Effects of MDMA (Ecstasy) on Prepulse Inhibition and Habituation of Startle in Humans after Pretreatment with Citalopram, Haloperidol, or Ketanserin

Abstract

Prepulse inhibition (PPI) of the acoustic startle response is : 3, MDMA; Ecstasy; Serotonin; Citalopram; Haloperidol; Ketanserin; Human; Prepulse inhibition; Habituation; StartleThe startle reflex is a contraction of the skeletal and facial musculature in response to a sudden intense stimulus, such as a loud noise. In humans, the eyeblink component of the startle reflex is measured using electromyography of the orbicularis oculi muscle. In rodents, a stabilimeter is used to register a whole-body flinch response. The startle reflex exhibits several forms of behavioral plasticity, such as prepulse inhibition N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 24 , NO . 3 MDMA-induced Effects on PPI and Habituation in Humans 241(PPI) and habituation, which are consistent phenomena across species. PPI refers to the normal suppression of the startle response when the startling stimulus is preceded by a weak prestimulus. PPI is regarded as an operational measure of sensorimotor gating reflecting the ability to filter cognitive or sensory information. Habituation refers to the decrement of the startle response observed with repeated presentation of the stimulus and is considered to be the simplest form of learning and a prerequisite of selective attention. Both PPI and habituation deficits have been found in patients with schizophrenia (Bolino et al. 1994;Braff et al. 1992;Geyer and Braff 1982) and schizotypal personality disorder (Cadenhead et al. 1993). Deficits in PPI are also seen in obsessive-compulsive disorder (Swerdlow et al. 1993) and Huntington's disease (Swerdlow et al. 1995).In animals, MDMA (3,4-methylenedioxy-N-methylamphetamine, "Ecstasy") releases serotonin (5-HT) and, to a lesser extent, dopamine. The pharmacological effects of MDMA-like drugs on PPI are well studied in rodents [for a review see (Geyer and Callaway 1994)]. Entactogens including MDMA, MDEA (N-ethyl-3,4-methylenedioxyamphetamine), AET (alpha-ethyltryptamine), as well as the serotonin releaser fenfluramine, impair both PPI and habituation of the startle reflex in rodents (Dulawa and Geyer 1996;Kehne et al. 1996;Mansbach et al. 1989;Martinez and Geyer 1997;Vollenweider et al. 1999a). The effects of MDMA-like drugs on PPI and startle habituation are reduced by pretreatment with selective serotonin uptake inhibitors, which prevent carrier-mediated release of presynaptic serotonin by MDMA (Kehne et al. 1992;Martinez and Geyer 1997). These findings support the hypothesis that the effects of MDMA on PPI and habituation are mediated via release of endogenous serotonin. In addition, the 5-HT 2A antagonist MDL 100,907 (now M100907) also reduces the effect of MDMA on PPI , indicating that the released serotonin affects PPI by stimulating postsynaptic 5-HT 2A receptors. Consistent with this conclusion, direct 5-HT 2A receptor activation has been found to disrupt PPI in rats and this effect is reversed by 5HT 2A antagonists Geyer 1994, 1997). In addition, both 5-HT 1A and 5-HT 1B agonists reduce PPI in rats and these effects are antagonized by the corres...

The Effects of Increased Central Serotonergic Activity on Prepulse Inhibition and Habituation of the Human Startle Response

“…The notion that the detrimental effects of imipramine on PPI in our previous study (Hammer et al, 2007) were due to an increased noradrenergic activity would be consistent with the results from other studies in which noradrenaline was found to reduce human PPI (Oranje et al, 2004;Quednow et al, 2004), although a possible anticholinergic effect cannot be ruled out, as imipramine has affinity for this receptor too. The discrepancy between the current study and the studies of Liechti et al (2001) and Vollenweider et al (1999), in which MDMA (or 'ecstasy,' which is a serotonin releasing agent with similar effects on the dopaminergic and noradrenergic system) was found to increase PPI in healthy volunteers, might be attributable to the additional effects of MDMA on the dopaminergic and/or noradrenergic system.…”

“…In a longitudinal study, Quednow et al (2004) found that the SSRI sertraline reduced habituation in patients with major depression, which is consistent with the results of the current study. Liechti et al (2001) found ketanserin to increase habituation, which is well in line with our findings, as the compound is a 5HTa/c antagonist, so an opposite effect of escitalopram is plausible. In contrast, Liechti et al (2001) found no effect of citalopram (SSRI) on habituation, probably owing to the fact that habituation was calculated as the decrement of mean startle amplitude from block 1 to 3, whereby the habituation deficits observed in the current study (over the first four trials) would have been masked.…”

“…Liechti et al (2001) found ketanserin to increase habituation, which is well in line with our findings, as the compound is a 5HTa/c antagonist, so an opposite effect of escitalopram is plausible. In contrast, Liechti et al (2001) found no effect of citalopram (SSRI) on habituation, probably owing to the fact that habituation was calculated as the decrement of mean startle amplitude from block 1 to 3, whereby the habituation deficits observed in the current study (over the first four trials) would have been masked. Similarly, in animal studies, fluvoxetine (SSRI) reduced habituation in rats (Geyer and Tapson, 1988), whereas administration of the 5-HT1A/1B agonist RU24969 reduced habituation in mice (Dulawa and Geyer, 2000).…”

“…The result of the current study, in which no effect of escitalopram (highly specific SSRI) was found on the PPI of healthy male volunteers, suggests that increased serotonergic activity does not affect PPI, and accordingly that the detrimental effect of imipramine on PPI, as found in our previous study, was due to an increase in noradrenergic activity. The line of thought that increased serotonergic activity does not affect PPI would be consistent with the studies of Phillips et al (2000) and Liechti et al (2001) in which no effects of respectively fluvoxamine and citalopram (both SSRIs) were found on PPI in healthy subjects. The evidence that not only an acute increased serotonergic activity, but also a chronically increased serotonergic activity seems to have no effect on PPI, is supplied by the study of Quednow et al (2004), in which no effects of sertraline (SSRI) on PPI were found in a population of patients with major depression.…”

“…In humans, GouzoulisMayfrank et al (1998) found increased PPI following stimulation of 5-HT receptors by administration of psilocybin, a 5-HT 1/2 agonist. Similarly, MDMA (among others a 5-HT releaser) appears to increase PPI in healthy humans (Vollenweider et al, 1999;Liechti et al, 2001). Other studies, however, failed to reproduce this enhancing effect of 5-HT on PPI (Phillips et al, 2000;Riba et al, 2002), probably owing to binding characteristics in general or different affinities for 5-HT receptors in specific.…”