Pharmacologic profile of MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites

Abstract

We report here an in vitro pharmacologic profile for MDMA (3,4-methylenedioxymethamphetamine) at various brain recognition sites. The rank order of affinities of MDMA at various brain receptors and uptake sites are as follows: 5-HT uptake greater than alpha 2-adrenoceptors = 5-HT2 serotonin = M-1 muscarinic = H-1 histamine greater than norepinephrine uptake = M-2 muscarinic = alpha 1-adrenoceptors = beta-adrenoceptors greater than or equal to dopamine uptake = 5-HT1 serotonin much greater than D-2 dopamine greater than D-1 dopamine. MDMA exhibited negligible affinities (greater than 500 microM) at opioid (mu, delta and kappa), central-type benzodiazepine, and corticotropin-releasing factor receptors, and at choline uptake sites and calcium channels.

MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment

“…However, the apparently low affinity of [ 3 H]MDMA for the human SERT (K m 910 nM) and for inhibiting [ 3 H]5-HT transport (IC 50 1,340 nM) was anticipated, as Mortensen et al (1999), in a side-by-side comparison, reported that MDMA potency for blocking the human SERT (IC 50 819 nM) was fourfold lower than corresponding values for the rat SERT (IC 50 196 nM). An overall comparison with rat transporters is instructive, as the affinity of MDMA for inhibiting 5-HT transport into rat synaptosomes was tenfold higher than for rat DAT or NET (Battaglia et al 1988). In a reexamination of these values, MDMA affinities for rat transporters confirmed this rank order of potencies (SERT>NET≫DAT), although the differences between SERT and NET were less robust than in later reports (Rothman and Baumann 2003).…”

“…Receptors may also contribute to MDMA effects, as MDMA-induced DA release is markedly attenuated by 5-HT2A receptor blockade (Yamamoto et al 1995;Gudelsky and Nash 1996). α2-Adrenergic receptors are also implicated in MDMAinduced 5-HT release (Battaglia et al 1988), as MDMA has a relatively high affinity for these receptors, and they are present on 5-HT terminals (Green et al 2003). Finally, a novel candidate receptor, the trace amine receptor1 (TA 1 ), may also mediate some of the pharmacological effects of MDMA (Bunzow et al 2001) by four or more mechanisms.…”

“…The serotonin neuron-selective toxicity of MDMA has been attributed to its higher affinity, uptake, or releasing capacity at the SERT, compared with the dopamine transporter (DAT) or norepinephrine (NE) transporter (NET, Rudnick and Wall 1992). This view is supported by data derived from the rodent brain, in which MDMA displays a tenfold higher affinity for blocking SERT-mediated 5-HT transport compared with its affinity for the DAT (Steele et al 1987;Battaglia et al 1988). In contrast, amphetamine selectively affects DA neurons, and methamphetamine apparently affects both neuronal subtypes, coinciding with their relative potencies at the three monoamine transporters (see McCann and Ricaurte 2004 for a review).…”

Neuroendocrine and Cardiovascular Effects of MDE in Healthy Volunteers

“…Both MDMA and MDE show high affinities at ser otonin (5-HT) uptake sites, and lower affinities at nor epinephrine and dopamine (DA) uptake sites of cen tral neurons (Battaglia et al 1988a). They are taken up into the neurons and cause release and reuptake in hibition of the endogenous transmitters (Johnson et al 1986(Johnson et al ,1988Steele et al 1987;Schmidt 1987).…”

“…They are taken up into the neurons and cause release and reuptake in hibition of the endogenous transmitters (Johnson et al 1986(Johnson et al ,1988Steele et al 1987;Schmidt 1987). In ad dition, the substances have low affinities at 5-HT2-, 5-HT1-, and D2-binding sites, but those seem to be less important for the drugs' action (Lyon et al 1986;Battaglia et al 1988a). …”