Investigation of serotonin-1A receptor function in the human psychopharmacology of MDMA

Abstract

Serotonin (5-HT) release is the primary pharmacological mechanism of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') action in the primate brain. Dopamine release and direct stimulation of dopamine D2 and serotonin 5-HT2A receptors also contributes to the overall action of MDMA. The role of 5-HT1A receptors in the human psychopharmacology of MDMA, however, has not yet been elucidated. In order to reveal the consequences of manipulation at the 5-HT1A receptor system on cognitive and subjective effects of MDMA, a receptor blocking study using the mixed beta-adrenoreceptor blocker/5-HT1A antagonist pindolol was performed. Using a double-blind, placebo-controlled within-subject design, 15 healthy male subjects were examined under placebo (PL), 20 mg pindolol (PIN), MDMA (1.6 mg/kg b.wt.), MDMA following pre-treatment with pindolol (PIN-MDMA). Tasks from the Cambridge Neuropsychological Test Automated Battery were used for the assessment of cognitive performance. Psychometric questionnaires were applied to measure effects of treatment on core dimensions of Altered States of Consciousness, mood and state anxiety. Compared with PL, MDMA significantly impaired sustained attention and visual-spatial memory, but did not affect executive functions. Pre-treatment with PIN did not significantly alter MDMA-induced impairment of cognitive performance and only exerted a minor modulating effect on two psychometric scales affected by MDMA treatment ('positive derealization' and 'dreaminess'). Our findings suggest that MDMA differentially affects higher cognitive functions, but does not support the hypothesis from animal studies, that some of the MDMA effects are causally mediated through action at the 5-HT1A receptor system.

Blockade of 5-HT2 Receptor Selectively Prevents MDMA-Induced Verbal Memory Impairment

“…These data suggest that 5-HT 1A receptors do not have a crucial role in the neuropharmacology of MDMAinduced memory impairment. These finding confirm recent results from a study assessing the role of 5-HT 1A receptors on MDMA effects on visual-spatial working memory as measured with a CANTAB test battery (Hasler et al, 2009) in a placebo-controlled study. A single dose of MDMA significantly impaired visual-spatial memory as compared with placebo.…”

Effects of a -blocker on the cardiovascular response to MDMA (Ecstasy)

“…Apart from sporadic use of cannabis, one subject reported a single previous experience with a hallucinogenic drug (psilocybin), two subjects had previously used both MDMA and a hallucinogen, and seven subjects were drug-naïve. Subjective (primary outcome) and neurocognitive results from the present study have previously been reported 10. Here we present the previously unpublished cardiovascular and adverse effects (secondary outcomes) of the same study subjects10 with one additional subject.…”

“…Subjective (primary outcome) and neurocognitive results from the present study have previously been reported 10. Here we present the previously unpublished cardiovascular and adverse effects (secondary outcomes) of the same study subjects10 with one additional subject.…”

“…Pindolol is an antagonist at central serotonin 5-HT 1 receptors 14. As described in detail elsewhere,10 pindolol moderately attenuated MDMA-induced increases in positive mood, dreaminess, derealisation and mania-like experience, indicating a possible role for serotonergic 5-HT 1 receptors in the mediation of these mood effects of MDMA. In contrast, pindolol had no effect on MDMA-induced cognitive performance impairment 10.…”

Disruption of prepulse inhibition by 3,4-methylenedioxymethamphetamine (MDMA): comparison between male and female wild-type and 5-HT1A receptor knockout mice

“…An involvement of 5-HT 1A Rs in the action of MDMA has not been clearly established. In human volunteers, there were only limited effects of pretreatment with the 5-HT 1A R antagonist, pindolol, on the MDMA-induced changes in sustained attention and visual-spatial memory (Hasler et al 2009), while in rats, MDMA-induced locomotor hyperactivity was modulated only to a minor extent by pre-treatment with the 5-HT 1A R antagonist, WAY 100, 635 (McCreary et al 1999). On the other hand, acute facilitation of social interaction by MDMA in rats was prevented by pre-treatment with WAY 100,635, but not by a 5-HT 1B R or 5-HT 2A R antagonist (Morley et al 2005).…”