008;, we sought to investigate these issues in more detail.…”

“…Starr et al (2008) reported plasma MDMA C max of 300 ng/ml in male LongEvans rats given i.p. injections of 3 mg/kg MDMA, and this concentration is in line with the findings reported here and elsewhere ).…”

“…Interestingly, neither of these endpoints was markedly altered by the 2.5-mg/kg dose of MDMA, a dose that generated clinically relevant amounts of MDMA in plasma. Previous studies showed that s.c. doses of 1-3 mg/kg MDMA induce large elevations in extracellular 5-HT in the brain (Baumann et al, 2008;Starr et al, 2008), yet these doses do not induce robust noncontingent behaviors or hyperthermia. By contrast, the 10-mg/kg dose of MDMA produced large and sustained increases in 5-HT syndrome and core temperature.…”

“…A wealth of pharmacodynamic data shows that neurochemical, endocrine, and behavioral effects of MDMA occur at similar doses in rats and humans (Schechter, 1988;Johanson et al, 2006;Baumann et al, 2007;Kolbrich et al, 2008a). However, few studies have examined MDMA pharmacokinetics in rats given doses of ,10 mg/kg, comparable to those taken by humans (Chu et al, 1996;Starr et al, 2008;, and just one assessed the relationship between pharmacodynamics and pharmacokinetics (Chu et al, 1996). Most MDMA pharmacokinetic studies in rats investigated doses of 10 mg/kg or higher (Valtier et al, 2007;Meyer et al, 2008;Upreti and Eddington, 2008;Mueller et al, 2009).…”

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

“…In human subjects the popular recreational drug "ecstasy" (MDMA) produces powerful, yet poorly understood, effects on somatosensation (for review, see Starr et al, 2008). We reported previously that single-dose (naive subject) systemic administration of MDMA suppresses the transmission of sensory signals through the rat somatosensory thalamus (Starr et al, 2008).…”