Psilocybin-Induced Deficits in Automatic and Controlled Inhibition are Attenuated by Ketanserin in Healthy Human Volunteers
Boris B Quednow, Michael Kometer, Mark A Geyer and Franz X Vollenweider
Neuropsychopharmacology, 2012, 37, 630–640
The serotonin-2A receptor (5-HT2AR) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT2AR or 5-HT1AR agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT2A/2CR antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 mg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT2AR stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT2AR system.
Keywords : prepulse inhibition; sensorimotor gating; Stroop task; psilocybin; ketanserin; 5-HT2A receptor
Automatic and controlled information-processing deficits, such as impairments in early and late inhibitory gating processes, are considered to constitute core symptoms of schizophrenia and appear to have a crucial role in the pathophysiology of schizophrenia (Braff et al, 2001; Geyer and Braff, 1987; McGhie and Chapman, 1961; Nuechterlein and Dawson, 1984; Nuechterlein et al, 1994; Venables, 1960). Although attentional and behavioral control processes have been linked to the serotonin system in general (Cools et al, 2008; Soubrie´, 1986), early automatic inhibition of sensory stimuli (also called sensorimotor gating; Sipes and Geyer, 1997; Vollenweider et al, 2007) as well as controlled behavioral inhibition have been linked recently to the function of serotonin-2A receptors (5-HT2ARs) in particular (Robinson et al, 2008; Winstanley et al, 2004). Given the long-standing hypothesis that 5-HT2ARs are implicated in the pathogenesis of schizophrenia (Dean, 2003; Geyer and Vollenweider, 2008; Meltzer, 1999; Meltzer et al, 2003; Quednow et al, 2010), 5-HT2AR changes might also contribute to disturbed inhibitory processes seen in schizophrenia patients. Therefore, we investigated the role of 5-HT2ARs in automatic and controlled inhibition processes in a model psychosis approach using the serotonergic hallucinogen psilocybin in healthy humans either pretreated with the 5-HT2A/2CR antagonist ketanserin or placebo. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a prodrug that is rapidly metabolized into the bioactive main metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine; Hasler et al, 1997, 2002) that acts as an agonist at 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7R
(Blair et al, 2000; Sard et al, 2005; Psychoactive Drug Screening Program (PDSP) : http://pdsp.med.unc.edu). Ketanserin has about a 50-fold greater antagonistic potency at 5-HT2AR than 5-HT2CR and also some weak affinity at 5-HT2B and 5-HT7R. Moreover, it is also strongly active at adrenergic a1 and histamine H1 receptors, and weakly active at some dopamine receptors (PDSP: http://pdsp. med.unc.edu). Given these activity profiles, it is conceivable that ketanserin blocks the activity of psilocin primarily at 5-HT2A/2CRs.
Prepulse inhibition (PPI)Fwhich has been established as an operational measure of sensorimotor gatingFis defined as a reduction of the startle reflex because of a weak sensory prestimulation (Braff et al, 1992; Graham, 1975). As patients with schizophrenia display impaired PPI (Braff et al, 1978, 1992; Kumari et al, 2000; Ludewig et al, 2003; Parwani et al, 2000; Quednow et al, 2006, 2008a; Swerdlow et al, 2006) drug-induced PPI deficits has become an important translational model of the gating impairment in schizophrenia.
Hallucinogenic 5-HT2AR agonists such as LSD, 5-MeODMT, DOB, and DOI decrease PPI in rats (Johansson et al, 1995; Krebs-Thomson et al, 2006; Ouagazzal et al, 2001; Padich et al, 1996; Sipes and Geyer, 1995b, 1997). The PPIdisrupting effects of DOI and LSD are blocked by the selective 5-HT2AR antagonist MDL100, 907, which supports the hypothesis that the PPI-disrupting effects of these hallucinogens are mediated by 5-HT2ARs (Halberstadt and Geyer, 2010; Ouagazzal et al, 2001; Padich et al, 1996; Sipes and Geyer, 1995b). However, a more recent study shows that the PPI-disrupting effects of 5-MeO-DMT could possibly be mediated by its agonistic effects at the 5-HT1AR because the PPI-disrupting effects were also abolished by WAY-100635 (Krebs-Thomson et al, 2006). Moreover, 5-HT1AR agonists such as 8-OH-DPAT or buspirone also diminish PPI in rats (Sipes and Geyer, 1995a; van den Buuse and Gogos, 2007) and humans (Gogos et al, 2006) but this effect seems to be limited to interstimulus intervals (ISIs) longer as 100 ms. In humans, the hallucinogen psilocybin decreases and increases PPI at short (o60 ms) and long ISIs (4120 ms), respectively (Gouzoulis-Mayfrank et al, 1998; Vollenweider et al, 2007). Consequently, the question arose whether the PPI-disrupting effects of psilocybin in humans could be attributed to its 5-HT2A or to its 5-HT1A agonist properties. Additional evidence from human genetic studies suggests that polymorphisms of the 5-HT2AR (Quednow et al, 2008b, 2009), but not the 5-HT1AR (Brauer et al, 2009; Quednow, unpublished data), modulates PPI in humans.
The Color Word Stroop Interference Test is an established measure of response inhibition, attentional control, and cognitive flexibility (Barch et al, 2009; MacLeod, 1991; Spreen and Strauss, 1998), in which color words written in different ink colors are presented. Participants are told to name the ink color of the words but to ignore its denotation. If ink color and denotation are conflicting, an over-learned process of reading (semantic information) interferes with an intentional process of color naming (contextual information), resulting in increased reaction time (RT) and errors. Performance on this task is linked to the activation of the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC; Botvinick et al, 2004; Carter et al, 1998; Cohen et al, 2000; Mansouri et al, 2009; Pardo et al, 1990)Fregions that are rich in 5-HT2AR (Adams et al, 2004; Forutan et al, 2002; Pazos et al, 1987). In the classical card Stoop Test, schizophrenia patients consistently displayed increased susceptibility to interference effects in RT. In contrast, on trial-by-trial versions of the task, normal RT interference but increased RT facilitation (RT enhancement in congruent trials) and increased error rates and RT in the conflicting trials have been demonstrated (for review see Henik and Salo, 2004). Neuroimaging studies suggested a conflict-related hypoactivation of the ACC during Stroop interference in schizophrenia patients (Melcher et al, 2008). Recently, it was shown that sensorimotor gating and performance in the Stroop task are correlated indicating that they may be mediated by common attentional or inhibitory processes (Scholes and Martin-Iverson, 2009).
Acute tryptophan depletion, which transiently depletes brain 5-HT, has been reported to decrease RT interference in the Stroop Test in some (Evers et al, 2006; Schmitt et al, 2000; Scholes et al, 2007) but not all studies (Gallagher et al, 2003; Horacek et al, 2005; Sobczak et al, 2002). Moreover, acute 5-HT release induced by dexfenfluramine or MDMA also did not alter Stroop Test performance (Andrews and
Anderson, 1998; Vollenweider et al, 1998a). More specifically, early studies found that the preferential 5-HT2AR agonist LSD impaired performance in the Stroop Test in healthy controls as well as in schizophrenia patients (Krus et al, 1963; Wapner and Krus, 1960). Recent evidence suggests that the 5-HT2A/1AR agonist psilocybin and the 5-HT2A/2CR agonist DMT disrupted a similar inhibitory mechanism of attention as measured with the inhibition-ofreturn (IOR) task, in which performance has been shown to be disturbed in schizophrenia (Daumann et al, 2008; Gouzoulis-Mayfrank et al, 2002, 2004, 2006a, b, 2007). Finally, cyproheptadineFan antagonist at 5-HT2A/2B/2C, 5- HT1A, and 5-HT7R with high affinity also for histamine and muscarinic receptors (PDSP: http://www.pdsp.med.unc. edu)Fimproves RT in the conflict condition of the Stroop Test in chronic schizophrenia patients (Chaudhry et al, 2002), whereas the partial 5-HT1AR agonist buspirone had no effect on Stroop performance in schizophrenia patients (Piskulic et al, 2009). Taken together, these results imply
that 5-HT2ARs are probably involved in controlled inhibitory mechanisms that are needed to accomplish tasks such as the Stroop Test.
Hence, we further investigated the role of the 5-HT2AR in the modulation of automatic (sensorimotor gating) and controlled (Stroop interference) inhibition processes in healthy human volunteers with a placebo-controlled, crossed, counterbalanced, and double-blind design. We examined whether a pretreatment with the 5-HT2A/2CR antagonist ketanserin could prevent the inhibition-disrupting
effects of psilocybin. Owing to previous studies, we expected that ketanserin pretreatment would reduce psilocybin-induced disruptions of PPI and Stroop interference, while preventing formation of an altered state of consciousness (ASC).