The Effects of the Preferential 5-HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on Interstimulus Interval

Abstract

Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT 2A receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT 2A receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 mg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dosedependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

“…Secondly, it is possible that differences between studies may be related to the stimulus characteristics of the PPI paradigm (eg the interval between prepulse and pulse) and their subsequent sensitivity to serotonergic manipulation. In support, Vollenweider et al (2007) recently reported an effect on PPI that was dependent on the interval between prepulse and pulse (ie lead interval), with psilocybin reducing PPI at short (30 ms), having no effects at medium (60 ms), and increasing PPI at long (120-2000 ms) intervals. Similar effects have also been reported with MDMA (Liechti et al, 2001).…”

“…The findings also concur with a number of studies that report the opposite effect (ie an increase in PPI with enhancement of serotonergic neurotransmission) with MDMA (Liechti et al, 2001) and the 5-HT 2A/1A agonist psilocybin (Gouzoulis-Mayfrank et al, 1998;Vollenweider et al, 1999). However, serotonergic manipulation has not consistently modulated PPI in all studies in humans, with some studies reporting no effects on PPI following acute enhancement of synaptic serotonin with the serotonin reuptake inhibitors, fenfluramine (Abel et al, 2007), fluvoxamine (Phillips et al, 2000b), citalopram (Liechti et al, 2001), and escitalopram (Jensen et al, 2007); and other studies reporting a reduction in PPI or no effects on PPI (depending on the ISI) with psilocybin (Vollenweider et al, 2007). While the reason for this inconsistency is unclear, there are some important possibilities worth discussing.…”

“…It is more likely that effects are related to the potency of serotonergic modulation. Indeed animal studies have shown evidence for dose-dependant effects of serotonin depletion (Prinssen et al, 2002) and serotonin agonists Vollenweider et al, 2007) on PPI. Secondly, it is possible that differences between studies may be related to the stimulus characteristics of the PPI paradigm (eg the interval between prepulse and pulse) and their subsequent sensitivity to serotonergic manipulation.…”

“…Enhancing serotonin neurotransmission with MDMA (3,4-methylenedioxy-N-methylamphetamine or ecstasy), a presynaptic serotonin releaser (Liechti et al, 2001), and the 5-HT 2A/1A agonist, psilocybin (GouzoulisMayfrank et al, 1998;Vollenweider et al, 1999), has been shown to increase PPI. However, the effects of psilocybin on PPI may be dependant on the ISI, with another study finding a decrease in PPI at ISIs of 30 ms, no effects at ISIs of 60 ms, and an increase in PPI at 120-2000 ms (Vollenweider et al, 2007). On the other hand, reducing serotonergic neurotransmission with ketanserin (a non-selective 5-HT 2 receptor antagonist) (Graham et al, 2002) or buspirone (a 5-HT 1A partial agonist acting presynaptically) (Gogos et al, 2006) has been found to reduce PPI.…”

Animal Models of Serotonergic Psychedelics

“…86 In humans, psilocybin disrupts PPI at short interstimulus intervals (ISIs), but has no effect at medium ISIs, and, notably, enhances PPI at long ISIs. 87,88 In rodents, some, but not all, of these studies suggest that psychedelics disrupt PPI at short, medium and long ISIs. 89−91 It is also worth noting that, while both lisuride and LSD disrupt PPI in rats, pretreatment with the 5-HT 2A antagonist α-phenyl-1-(2-phenylethyl)-4-piperidinemethanol (MDL11939) reverses the effect of LSD, but not that of lisuride.…”