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

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMAinduced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of LongEvans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whiskerevoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may "distort," rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

Characterization of electroencephalographic and biochemical responses at 5‐HT promoting drug‐induced onset of serotonin syndrome in rats

“…; Starr et al . ). It is well known that behavioral responses can be altered in complex ways because of the interaction between serotonergic and catecholaminergic systems.…”

“…In support of this concept, 'binge' dosing (three or more doses in one session) was often used to elicit a long lasting increase in extracellular brain 5HT for achieving a recreational or neurological response (Baumann et al 2008b). In addition to 5HT, MDMA also causes excessive increases in extracellular dopamine and noradrenalin (Baumann et al 2008a;Starr et al 2012). It is well known that behavioral responses can be altered in complex ways because of the interaction between serotonergic and catecholaminergic systems.…”

Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats

“…This hypothesis can well explain the influences of underlying environmental factors for intensifying the MDMA-induced syndrome. It is known that MDMA can elicit an increase in many kinds of neurotransmitters in the brain (Nair and Gudelsky, 2006; Baumann et al, 2008; Starr et al, 2012; Anneken et al, 2013). In the absence of environmental factors, however, the responses of other kinds of neurotransmitters to MDMA are too small to have an impact on the syndrome.…”

The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

“…Moderate affinity (10µM-100µM) targets included the norepinephrine and dopamine transporters, and 5-HT 1 receptors, and low affinity (>100µM) targets included dopamine-D1 and -D2 receptors and the choline transporter. A small number of studies have shown that MDMA produces modest increases in extracellular levels of glutamate (Anneken & Gudelsky, 2012;Nash & Yamamoto, 1992) and acetylcholine (Acquas et al, 2001;Nair & Gudelsky, 2006a, 2006b), but there is limited evidence for effects on extracellular norepinephrine (Starr, Page, & Waterhouse, 2012) or GABA (Bankson & Yamamoto, 2004;Yamamoto, Nash, & Gudelsky, 1995). In contrast, a great deal of research on MDMA has focused on 5-HT and dopamine mechanisms.…”