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Sensorimotor gating and attentional set-shifting are improved by the μ-opioid receptor agonist morphine in healthy human volunteers

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Prepulse inhibition (PPI) of the acoustic startle response (ASR) has been established as an operational measure of sensorimotor gating. Animal and human studies have shown that PPI can be modulated by dopaminergic, serotonergic, and glutamatergic drugs and consequently it was proposed that impaired sensorimotor gating in schizophrenia parallels a central abnormality within the corresponding neurotransmitter systems. Recent animal studies suggest that the opioid system may also play a role in the modulation of sensorimotor gating. Thus, the present study investigated the influence of the μ-opioid receptor agonist morphine on PPI in healthy human volunteers. Eighteen male, non-smoking healthy volunteers each received placebo or 10 mg morphine sulfate (p.o.) at a two week interval in a double-blind, randomized, and counterbalanced order. PPI was measured 75 min after drug/placebo intake. The effects of morphine on mood were measured by the Adjective Mood Rating Scale and side effects were assessed by the List of Complaints. Additionally, we administered a comprehensive neuropsychological test battery consisting of tests of the Cambridge Neuropsychological Test Automated Battery and the Rey Auditory Verbal Learning Test. Morphine significantly increased PPI without affecting startle reactivity or habituation. Furthermore, morphine selectively improved the error-rate in an attentional set-shifting task but did not influence vigilance, memory, or executive functions. These results imply that the opioid system is involved in the modulation of PPI and attentional set-shifting in humans and they raise the question whether the opioid system plays a crucial role also in the regulation of PPI and attentional set-shifting in schizophrenia.
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Boris B. Quednow et al. Sensorimotor gating is improved by morphine
Sensorimotor gating and attentional set-shifting are
improved by the μ-opioid receptor agonist morphine
in healthy human volunteers
Boris B. Quednow
1
, Philipp A. Csomor
1
, Joelle Chmiel
1
,
Thilo Beck
2
, Franz X. Vollenweider
1
1
University Hospital of Psychiatry, Experimental Psychopathology and Brain Imaging,
University of Zurich, Switzerland
2
Association for Risk Reduction in Use of Drugs (ARUD), Zürich, Switzerland
Revised manuscript submitted for publication as a
Regular research article
to the
The International Journal of Neuropsychopharmacology.
Statistical summary:
Abstract word count: 250
Text word count (without citations): 5200
Number of tables: 4
Number of figures: 2
Corresponding Author:
Boris B. Quednow, Ph.D., Dipl.-Psych.
University Hospital of Psychiatry
Lenggstrasse 31
CH-8008 Zurich, Switzerland
Tel.: 0041-44-384-2777
Fax: 0041-44-384-3396
E-Mail: quednow@bli.uzh.ch
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
2
Abstract
Prepulse inhibition (PPI) of the acoustic startle response (ASR) has been established as an operational
measure of sensorimotor gating. Animal and human studies have shown that PPI can be modulated by
dopaminergic, serotonergic, and glutamatergic drugs and consequently it was proposed that impaired
sensorimotor gating in schizophrenia parallels a central abnormality within the corresponding
neurotransmitter systems. Recent animal studies suggest that the opioid system may also play a role in
the modulation of sensorimotor gating. Thus, the present study investigated the influence of the μ-
opioid receptor agonist morphine on PPI in healthy human volunteers.
Eighteen male, non-smoking healthy volunteers each received placebo or 10 mg morphine sulfate
(p.o.) at a two week interval in a double-blind, randomized, and counterbalanced order. PPI was
measured 75 min after drug/placebo intake. The effects of morphine on mood were measured by the
Adjective Mood Rating Scale and side effects were assessed by the List of Complaints. Additionally,
we administered a comprehensive neuropsychological test battery consisting of tests of the Cambridge
Neuropsychological Test Automated Battery and the Rey Auditory Verbal Learning Test.
Morphine significantly increased PPI without affecting startle reactivity or habituation. Furthermore,
morphine selectively improved the error-rate in an attentional set-shifting task but did not influence
vigilance, memory, or executive functions.
These results imply that the opioid system is involved in the modulation of PPI and attentional set-
shifting in humans and they raise the question whether the opioid system plays a crucial role also in
the regulation of PPI and attentional set-shifting in schizophrenia.
Keywords: Prepulse inhibition, acoustic startle response, sensorimotor gating, morphine,
schizophrenia, μ-opioid receptor, CANTAB.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
3
Introduction
Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as an operational measure of
sensorimotor gating that is proposed to reflect the ability to regulate sensory input by filtering out
irrelevant or distracting stimuli in order to prevent sensory information overflow (Braff et al., 1978;
Braff et al., 1992). PPI refers to the reduction of the startle response when a distinctive weak
prestimulus is presented 30 to 500 ms before a startle-eliciting stimulus (Graham, 1975).
In accordance with the filter deficit model of schizophrenia, diminished sensorimotor gating has been
consistently demonstrated in patients with schizophrenia (Braff et al., 1978; Braff et al., 1992; Kumari
et al., 2000; Ludewig et al., 2003; Parwani et al., 2000; Quednow et al., 2006c). It has been
hypothesized that the cognitive deficits and the positive symptoms in schizophrenia are related to the
deficient sensorimotor gating (Braff et al., 2001).
In rats schizophrenia-like PPI deficits can be induced by direct and indirect dopamine (DA) receptor
agonists, serotonin-2A (5-HT
2A
) receptor agonists, and N-methyl-D-aspartate (NMDA) antagonists
(for review see Geyer et al., 2001). Given that drug-induced PPI-deficits can be abolished by pre- or
posttreatment with antipsychotics, it was proposed that impaired sensorimotor gating in schizophrenia
parallels central neurochemical abnormalities underlying the disease (Geyer et al., 2001). In addition,
evidence from cross-sectional and longitudinal clinical studies suggest that atypical antipsychotics are
especially effective in improving deficient PPI in schizophrenia patients (Kumari et al., 1999; Kumari
et al., 2002; Leumann et al., 2002; Oranje et al., 2002; Quednow et al., 2006c). Similarly, the atypical
antipsychotics clozapine and quetiapine also enhance PPI in healthy human volunteers exhibiting low
baseline PPI levels (Swerdlow et al., 2006; Vollenweider et al., 2006). Consequently, drug-induced
PPI deficits have been established as a translational model of antipsychotic activity (Swerdlow and
Geyer, 1998).
Although the role of the dopaminergic, serotonergic, and glutamatergic neurotransmitter systems with
respect to PPI is well investigated, the contribution of other neurotransmitter systems – such as the
opioid system – in the modulation of PPI is unclear. However, the investigation of the involvement of
the opioid system in sensorimotor gating is of special interest because the opioid system may
participate in the pathogenesis of schizophrenia (Bloom et al., 1976; Jacquet and Marks, 1976;
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
4
Schmauss and Emrich, 1985; Terenius et al., 1976). Moreover, the opioid and dopaminergic reward
system and the cortico-striato-pallido-thalamic (CSPT) circuitry involved in the regulation of PPI
show a considerable anatomical overlap (Swerdlow et al., 1999). Nevertheless, the influence of the
opioid system on PPI is not well-studied in animals and studies in humans are currently lacking.
Recently, it has been shown that the selective κ-opioid receptor agonist U50488 disrupts PPI in rats
and clozapine prevented this disruption. Moreover, the selective κ-opioid receptor antagonist
norbinaltorphimine also prevented the U50488-induced PPI deficit, whereas norbinaltorphimine alone
did not alter PPI (Bortolato et al., 2005). Although the μ-opioid receptor agonists morphine and heroin
did not significantly alter PPI in rats (Leitner, 1989; Ouagazzal et al., 2001; Swerdlow et al., 1991),
heroin clearly tended to increase PPI dose-dependently (Swerdlow et al., 1991). In mice, the
endogenous μ-opioid receptor agonist endomorphin-1 on its own also did also not alter PPI but
attenuated PPI deficits induced by the direct dopamine receptor agonist apomorphine (Ukai and
Okuda, 2003). Finally, the non-selective μ-, δ-, and κ-opioid receptor antagonist naloxone did not
influence PPI in rats but prevented the loss of PPI induced by the indirect dopamine agonist
amphetamine, whereas apomorphine-induced PPI deficits were not altered by naloxone. The authors
concluded that dopamine-opioid interactions in the nucleus accumbens could possibly account for
these results (Swerdlow et al., 1991). Summarized, previous animal data did not provide a clear
picture with respect to the role of the opioid system for sensorimotor gating.
The involvement of the opioid system in higher cognitive functions is – apart from reward
mechanisms and pain modulation – not well-understood (Gianoulakis, 2004; McNally and Akil, 2002;
Waldhoer et al., 2004). Nevertheless, there is some evidence that activation of the μ-opioid receptor by
[D-Ala(2), N-Met-Phe(4), Gly(5)]-enkephalin (DAMGO) impairs working memory in mice which can
be reversed by the κ-opioid receptor agonist dynorphin (Itoh et al., 1994). Dynorphin also improves
memory dysfunction in animal models of amnesia and these effects can be reversed by
norbinaltorphimine (Ilyutchenok and Dubrovina, 1995; Ukai et al., 1997). In vitro studies on
hippocampal neurons showed that opioids acting on the μ-opioid receptor facilitate the induction of
long-term potentiation (LTP) of synaptic transmission which has been postulated as a cellular
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
5
mechanism for learning and memory. In contrast, the κ-opioid receptor agonists dynorphin and
U50488 inhibit LTP (Simmons and Chavkin, 1996; Wagner et al., 1993; Weisskopf et al., 1993).
However, μ-opioid receptor agonists do not generally impair cognitive functioning in humans (for
review see Ersek et al., 2004). Only high doses of selective μ-opioid receptor agonists seem to
decrease delayed verbal memory performance in healthy humans (Cleeland et al., 1996; Hanks et al.,
1995; Kerr et al., 1991), whereas short-term memory or working memory as well as other cognitive
domains remained widely unimpaired even after high doses (Cleeland et al., 1996; Evans and Smith,
1964; Hanks et al., 1995; Hill and Zacny, 2000; O'Neill et al., 2000; Walker and Zacny, 1998). On the
contrary, some studies in healthy volunteers have shown that morphine and codeine (which is
metabolized into morphine) increase the accuracy in choice reaction time tasks (Hanks et al., 1995;
O'Neill et al., 2000), enhance perceptual speed and logical reasoning (Evans and Smith, 1964), and
improve learning and delayed recall in a serial learning task (Liljequist, 1981). Interestingly, naloxone
impaired delayed recall while decreasing learning, immediate recall, accuracy of spatial orientation,
monitoring of word presentations, and increasing choice reaction time (Cohen et al., 1983; Martin del
Campo et al., 1992).
Since the role of μ-opioid receptors in the modulation of sensorimotor gating has not been studied in
humans so far, we investigated the effects of the μ-opioid receptor agonist morphine on PPI, startle
reactivity and habituation of ASR in healthy human volunteers in a randomized, double-blind,
placebo-controlled, and counterbalanced design. In addition, we administered a comprehensive
neuropsychological test battery to explore the effects of morphine on higher cognitive functions and to
further investigate whether morphine-induced changes in sensorimotor gating are associated with
changes in cognitive performance. Based on the finding that heroin tended to increase PPI in rats
(Swerdlow et al., 1991), we expected to find an enhancing effect of morphine on PPI in human
volunteers. While previous human studies found impaired delayed recall performance only after high
doses and reported no or enhancing effects on several cognitive domains after low and moderate doses
of morphine, we anticipated no significant effect on neuropsychological performance by the relatively
low dose of morphine sulfate (10 mg) administered in the present study.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
6
Method
Participants
Since menstrual cycle and smoking have been shown to influence PPI (Duncan et al., 2001; Kumari
and Gray, 1999; Swerdlow et al., 1997) only male non-smoking subjects were included. Eighteen
healthy volunteers (aged 19-31 years) were recruited through internet advertisement from local
universities. Subjects’ physical health was confirmed by medical history, clinical examination,
electrocardiography, and blood analysis. To ensure mental health, all subjects underwent a psychiatric
screening interview based on the DIA-X computerized diagnostic expert system (Wittchen and Pfister,
1997). Furthermore, subjects were examined with the Freiburg Personality Inventory (FPI)
(Fahrenberg et al., 1984) and the Hopkins Symptom Checklist (SCL-90-R) (Derogatis, 1977); scores
differing two standard deviations from the mean value of normative data in any subscale of these
questionnaires were used as exclusion criteria (no subjects had to be excluded by these criteria). All
subjects were also screened for hearing impairment by means of a brief hearing test. The
demographical data are shown in Table 1.
None of the subjects had a past or present psychiatric or neurological disorder, or a severe physical
illness. Moreover, none of them reported a family history of psychiatric disorders, which are known to
have an impact on PPI, specifically schizophrenia spectrum disorders or obsessive-compulsive
disorder. All participants negated use of psychotropic medication or illicit drug use, which was
confirmed by urine toxicologies on both test days.
This study was approved by the Ethics Committee of the University Hospital of Psychiatry, Zurich.
After receiving a written and oral description of the aim of this study, all participants gave written
informed-consent statements before inclusion.
******* Insert Table 1 *******
Morphine
Morphine (Sevredol™) was obtained from Mundipharma, Basel, Switzerland and was prepared as
gelatine capsules of 10 mg morphine sulfate (equivalent to 7.5 mg morphine) at the pharmacy of the
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
7
Psychiatric University Hospital Zurich. Lactose placebo and morphine were administered in gelatine
capsules of identical appearance.
Study Design
The study design was double-blind, placebo-controlled and included two experimental conditions
(morphine and placebo). All subjects received placebo and a single dose of morphine in a randomized
and counterbalanced order at one of two experimental days separated by a 2-week interval.
Sessions were conducted in a calm and comfortable laboratory environment. Participants were told to
abstain from alcohol the day prior to each test session, not to drink caffeine-containing beverages and
not to eat six hours prior to each session. Thirty minutes after arriving in the laboratory, subjects
received placebo or morphine in capsules. Heart rate and blood pressure were recorded 10 min before
as well as 65 and 160 min after drug/placebo intake. To coincide with the mean peak effects of
morphine (Collins et al., 1998) startle measures were obtained 75 min after drug/placebo intake. The
neuropsychological test battery was conducted directly after the startle measurement (~100 min after
drug/placebo intake) and lasted about 45 min. The Adjective Mood Rating Scale (AMRS) (Janke and
Debus, 1978) was administered 10 min before and 70 min after drug/placebo intake. Finally, the List
of Complaints (von Zerssen, 1971) was assessed about 165 min after drug/placebo intake. After the
acute drug effects of morphine subsided completely and the participants reported well-being, they
were dismissed.
Startle Response Measurement
The eye-blink component of the acoustic startle response was measured using an EMG startle system
(EMG-SR-LAB, San Diego Instruments, Inc., San Diego, CA). Two silver/silver-chloride electrodes
were placed below the right eye over the orbicularis oculi muscle and a ground electrode was placed
on the glabella. All electrode resistances were < 5 k. A square wave calibrator established sensitivity
to be 0.38 µV/digital unit. The system recorded 600 samples at 1 kHz sampling rate. EMG data were
band-pass filtered 100 to 1000 Hz by the acquisition hardware. Acoustic startle stimuli were presented
through headphones (TDH-39-P, Maico, Minneapolis, MN). Subjects were seated comfortably in an
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
8
armchair, instructed to relax, and told that they would hear a sequence of white noise bursts. They
were asked to stay awake while staring at a fixed point (passive attention paradigm). Each session
began with a 2-min acclimation period of 70-dB background noise that continued throughout the
session. The session consisted of a total of 73 trials separated by inter-trial intervals varying between
10 and 20 seconds. The trials consisted of four conditions: 115-dB pulse-alone (PA-115) trials of 40
ms duration; 86-dB prepulse-alone (PPA-86) trials of 20 ms duration, prepulse-pulse (PP) trials
consisting of a PA-115 shortly preceded by a PPA-86, and a non-stimulus condition (NS). All stimuli
consisted of broadband white noise. Rise and fall time of PA and PP trials were less than one ms. Five
interstimulus intervals (ISIs; onset-to-onset) were used for the PP trials: 30, 60, 120, 240, or 2000 ms
(PP30, PP60, PP120, PP240, PP2000). The initial trial was a PA-115 trial that was separated for
further analyses. The first and last block of a session consisted of four PA-115 trials and was used for
the calculation of habituation but not of PPI. The two middle blocks (second and third block), each
consisted of four PA-115 trials, four PPA-86 trials, four of each of the PP trials, and four NS trials
presented in a pseudorandom order. Data were analyzed with the Windows based software
emgBLINK version 1.2 (CST, Zürich, Switzerland). Before scoring, the EMG was smoothed with a
time constant of 10 ms. Baseline amplitude was calculated by the mean response amplitude of the first
50 ms before stimulus onset. Stimulus response amplitudes were assessed as peak response minus
baseline value of the respective trial. Peak response was defined as the highest reaction in the time-
window between stimulus onset to 150 ms after stimulus onset. Every trial was examined for
spontaneous eye-blinks and other possible signs of corrupted EMG signal; if present the trial was
excluded from data analysis, which was the case in 2.5% of all trials. Subjects with error trials > 50%
were excluded from data analysis. Based on this criterion, two of the 18 participating subjects were
excluded from analysis only of the startle data.
As described in detail elsewhere (Quednow et al., 2006b; Quednow et al., 2006c), the following startle
measures were examined: 1) startle reactivity [mean amplitude of PA-115 trials in the first block]; 2)
percent habituation [=100×(first block of PA-115 trials–last block of PA-115 trials)/first block of PA-
115 trials); 3) slope of the habituation curve across four blocks of PA-115 trials [b=(nΣxy–(Σx)(
Σy))/(nΣx
2
–(Σx)
2
), where x=block number, y=startle amplitude of PA trials per block]; 4) percent PPI
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
9
and percent prepulse facilitation (PPF) [=100×(PA-115 trials–PP trials)/PA-115 trials]; 5) reactivity to
prepulse stimuli and NS condition [mean amplitude of PPA-86 and NS trials each within the second
and third block]; and 6) peak response latency [mean latency to maximal response amplitude occurring
within 150 ms after PA-115 trials].
Psychometric Measures
On the screening day, all subjects completed the FPI (Fahrenberg et al., 1984), which measured nine
personality traits, and the SCL-90 (Derogatis, 1977), which assessed nine symptom clusters, a global
severity index (GSI), a positive symptom distress index (PSDI) and a positive symptom total score
(PST). On each experimental day all subjects completed the AMRS (Janke and Debus, 1978) twice,
which assessed seven mood subscales. At the end of each experimental day, all subjects completed the
List of Complaints (von Zerssen, 1971) consisting of 65 common psychosomatic symptoms which
were summed for a total score.
Neuropsychological test Battery
The battery comprises of the German version of the Rey Auditory Verbal Learning Test (RAVLT)
(Helmstaedter et al., 2001; Rey, 1958) and six tests of the Cambridge Neuropsychological Test
Automated Battery (CANTAB, www.cantab.com
), which were performed on an IBM-compatible
personal computer with a touch-screen monitor (Elo IntelliTouch, Ottobrunn, Germany).
RAVLT: This task measures verbal declarative memory performance with regard to the supraspan (trial
1), learning performance (Σ trials 1-5), recall of interference list (list B), recall after interference (trial
6), delayed recall (trial 7 after 30 min), loss after consolidation (trial 5 minus trial 7), and adjusted
recognition performance (p(list A)). Administration of the RAVLT and calculation of the several
parameters have been described in detail elsewhere (Quednow et al., 2006a).
CANTAB: The Motor Screening Task (MOT) was used to introduce the subjects to the touch-screen
procedure by touching the center point of flashing crosses on the screen as soon as possible after
appearance. The response latency was assessed. The Rapid Visual Information Processing Task (RVP)
is a visual continuous performance task using predefined sequences of three digits presented at a rate
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
10
of 100 per minute to assess sustained attention over a period of four min. Sustained attention
performance was assessed by total correct responses to target sequences (total hits), discrimination
performance (A’) and latency to hit responses. The Intra/Extradimensional Attentional Set Shifting
Task (ID/ED) is a test for rule acquisition and reversal, featuring visual discrimination and attentional
set-shifting, analogous to the Wisconsin Card Sorting Task (Heaton, 1981). Performance was assessed
by the number of trials (adjusted to the number of completed stages), the total number of errors
(adjusted to the number of completed stages), the errors made up to the extra-dimensional shift (Pre-
ED errors) and the errors made at the extra-dimensional stage of the task (ED errors). The Stockings of
Cambridge Task (SOC) measures the subject's spatial planning ability, based upon the Tower of
London Task (Shallice, 1982). The total number of problems solved in the minimum number of
moves, the number of moves to reach criterion, initial thinking time and subsequent thinking time
were all assessed. The Spatial Recognition Memory Task (SRM) proves visual spatial memory in a 2-
choice forced discrimination paradigm. Performance was indexed by the mean latency to correct
responses, and percent of correct hits of a maximum of 20. Finally, the Spatial Working Memory Task
(SWM) tests spatial working memory and strategy performance. The subject had to find a blue 'token'
in each displayed box, whilst not returning to boxes in which a blue token had already been found.
Performance was indexed by a strategy score, which represents the number of times the subject begins
a new search with the same box. A high score represents poor use of this strategy and a low score
equates to effective use. Furthermore, the total number of errors and between errors (searching a token
in a box where one had already been found) was assessed.
Statistical Analysis
All data were analyzed by SPSS 12.0 for Windows. Startle data, psychometrical data and
neuropsychological data were analyzed by analyses of variance (ANOVA) with repeated
measurements. Based on significant main effects, Least Significant Difference (LSD) post-hoc
comparisons were performed (in case of graded within-subject factors). Frequency differences within
single complaints were analyzed by McNemar tests. Interrelationships between startle parameter,
psychometrical scales, neuropsychological variables, and demographic data were tested using
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
11
Pearson’s product-moment-correlation. The confirmatory statistical comparisons were carried out at a
significance level set at p<.05 (2-tailed). Within the correlation analyses, the significance level was set
at p<.01 (2-tailed) in order to avoid accumulation of α-error. Finally, effect sizes were calculated with
G*Power 3 (Faul et al., 2007) according to the conventions of Cohen (1988).
Results
Startle Measurements
A 4x2 (ISI condition x treatment) repeated measurement ANOVA with the four PPI conditions (PP30,
PP60, PP120, PP240) revealed significant main effects for the factors treatment [F(1,45)=6.04; p<.05]
and ISI condition [F(3,45)=24.97; p<.001] but no significant interaction of both factors. LSD post-hoc
tests revealed that morphine significantly increased PPI in the PP60 [p<.05, d=0.55] and in the PP240
condition [p<.05, d=0.54] (see Figure 1). A repeated measurement ANOVA with the PPF condition
PP2000 did not show a significant drug effect.
******* Insert Figure 1 *******
Given that the PPI-enhancing effects of clozapine in healthy volunteers is limited to subjects with low
PPI levels (Vollenweider et al., 2006) we investigated the influence of placebo PPI levels on the drug
effects. We divided the sample into low vs. high PPI groups by median split in the PP60 and PP240
PPI condition each. Then we calculated a 2x2 (group x treatment) repeated measurement ANOVA
with both corresponding PPI conditions separately. While we found significant main effects for the
factors treatment [F
PP60
(1,14)=4.61; p<.05; F
PP240
(1,14)=5.22; p<.001] and group [F
PP60
(1,14)=30.12;
p<.001; F
PP240
(1,14)=19.27; p<.001] we could not detect significant interactions of both factors in both
PP conditions. Thus, the drug effect was not limited to subjects with low PPI.
Morphine did not alter startle reactivity, habituation, peak response latency, reactivity to prepulse
stimuli and amplitude in NS trials (see Table 2). Finally, reactivity to prepulse stimuli (PPA-86) and
to NS trials did not differ significantly.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
12
******* Insert Table 2 *******
AMRS, List of Complains, and Cardiovascular Measures
The AMRS subscales were analyzed with 2x2 (treatment x rating) repeated measurement ANOVAs
(see Table 3 showing the AMRS change scores between the baseline rating and the rating 70 min after
drug/placebo intake). No significant treatment x rating interaction and no significant main effect of the
factor treatment occurred. A significant main effect of the factor rating could be shown only for the
AMRS subscales performance-related activity [F(1,17)=7.09; p<.05] and general inactivation
[F(1,17)=5.17; p<.05], indicating a decrease of general activity across both test sessions. However,
there were only weak statistical trends for an increase of anxiety-depression and dreaminess under
morphine (see Table 3).
******* Insert Table 3 *******
The rate (±SD) of side-effects – measured with the List of Complaints – did not significantly differ
between placebo (2.06±1.70) and morphine (2.89±3.09) [F(1,17)=1.34; p=.26; d=0.27]. Analyses with
McNemar tests at item level did not show any significant differences between both drug conditions. In
sum, Tiredness was the most frequent complaint (mentioned under placebo: 7 times/under morphine: 8
times) followed by Faintness (4/6) and Addephagia (4/5).
A 2x2x3 (treatment x systolic vs. diastolic blood pressure x rating) repeated measurement ANOVA of
the blood pressure ratings did not reveal an impact of morphine on systolic or diastolic blood pressure.
Moreover, a 2x3 (treatment x rating) repeated measurement ANOVA of the heart rate did also not
show any influence of the study medication on heart rate (cardiovascular data not shown).
Neuropsychological Data
Repeated measurement ANOVAs revealed a significant main effect of treatment with respect to the
pre-extra-dimensional shift errors (pre-ED errors) whereas all other neuropsychological parameters did
not significantly differ (see Table 4). A 2x9 (treatment x ID/ED stages) repeated measurement
ANOVA of the error rates across the nine ID/ED stages revealed a significant main effect of the factor
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
13
stage [F(8,136)=11.4; p<.001] but only a statistical trend for the factor treatment [F(1,136)=2.97;
p=.09] and no significant interaction of both factors (see Figure 2). For an exploratory approach we
analyzed the single stages separately by means of LSD post-hoc tests. It turned out that the error rates
in the first stage Simple discrimination [p<.001, d=0.97] and in the sixth stage Intradimensional shift
[p<.05, d=0.51] were significantly improved under morphine.
******* Insert Table 4 *******
******* Insert Figure 2 *******
Correlational Analyses
To assess whether the significant PPI enhancement parallels the significant decrease in the ID/ED pre-
ED error rate we correlated the change-scores of both parameters, which were indeed not significantly
associated. However, the change score of the error rate in the Simple discrimination stage was
positively correlated with the change score of the mean %PPI across ISI conditions [r=0.66, p<.01,
n=16], indicating that subjects with increased PPI also made less errors under morphine. Moreover,
PPI enhancement (PP30 and PP60 conditions) was significantly correlated with decrease of SOC
subsequent thinking time [r
PP30
=-0.63, p<.01, n=16; r
PP60
=0.64, p<.01, n=16].
Interestingly, mean %PPI across ISI conditions at placebo condition was negatively correlated with the
FPI subscale Inhibition [r=-0.66, p<.01, n=16], reflecting that subjects with low PPI show high social
inhibition (in the sense of shyness). With exception of a significant correlation between slope of
habituation curve and verbal IQ [r=-0.67, p<.01, n=16] (pointing that a high IQ goes along with a
strong habitation capacity) no other demographic variables were significantly correlated with PPI,
habituation, and startle reactivity.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
14
Discussion
To our knowledge, this is the first study investigating the effects of the μ-opioid receptor agonist
morphine on sensorimotor gating and attentional set-shifting in healthy human volunteers. The study
yielded two main results: Firstly, morphine significantly increased PPI across all of the investigated
ISI conditions without influencing startle reactivity and habituation. The strongest effect sizes
occurred in the 60 ms and 240 ms ISI condition. The PPI-enhancing effect was seen in most of the
subjects and was not limited to subjects with low PPI as shown previously for the atypical
antipsychotics clozapine and quetiapine (Swerdlow et al., 2006; Vollenweider et al., 2006). Secondly,
morphine selectively improved the Pre-extradimensional (Pre-ED) error-rate in the ID/ED Task but
did not significantly affect other neuropsychological domains such as vigilance, memory, or executive
functions. Interestingly, the PPI improvement (summed across conditions) was associated with the
decrease of errors at the first stage (Simple discrimination) of the ID/ED Task. Moreover, at the
relatively low dose morphine did not significantly affect mood and did not cause more side-effects
than placebo.
The morphine-induced increase of PPI in our healthy volunteers is in line with the previously reported
increase of PPI by heroin in rats (Swerdlow et al., 1991). Furthermore, morphine did not alter startle
amplitude or habituation which is also in accordance with previous studies (Leitner, 1989; Ouagazzal
et al., 2001; Swerdlow et al., 1991). Some previous studies also reported PPI-improving effects of
psychoactive drugs in healthy human volunteers: nicotine increased PPI in smokers and non-smokers
(Kumari et al., 1997; Postma et al., 2006), clozapine and quetiapine enhanced PPI in subjects
exhibiting low PPI levels (Swerdlow et al., 2006; Vollenweider et al., 2006), and the serotonin releaser
MDMA (Vollenweider et al., 1999), as well as the hallucinogenic serotonin-2A/1A agonist psilocybin
increased PPI exclusively at long ISIs (Gouzoulis-Mayfrank et al., 1998; Vollenweider et al., 2007).
How could the PPI-enhancing effect of morphine be explained? The opioid-system interacts with
several neurotransmitter systems such as dopamine, glutamate, GABA, acetylcholine, and substance P
within core regions critically involved in sensorimotor gating such as nucleus accumbens (NAc),
ventral pallidum (VP), and ventral tegmental area (VTA) (McGehee, 2006; Napier and Mitrovic,
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
15
1999; Pan, 1998; Swerdlow et al., 2001; Xi and Stein, 2002). Since Ukai and Okuda (2003) have
shown that the μ-opioid receptor agonist endomorphin-1 could inhibit the apomorphine-induced PPI
deficit in mice and as it has been found that naloxone could prevent amphetamine-induced disruption
of PPI in rats (Swerdlow et al., 1991) one could speculate that opiate-dopamine interactions may
account for the PPI-increasing effect of morphine. This would also fit with the hypothesis that opioid-
dopamine interactions play a role in the pathogenesis of schizophrenia (Schmauss and Emrich, 1985).
However, μ-opioid receptor agonists such as morphine disinhibit dopaminergic neurons in the VTA
through inhibition of GABAergic interneurons and increase dopamine release in the NAc, an effect
which is widely accepted to explain a part of the addictive and rewarding properties of opioids (Koob,
2000; Pan, 1998; Xi and Stein, 2002). Since it has been consistently shown that even an increase of
dopamine in the NAc disrupts PPI in rats (for review see Swerdlow et al., 2001), opioid-dopamine
interactions in the NAc are not very likely to explain the present finding of an μ-opioid receptor-
mediated increase of PPI. Even the finding of Bortolato et al (2005) that κ-opioid receptor activation
disrupts PPI does not support dopamine-opioid interactions as an explanation of opioid induced PPI
alterations because κ-opioid receptor activation decreases dopamine release in the NAc (Pan, 1998).
However, μ-opioid receptor agonists are also modulating GABAergic and glutamatergic
neurotransmission in the VP and VTA (Johnson and Napier, 1997; Mitrovic and Napier, 2002; Napier
and Mitrovic, 1999; Xi and Stein, 2002) and these neurotransmitter systems have been shown as
critically involved in the processing of PPI in these regions (for review see Swerdlow et al., 2001).
Moreover, evidence from behavioral and in vitro electrophysiological studies suggests that μ-opioid
receptors interact with serotonin-2A receptors in the medial prefrontal cortex (MPFC) (Domino, 1986;
Marek, 2003; Marek and Aghajanian, 1998a; Marek and Aghajanian, 1998b; Marek et al., 2001), and
serotonergic activity in the cortex (and in the VP) has been demonstrated to be an important substrate
of PPI-modulation in rats (Geyer et al., 2001; Sipes and Geyer, 1997; Swerdlow et al., 2001). With
regard to the present findings it should be noted that especially low doses of μ-opioid receptor agonists
antagonized behavioral effects of hallucinogens mainly acting on serotonin-2A receptors, whereas
larger doses rather enhance these effects (Domino, 1986). In addition, it has been shown that even
subthreshold doses of morphine can strongly modulate other dopaminergic, GABAergic or
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
16
glutamatergic neurotransmissions in the VTA, VP and NAc (Napier and Mitrovic, 1999). Thus, larger
doses of morphine may loose the ability to increase PPI, which would explain the finding that high
doses of morphine did not change PPI in rats (Leitner, 1989; Ouagazzal et al., 2001).
Given the facts that activation of nicotinic acetylcholine receptors can increase PPI (Kumari et al.,
1997; Postma et al., 2006) and that μ-opioid receptor activation can also modulate acetylcholine
release in the NAc (McGehee, 2006), it is also conceivable that nicotinic-opioid receptor interactions
may contribute to the PPI increase under morphine.
Finally, it is an interesting conjunction that the κ-opioid receptor agonist U50488 disrupts PPI
(Bortolato et al., 2005) whereas we found a PPI-enhancing effect following μ-opioid receptor
activation. These findings are in accordance with the hypothesis that activation of κ-opioid receptors
antagonize various μ-opioid receptor-mediated actions in the brain (Pan, 1998).
It should be noted that previous animal studies investigating the effects of morphine on PPI mostly
applied only a single ISI of 100 ms and that we found the strongest effects at lead intervals of 60 and
240 ms. Furthermore, the sample sizes of these animal studies were generally smaller (n=8-12) than in
our investigation (Leitner, 1989; Ouagazzal et al., 2001; Swerdlow et al., 1991). Therefore, differences
in ISI, sample size, and morphine dose (see above) or unknown species-specific mechanisms could
possibly account for the fact that previous animal studies did not detect a significant increase of PPI
under morphine.
In conclusion, the PPI-enhancing effect of morphine could be possibly be mediated by interactions
between μ-opioid receptors and glutamatergic, GABAergic or nicotinic innervations of the VP or VTA
or by interactions with the serotonin system within the MPFC or VP. However, animal studies are
needed to explore these supposed neurotransmitter interactions in more detail.
Given that PPI-enhancing effects are seen as an indicator of antipsychotic activity (Swerdlow and
Geyer, 1998) the present findings raise the question whether morphine could have antipsychotic
properties. Interestingly, morphine is to be regarded as the first specific antipsychotic in the history of
psychopharmacology. It was widely used for the treatment of affective and psychotic disorders until it
fell into disfavor by the beginning of the 19
th
century because of its addictive potential (Comfort,
1977). An observation by Comfort (1977) could also point toward antipsychotic activity: “...a clinical
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
17
impression remains, unsupported by any good figures, that among addicts there are some who would
have become psychotic if not addicted, and who use morphinoids (heroin in particular) to hold at bay
intolerable prepsychotic sensations, and that these are sharply exacerbated by withdrawal” (p. 448).
In the 1970s a possible involvement of endogenous opioids in the pathogenesis of schizophrenia was
proposed (Bloom et al., 1976; Jacquet and Marks, 1976; Terenius et al., 1976), but following clinical
studies with opioid agonists and antagonists did not reveal marked clinical effectiveness of these
substances in schizophrenia patients (for review see Schmauss and Emrich, 1985). However, from the
current perspective these studies suffered from small sample sizes, short observation periods and lack
of placebo control. Taken together, our findings suggest that the μ-opioid receptor may possibly be an
interesting drug target for the treatment of schizophrenia.
With regard to the self-medication hypothesis of addictive disorders (Khantzian, 1985) our findings
raise a further question: Do opioid addicts have PPI deficits? Surprisingly, there are no PPI data of
opioid addicts available so far and it would be of great interest to learn whether PPI is decreased in
these patients and what happens with PPI during withdrawal and when opioids are administered.
The data further show that morphine reduces the Pre-ED error-rate in the ID/ED Task, especially in
the stages Simple discrimination (SDI) stage and Intradimensional shift (ID). The error rate during the
Extradimensional shift (ED) was not significantly improved, albeit also decreased, while reversal
learning was unaffected by morphine. Whereas the SDI stage requires only visual discrimination
learning, in the ID stage subjects have to learn the transfer of a rule within the same perceptual
dimension (e.g. shape). By contrast, the ED stage requires the shift to a new – previously irrelevant –
perceptual dimension (e.g color) while the previously attended feature must be disregarded (Owen et
al., 1991). It has been consistently reported that schizophrenia patients display deficits in the ID and
ED stages of the ID/ED Task (Elliott et al., 1995; Hutton et al., 1998; Jazbec et al., 2007; Pantelis et
al., 1999). These previous studies primarily investigated the attrition rate and the trials to reach
criterion as dependent variables and these parameters were not significantly affected by morphine in
the present study (data not shown). However, it has been shown that schizophrenia patients committed
more errors especially in the SDI and ID stages rather than in the ED stage (Pantelis et al., 1999) and
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
18
errors on the ID stage were associated with disorganized symptom characteristics of schizophrenia
(Pantelis et al., 2004). Moreover, abstinent heroin abusers also showed significant impairment of
performance at the ID but not at the ED stage (Ornstein et al., 2000). Lesion studies and studies with
patients suffering from Parkinson’s or Huntington’s disease suggest that the prefrontal cortex and the
basal ganglia are involved in performing ED shifts (Dias et al., 1996; Downes et al., 1989; Lawrence
et al., 1996; Owen et al., 1992; Owen et al., 1991). The ability to reverse stimulus-reward connections
within a perceptual dimension (reversal learning), on the other hand, is more associated with the
orbitofrontal cortex (Dias et al., 1996).
The involvement of the opioid system in attentional set-shifting is scarcely investigated. A recent
study reported that the mixed μ-, δ-, and κ-opioid receptor antagonist naltrexone attenuated the
impairment in ED shifts in aged rats (Rodefer and Nguyen, 2006) but studies in humans are lacking.
Nevertheless, our finding is in line with previous studies showing morphine-induced improvement of
neuropsychological performance in tests supposedly involving similar attentional processes like visual
discrimination learning such as choice reaction time tasks (Hanks et al., 1995; O'Neill et al., 2000) and
perceptual and semantic evaluation tasks (Evans and Smith, 1964). The idea that morphine could
improve cognition is not new. Based on self-experiments examining the effect of morphine on choice
reaction tasks, Kraepelin (1892) already concluded that morphine “immediately facilitates the
perception of external stimuli, … , whereas the implementation of choice is aggravated in the same
time” [“… (Morphin) erleichtert … sofort die Auffassung äusserer Eindrücke, … , während die
Ausführung des Wahlactes in ganz ähnlichem Tempo erschwert wird” p. 255].
A further important result is that the morphine-induced increase in PPI was correlated with the
decrease of the error-rate within the SDI stage of the ID/ED Task. The SDI stage measures alertness
rather than rule acquisition like later stages of the task (Jazbec et al., 2007). This correlation is in
accordance with our previous observation that psilocybin-induced deficits of sustained attention
deficits were associated with PPI reduction at short ISI intervals (Vollenweider et al., 2007). These
findings support the hypothesis that deficits in sensorimotor gating may underlie the more complex
attentional and cognitive abnormalities in schizophrenia (Braff et al., 2001). Since we have shown that
morphine enhance PPI and attentional set-shifting processes that are both impaired in schizophrenia
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
19
– the μ-opioid receptor might be a promising target for the development of specific cognitive
enhancers for schizophrenia patients. Furthermore, abstinent opiate addicts also show worse
performance at the ID stage and morphine specifically improves this kind of visual discrimination
learning what might support the self-medication hypothesis of opiate addiction (Khantzian, 1985). It
would be of interest if opiate addicts receiving heroin substitution would show improved ID
performance compared to abstinent subjects.
In conclusion our findings imply that the μ-opioid system is involved in the modulation of PPI and
attentional set-shifting. These results raise the question whether the opioid system plays a crucial role
also in the regulation of PPI and attentional set-shifting in schizophrenia in which both functions were
shown as deficient. Future preclinical studies should evaluate if μ-opioid receptors could be a potential
drug target for new antipsychotic agents or cognitive enhancers for schizophrenic patients. Moreover,
animal studies are needed to enlighten the anatomical structures and neurochemical mechanisms
underlying the morphine-induced increase of PPI and attentional set-shifting in our healthy human
volunteers.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
20
Acknowledgements
Dr. Quednow was supported by the Deutsche Forschungsgemeinschaft (DFG, grant QU 218/1-1) and
by the Nachwuchsförderungskredit of the University of Zurich. In addition, Philipp Csomor received
support by a grant from the Stiftung für Klinische Neuro-Psychiatrische Forschung, Berne,
Switzerland. Dr. Franz Vollenweider was additionally supported by a NARSAD (The Mental Health
Research Association) Independent Investigator Award, USA. The authors would like to thank Dr.
Nicolas Langlitz for his helpful comments and Carmen Ghisleni for technical assistance.
Statement of Interest
Mundipharma, Basel, Switzerland contributed supplemental funding. Experimental design, data
acquisition, statistical analyses, and interpretation of the results were done without input from any
pharmaceutical company. All authors reported no biomedical financial interests or potential conflicts
of interest.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
21
References
Bloom F, Segal D, Ling N, Guillemin R (1976). Endorphins: profound behavioral effects in rats suggest new
etiological factors in mental illness. Science, 194: 630-632.
Bortolato M, Aru GN, Frau R, Orru M, Fa M, Manunta M, Puddu M, Mereu G, Gessa GL (2005). Kappa
opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats. Biological
Psychiatry, 57: 1550-1558.
Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978). Prestimulus effects on human startle reflex in
normals and schizophrenics. Psychophysiology, 15: 339-343.
Braff DL, Geyer MA, Swerdlow NR (2001). Human studies of prepulse inhibition of startle: normal subjects,
patient groups, and pharmacological studies. Psychopharmacology (Berl), 156: 234-258.
Braff DL, Grillon C, Geyer MA (1992). Gating and habituation of the startle reflex in schizophrenic patients.
Archives of General Psychiatry, 49: 206-215.
Cleeland CS, Nakamura Y, Howland EW, Morgan NR, Edwards KR, Backonja M (1996). Effects of oral
morphine on cold pressor tolerance time and neuropsychological performance.
Neuropsychopharmacology, 15: 252-262.
Cohen J (1988). Statistical power analysis for the behavioral sciences Hillsdale, NJ: Lawrence Earlbaum
Associates.
Cohen RM, Cohen MR, Weingartner H, Pickar D, Murphy DL (1983). High-dose naloxone affects task
performance in normal subjects. Psychiatry Research, 8: 127-136.
Collins SL, Faura CC, Moore RA, McQuay HJ (1998). Peak plasma concentrations after oral morphine: a
systematic review. Journal of Pain and Symptom Management, 16: 388-402.
Comfort A (1977). Morphine as an antipsychotic. Relevance of a 19th-century therapeutic fashion. Lancet, 2:
448-449.
Derogatis LR (1977). SCL-90-R, administration, scoring, and procedures manual-I for the R(evised) version.
Baltimore: John Hopkins University School of Medicine.
Dias R, Robbins TW, Roberts AC (1996). Dissociation in prefrontal cortex of affective and attentional shifts.
Nature, 380: 69-72.
Domino EF (1986). Opioid-hallucinogen interactions. Pharmacology, Biochemistry, and Behavior, 24: 401-405.
Downes JJ, Roberts AC, Sahakian BJ, Evenden JL, Morris RG, Robbins TW (1989). Impaired extra-
dimensional shift performance in medicated and unmedicated Parkinson's disease: evidence for a
specific attentional dysfunction. Neuropsychologia, 27: 1329-1343.
Duncan E, Madonick S, Chakravorty S, Parwani A, Szilagyi S, Efferen T, Gonzenbach S, Angrist B,
Rotrosen J (2001). Effects of smoking on acoustic startle and prepulse inhibition in humans.
Psychopharmacology (Berl), 156: 266-272.
Elliott R, McKenna PJ, Robbins TW, Sahakian BJ (1995). Neuropsychological evidence for frontostriatal
dysfunction in schizophrenia. Psychological Medicine, 25: 619-630.
Ersek M, Cherrier MM, Overman SS, Irving GA (2004). The cognitive effects of opioids. Pain Management
Nursing, 5: 75-93.
Evans WO, Smith RP (1964). Some effects of morphine and amphetamine on intellectual functions and mood.
Psychopharmacologia, 6: 49-56.
Fahrenberg J, Hampel R, Selg H (1984).
Das Freiburger Persönlichkeitsinventar (FPI). Göttingen: Hogrefe.
Faul F, Erdfelder E, Lang A-G, Buchner A (2007). G*Power 3: A flexible statistical power analysis program
for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39: 175-191
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001). Pharmacological studies of prepulse
inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.
Psychopharmacology (Berl), 156: 117-154.
Gianoulakis C (2004). Endogenous opioids and addiction to alcohol and other drugs of abuse. Current Topics in
Medicinal Chemistry, 4: 39-50.
Gouzoulis-Mayfrank E, Heekeren K, Thelen B, Lindenblatt H, Kovar KA, Sass H, Geyer MA (1998).
Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in
humans. Behav Pharmacol, 9: 561-566.
Graham FK (1975). Presidential Address, 1974. The more or less startling effects of weak prestimulation.
Psychophysiology, 12: 238-248.
Hanks GW, O'Neill WM, Simpson P, Wesnes K (1995). The cognitive and psychomotor effects of opioid
analgesics. II. A randomized controlled trial of single doses of morphine, lorazepam and placebo in
healthy subjects. European Journal of Clinical Pharmacology, 48: 455-460.
Heaton RK (1981). The Wisconsin Card Sorting Test manual. Odessa, FL: Psychological Assessment
Resources.
Helmstaedter C, Lendt M, Lux S (2001). VLMT - Verbaler Lern- und Merkfähigkeitstest. Göttingen: Beltz
Test.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
22
Hill JL, Zacny JP (2000). Comparing the subjective, psychomotor, and physiological effects of intravenous
hydromorphone and morphine in healthy volunteers. Psychopharmacology (Berl), 152: 31-39.
Hutton SB, Puri BK, Duncan LJ, Robbins TW, Barnes TR, Joyce EM (1998). Executive function in first-
episode schizophrenia. Psychological Medicine, 28: 463-473.
Ilyutchenok RY, Dubrovina NI (1995). Memory retrieval enhancement by kappa opioid agonist and mu, delta
antagonists. Pharmacology, Biochemistry, and Behavior, 52: 683-687.
Itoh J, Ukai M, Kameyama T (1994). Dynorphin A-(1-13) potently improves the impairment of spontaneous
alternation performance induced by the mu-selective opioid receptor agonist DAMGO in mice. The
Journal of Pharmacology and Experimental Therapeutics, 269: 15-21.
Jacquet YF, Marks N (1976). The C-fragment of beta-lipotropin: an endogenous neuroleptic or
antipsychotogen? Science, 194: 632-635.
Janke W, Debus G (1978). Die Eigenschaftsworterliste (EWL), Manual. Gottingen: Hogrefe.
Jazbec S, Pantelis C, Robbins T, Weickert T, Weinberger DR, Goldberg TE (2007). Intra-
dimensional/extra-dimensional set-shifting performance in schizophrenia: impact of distractors.
Schizophrenia Research, 89: 339-349.
Johnson PI, Napier TC (1997). Morphine modulation of GABA- and glutamate-induced changes of ventral
pallidal neuronal activity. Neuroscience, 77: 187-197.
Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, Buffington V, Mackie A (1991).
Concentration-related effects of morphine on cognition and motor control in human subjects.
Neuropsychopharmacology, 5: 157-166.
Khantzian EJ (1985). The self-medication hypothesis of addictive disorders: focus on heroin and cocaine
dependence. American Journal of Psychiatry, 142: 1259-1264.
Koob GF (2000). Neurobiology of addiction. Toward the development of new therapies. Annals of the New York
Academy of Sciences, 909: 170-185.
Kraepelin E (1892). Ueber die Beeinflussung einfacher psychischer Vorgänge durch einige Arzneimittel. Jena:
Gustav Fischer.
Kumari V, Cotter PA, Checkley SA, Gray JA (1997). Effect of acute subcutaneous nicotine on prepulse
inhibition of the acoustic startle reflex in healthy male non-smokers. Psychopharmacology (Berl), 132:
389-395.
Kumari V, Gray JA (1999). Smoking withdrawal, nicotine dependence and prepulse inhibition of the acoustic
startle reflex. Psychopharmacology (Berl), 141: 11-15.
Kumari V, Soni W, Mathew VM, Sharma T (2000). Prepulse inhibition of the startle response in men with
schizophrenia: effects of age of onset of illness, symptoms, and medication. Archives of General
Psychiatry, 57: 609-614.
Kumari V, Soni W, Sharma T (1999). Normalization of information processing deficits in schizophrenia with
clozapine. American Journal of Psychiatry, 156: 1046-1051.
Kumari V, Soni W, Sharma T (2002). Prepulse inhibition of the startle response in risperidone-treated patients:
comparison with typical antipsychotics. Schizophrenia Research, 55: 139-146.
Lawrence AD, Sahakian BJ, Hodges JR, Rosser AE, Lange KW, Robbins TW
(1996). Executive and
mnemonic functions in early Huntington's disease. Brain, 119 ( Pt 5): 1633-1645.
Leitner DS (1989). Multisensory deficits in rats produced by acute exposure to cold swim stress. Behav
Neurosci, 103: 151-157.
Leumann L, Feldon J, Vollenweider FX, Ludewig K (2002). Effects of typical and atypical antipsychotics on
prepulse inhibition and latent inhibition in chronic schizophrenia. Biological Psychiatry, 52: 729-739.
Liljequist R (1981). Codeine-induced memory changes: nature and relationship to opiate system. European
Journal of Clinical Pharmacology, 20: 99-107.
Ludewig K, Geyer MA, Vollenweider FX (2003). Deficits in prepulse inhibition and habituation in never-
medicated, first-episode schizophrenia. Biological Psychiatry, 54: 121-128.
Marek GJ (2003). Behavioral evidence for mu-opioid and 5-HT2A receptor interactions. European Journal of
Pharmacology, 474: 77-83.
Marek GJ, Aghajanian GK (1998a). 5-Hydroxytryptamine-induced excitatory postsynaptic currents in
neocortical layer V pyramidal cells: suppression by mu-opiate receptor activation. Neuroscience, 86:
485-497.
Marek GJ, Aghajanian GK (1998b). The electrophysiology of prefrontal serotonin systems: therapeutic
implications for mood and psychosis. Biological Psychiatry, 44: 1118-1127.
Marek GJ, Wright RA, Gewirtz JC, Schoepp DD (2001). A major role for thalamocortical afferents in
serotonergic hallucinogen receptor function in the rat neocortex. Neuroscience, 105: 379-392.
Martin del Campo AF, McMurray RG, Besser GM, Grossman A (1992). Effect of 12-hour infusion of
naloxone on mood and cognition in normal male volunteers. Biological Psychiatry, 32: 344-353.
McGehee DS (2006). Nicotinic and opioid receptor interactions in nicotine addiction. Molecular Interventions,
6: 311-314.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
23
McNally GP, Akil H (2002). Opioid peptides and their receptors: overview of function in pain modulation. In:
Davis KL, Charney D, Coyle JT, Nermeroff C (Eds.) Neuropsychopharmacology: The 5th generation
of progress (pp. 35-46) Philadelphia: Lippincott, Williams & Wilkins.
Mitrovic I, Napier TC (2002). Mu and kappa opioid agonists modulate ventral tegmental area input to the
ventral pallidum. European Journal of Neuroscience, 15: 257-268.
Napier TC, Mitrovic I (1999). Opioid modulation of ventral pallidal inputs. Annals of the New York Academy
of Sciences, 877: 176-201.
O'Neill WM, Hanks GW, Simpson P, Fallon MT, Jenkins E, Wesnes K (2000). The cognitive and
psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four)
oral doses of dextropropoxyphene, morphine, lorazepam and placebo. Pain, 85: 209-215.
Oranje B, Van Oel CJ, Gispen-De Wied CC, Verbaten MN, Kahn RS (2002). Effects of typical and atypical
antipsychotics on the prepulse inhibition of the startle reflex in patients with schizophrenia. Journal of
Clinical Psychopharmacology, 22: 359-365.
Ornstein TJ, Iddon JL, Baldacchino AM, Sahakian BJ, London M, Everitt BJ, Robbins TW (2000).
Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers.
Neuropsychopharmacology, 23: 113-126.
Ouagazzal AM, Jenck F, Moreau JL (2001). Drug-induced potentiation of prepulse inhibition of acoustic
startle reflex in mice: a model for detecting antipsychotic activity? Psychopharmacology (Berl), 156:
273-283.
Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP, Lange KW, Robbins TW (1992).
Fronto-striatal cognitive deficits at different stages of Parkinson's disease. Brain, 115 ( Pt 6): 1727-
1751.
Owen AM, Roberts AC, Polkey CE, Sahakian BJ, Robbins TW (1991). Extra-dimensional versus intra-
dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or
amygdalo-hippocampectomy in man. Neuropsychologia, 29: 993-1006.
Pan ZZ (1998). mu-Opposing actions of the kappa-opioid receptor. Trends in Pharmacological Sciences, 19:
94-98.
Pantelis C, Barber FZ, Barnes TR, Nelson HE, Owen AM, Robbins TW (1999). Comparison of set-shifting
ability in patients with chronic schizophrenia and frontal lobe damage. Schizophrenia Research, 37:
251-270.
Pantelis C, Harvey CA, Plant G, Fossey E, Maruff P, Stuart GW, Brewer WJ, Nelson HE, Robbins TW,
Barnes TR (2004). Relationship of behavioural and symptomatic syndromes in schizophrenia to spatial
working memory and attentional set-shifting ability. Psychological Medicine, 34: 693-703.
Parwani A, Duncan EJ, Bartlett E, Madonick SH, Efferen TR, Rajan R, Sanfilipo M, Chappell PB,
Chakravorty S, Gonzenbach S, Ko GN, Rotrosen JP (2000). Impaired prepulse inhibition of acoustic
startle in schizophrenia. Biological Psychiatry, 47: 662-669.
Postma P, Gray JA, Sharma T, Geyer M, Mehrotra R, Das M, Zachariah E, Hines M, Williams SC,
Kumari V (2006). A behavioural and functional neuroimaging investigation into the effects of nicotine
on sensorimotor gating in healthy subjects and persons with schizophrenia. Psychopharmacology
(Berl), 184: 589-599.
Quednow BB, Jessen F, Kuhn KU, Maier W, Daum I, Wagner M (2006a). Memory deficits in abstinent
MDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction. Journal of
Psychopharmacology, 20: 373-384.
Quednow BB, Kuhn KU, Beckmann K, Westheide J, Maier W, Wagner M (2006b). Attenuation of the
prepulse inhibition of the acoustic startle response within and between sessions. Biological Psychology,
71: 256-263.
Quednow BB, Wagner M, Westheide J, Beckmann K, Bliesener N, Maier W, Kuhn KU (2006c).
Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated
with amisulpride or olanzapine. Biological Psychiatry, 59: 536-545.
Rey A (1958). L'examen clinique en psychologie. Paris: Presse Universitaire de France.
Rodefer JS, Nguyen TN (2006). Naltrexone reverses age-induced cognitive deficits in rats. Neurobiology of
Aging.
Schmauss C, Emrich HM (1985). Dopamine and the action of opiates: a reevaluation of the dopamine
hypothesis of schizophrenia. With special consideration of the role of endogenous opioids in the
pathogenesis of schizophrenia. Biological Psychiatry, 20: 1211-1231.
Shallice T (1982). Specific impairments of planning. Philosophical Transactions of the Royal Society of London.
Series B, Biological Sciences, 298: 199-209.
Simmons ML, Chavkin C (1996). Endogenous opioid regulation of hippocampal function. International
Review of Neurobiology, 39: 145-196.
Sipes TE, Geyer MA (1997). DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the
ventral pallidum. Brain Research, 761: 97-104.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
24
Swerdlow NR, Braff DL, Geyer MA (1999). Cross-species studies of sensorimotor gating of the startle reflex.
Annals of the New York Academy of Sciences, 877: 202-216.
Swerdlow NR, Caine SB, Geyer MA (1991). Opiate-dopamine interactions in the neural substrates of acoustic
startle gating in the rat. Progress in Neuropsychopharmacology & Biological Psychiatry, 15: 415-426.
Swerdlow NR, Geyer MA (1998). Using an animal model of deficient sensorimotor gating to study the
pathophysiology and new treatments of schizophrenia. Schizophrenia Bulletin, 24: 285-301.
Swerdlow NR, Geyer MA, Braff DL (2001). Neural circuit regulation of prepulse inhibition of startle in the rat:
current knowledge and future challenges. Psychopharmacology (Berl), 156: 194-215.
Swerdlow NR, Hartman PL, Auerbach PP (1997). Changes in sensorimotor inhibition across the menstrual
cycle: implications for neuropsychiatric disorders. Biological Psychiatry, 41: 452-460.
Swerdlow NR, Talledo J, Sutherland AN, Nagy D, Shoemaker JM (2006). Antipsychotic effects on prepulse
inhibition in normal 'low gating' humans and rats. Neuropsychopharmacology, 31: 2011-2021.
Terenius L, Wahlstrom A, Lindstrom LH, Widerlor E (1976). Increased CSF levels of endorphins in chronic
psychosis. Neuroscience Letters, 3: 157-162.
Ukai M, Itoh J, Kobayashi T, Shinkai N, Kameyama T (1997). Effects of the kappa-opioid dynorphin A(1-
13) on learning and memory in mice. Behavioural Brain Research, 83: 169-172.
Ukai M, Okuda A (2003). Endomorphin-1, an endogenous mu-opioid receptor agonist, improves apomorphine-
induced impairment of prepulse inhibition in mice. Peptides, 24: 741-744.
Vollenweider FX, Barro M, Csomor PA, Feldon J (2006). Clozapine enhances prepulse inhibition in healthy
humans with low but not with high prepulse inhibition levels. Biological Psychiatry, 60: 597-603.
Vollenweider FX, Csomor PA, Knappe B, Geyer MA, Quednow BB (2007). The Effects of the Preferential 5-
HT2A Agonist Psilocybin on Prepulse Inhibition of Startle in Healthy Human Volunteers Depend on
Interstimulus Interval. Neuropsychopharmacology.
Vollenweider FX, Remensberger S, Hell D, Geyer MA (1999). Opposite effects of 3,4-
methylenedioxymethamphetamine (MDMA) on sensorimotor gating in rats versus healthy humans.
Psychopharmacology (Berl), 143: 365-372.
von Zerssen D (1971). Die Beschwerde-Liste als Test. Therapiewoche, 25: 1908-1920.
Wagner JJ, Terman GW, Chavkin C (1993). Endogenous dynorphins inhibit excitatory neurotransmission and
block LTP induction in the hippocampus. Nature, 363: 451-454.
Waldhoer M, Bartlett SE, Whistler JL (2004). Opioid receptors. Annual Review of Biochemistry, 73: 953-990.
Walker DJ, Zacny JP (1998). Subjective, psychomotor, and analgesic effects of oral codeine and morphine in
healthy volunteers. Psychopharmacology (Berl), 140: 191-201.
Weisskopf MG, Zalutsky RA, Nicoll RA (1993). The opioid peptide dynorphin mediates heterosynaptic
depression of hippocampal mossy fibre synapses and modulates long-term potentiation. Nature, 362:
423-427.
Wittchen H-U, Pfister H (1997). DIA-X-Interviews: Manual für Screening-Verfahren und Interview. Frankfurt:
Swets & Zeitlinger.
Xi ZX, Stein EA (2002). GABAergic mechanisms of opiate reinforcement. Alcohol and alcoholism, 37: 485-
494.
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
25
Figure Legends
Figure 1: Prepulse inhibition (PPI; interstimulus intervals (ISI): 30-240 ms) and Prepulse Facilitation
(PPF; ISI 2000 ms) of acoustic startle response under morphine and placebo (means and standard error
of means). PPI is improved after 10 mg morphine sulfate (LSD post-hoc tests: *p<.05).
Figure 2: Error rates across the nine stages of the Intra/Extradimensional Attentional Set Shifting
Task (ID/ED) of the Cambridge Neuropsychological Test Automated Battery (CANTAB) (means and
standard error of means). Morphine decrease the error rate in the first stage Simple discrimination and
in the sixth stage Intradimensional shift (LSD post-hoc tests: *p<.05; ***p<.001).
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
26
Table 1: Demographic and psychometric data of the 18 healthy human volunteers
Mean (± SD)
Age
23.9 (±2.9)
Weight (kg)
73.8 (±7.2)
Height (m)
1.80 (±0.1)
Body Mass Index (BMI)
22.8 (±1.4)
Verbal IQ
104.5 (±11.0)
SCL-90
Somatisation
0.26 (±0.28)
Obsessive compulsion
0.53 (±0.45)
Interpersonal sensitivity
0.33 (±0.48)
Depression
0.31 (±0.43)
Anxiety
0.18 (±0.26)
Hostility
0.33 (±0.49)
Phobic anxiety
0.06 (±0.14)
Paranoid ideation
0.36 (±0.46)
Psychoticism
0.17 (±0.37)
Positive symptom total
19.0 (±15.5)
Global severity index
0.29 (±0.32)
Positive symptom distress index
1.25 (±0.28)
FPI
Nervousness
3.35 (±2.60)
Aggression
3.61 (±2.55)
Depression
2.82 (±2.72)
Excitability
2.47 (±2.10)
Sociability
9.35 (±2.83)
Patience
5.06(±2.05)
Dominance
2.47 (±1.74)
Inhibition
3.18 (±2.21)
Frankness
4.88 (±1.36)
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
27
Table 2 Means and standard deviation of means (in parentheses) of the amplitude of 115 dB-pulse-alone (PA-115) trials in the first block (startle
reactivity), the amplitude of 86 dB-prepulse-alone (PPA-86) trials (reactivity to prepulse stimuli), the amplitude in no-stimulus (NS) trials,
the percent prepulse inhibition (PPI) summed across ISI conditions (PP30-PP240), the percent habituation between first and last block of
PA-115 trials, the slope of the habituation curve, and the latency of startle response peak in PA-115 trials under placebo and 10 mg
morphine sulfate in 16 healthy volunteers.
Startle measures
Placebo Morphine Effect size d F df,df
error
p
Mean amplitude of PA-115 trials (first block)
(Arbitrary units)
543.0
(±383.1)
549.8
(±376.2)
0.04
0.02
1,15 0.89
Mean amplitude of PPA-86 trials
(Arbitrary units)
25.7 (±55.0) 22.8 (±33.0) 0.08
0.11
1,15 0.75
Mean amplitude of NS trials
(Arbitrary units)
8.8 (±3.3) 10.6 (±6.8) 0.26
1.15
1,15 0.30
Mean Σ percent PPI
(PP30-PP240 conditions)
37.2 (±20.5) 46.3 (±20.1) 0.61
6.04
1,15
0.03
Mean percent habituation of PA-115 trials
(between first and last block)
50.3 (±26.7) 53.7 (±21.3) 0.12
0.24
1,15 0.63
Habituation of PA-115 trials across 4 blocks
(linear gradient coefficient b)
-87.6 (±73.6) -93.4 (±58.9) 0.08
0.11
1,15 0.74
Mean peak response latency
(milliseconds)
64.3 (±8.1) 67.2 (±15.1) 0.21
0.68
1,15 0.42
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
28
Table 3 Means and standard deviation of means (in parentheses) of the change scores (baseline scores minus scores 70 min after drug/placebo
intake) of the subscales of the Adjective Mood Rating Scale (AMRS) under placebo and 10 mg morphine sulfate in 18 healthy volunteers.
AMRS subscales
Placebo Morphine Effect size d F df,df
error
p
Performance-related activity
1.33 (±2.87) 2.11 (±3.56) 0.23
0.93
1,17 0.35
General inactivation
-1.39 (±3.36) -2.22 (±5.64) 0.13
0.31
1,17 0.59
Extroversion-introversion
-0.11 (±1.60) 1.00 (±2.81) 0.33
1.93
1,17 0.18
General well-being
0.17 (±1.72) 0.94 (±2.55) 0.23
0.95
1,17 0.34
Emotional excitability
-0.06 (±1.80) -0.11 (±1.23) 0.02
0.01
1,17 0.92
Anxiety-depresssion
0.33 (±1.19) -0.50 (±1.69) 0.35
2.25
1,17 0.15
Dreaminess
0.00 (±0.77) -0.67 (±1.75) 0.38
2.62
1,17 0.12
Boris B. Quednow et al. Sensorimotor gating is improved by morphine
29
Table 4 Means and standard deviation of means (in parentheses) of RAVLT variables and CANTAB task scores under placebo and 10 mg
morphine sulfate in 18 healthy volunteers.
Tests Placebo Morphine Effect size d F df,df
error
p
RAVLT
Supraspan (trial 1) 10.8 (±2.29) 11.1 (±2.00) 0.12 0.33 1,17 0.57
Learning performance (Σ trials 1-5) 67.3 (±6.59) 67.4 (±7.29) 0.04 0.03 1,17 0.87
Recall of interference list (list B) 11.4 (±2.57) 10.7 (±2.47) 0.32 1.91 1,17 0.19
Recall after interference list (trial 6) 13.9 (±1.86) 13.6 (±2.15) 0.20 0.90 1,17 0.36
Delayed recall (trial 7) 13.8 (±1.86) 13.1 (±3.19) 0.30 1.78 1,17 0.20
Loss after consolidation (trial 5 minus 7) 0.78 (±1.35) 1.33 (±2.11) 0.31 1.80 1,17 0.20
Adjusted recognition performance p(A) 0.93 (±0.07) 0.92 (±0.13) 0.10 0.05 1,17 0.83
CANTAB
Motor Screening (MOT)
Response latency (ms) 654 (±81.3) 671 (±125.5) 0.17 0.53 1,17 0.48
Rapid Visual Information Processing (RVP)
Total Hits 21.4 (±2.99) 21.2 (±4.37) 0.07 0.06 1,17 0.81
Discrimination performance (A’) 0.95 (±0.03) 0.95 (±0.04) 0.06 0.05 1,17 0.82
Response latency (ms) 434 (±68.6) 456 (±114.9) 0.29 1.57 1,17 0.23
ID/ED Attentional Set Shifting (ID/ED)
Total trials (adjusted) 72.4 (±11.1) 67.9 (±7.2) 0.35 2.16 1,17 0.16
Total errors (adjusted) 12.6 (±5.64) 9.6 (±4.29) 0.42 3.23 1,17 0.09
Pre-ED errors 7.2 (±1.76) 5.3 (±1.57) 0.88 13.81 1,17
0.002
ED errors 3.6 (±4.19) 2.1 (±1.28) 0.34 2.12 1,17 0.16
Stockings of Cambridge (SOC)
Problems solved in minimum moves 9.8 (±1.44) 9.7 (±1.28) 0.07 0.10 1,17 0.76
Moves to reach criterion 4.0 (±0.32) 4.0 (±0.31) 0.03 0.02 1,17 0.90
Initial thinking time (ms) 5065 (±2625) 5304 (±2415) 0.08 0.12 1,17 0.74
Subsequent thinking time (ms) 192 (±245.9) 212 (±196.9) 0.07 0.08 1,17 0.78
Spatial Recognition Memory
Response latency (ms) 1961 (±568.4) 2094 (±574.8) 0.22 0.85 1,17 0.37
Percent correct hits 83.6 (±10.5) 85.8 (±6.47) 0.21 0.81 1,17 0.38
Spatial Working Memory (SWM)
Strategy score 26.7 (±6.59) 25.8 (±5.22) 0.20 0.72 1,17 0.41
Total number of errors 6.2 (±6.01) 5.6 (±6.90) 0.07 0.09 1,17 0.77
Between errors 5.9 (±5.81) 5.4 (±6.97) 0.06 0.05 1,17 0.83
-20
-10
0
10
20
30
40
50
60
70
80
30ms 60ms 120ms 240ms 2000ms
% PPI
Placebo Morphine
*
*
Figure 1
Quednow et al.
Figure 2
0
1
2
3
4
5
Simp
l
e Discrimination
S
i
m
pl
e
R
ever
sal
Com/pound Discrimination
C
om
pou
nd
Di
scr
i
m
i
nat
i
on
Compound Reversal
I
nt
r
adim
ensi
onal
Shift
R
ever
sal
Ext
radi
m
ensi
onal
S
hif
t
Reversal
No of errors
Placebo
Morphine
***
*
Pre-ED errors
ED errors
Quednow et al.
... In an early study, Primac et al. (1957) did not find an effect of a low dose of the opioid agonist Meperidine administered to ten participants on the Wisconsin Card Sorting Test (WCST). More recently, Quednow and colleagues (Quednow, Csomor, Chmiel, Beck, & Vollenweider, 2008) using a low dose of 10 mg PO of morphine in 18 males did not observe effects on the Stockings of Cambridge tasks or extradimensional set switching. However, their low dose of morphine did reduce the error rate on intradimensional set shifts, suggesting that low doses of opioids might help to improve the application of a task rule within the same perceptual dimension. ...
... The ability to regulate sensory input by filtering out irrelevant stimuli (to prevent sensory overflow) can also be enhanced by opioid agonists, as suggested by a study where a low dose of morphine (10 mg PO) in 18 males enhanced modulation of the startle reflex to a noise burst following a prestimulus, a phenomenon called prepulse inhibition (Quednow et al., 2008). At first sight, these findings seem difficult to reconcile with the findings reported by Arnsten et al. (1983Arnsten et al. ( , 1984. ...
... one possibility is that the task by Quednow et al. (2008) involved increased levels of distress because of the loud auditory noise involved in the task. Opioids might help to downregulate stress responses under such conditions, perhaps improving sensorimotor gating relative to placebo. ...
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... An old study by Primac and colleagues (1957) did not find an effect of a low dose of the opioid agonist Meperidine administered to 4 female and 6 male participants on the Wisconsin Card Sorting Test. Likewise, Quednow and colleagues (Quednow, Csomor, Chmiel, Beck, & Vollenweider, 2008) using a low dose of 10 mg PO morphine in 18 males did not observe effects on the Stockings of Cambridge tasks, nor on extradimensional set switching. However, their low dose of morphine did reduce the error rate on intradimensional set shifts, suggesting that low doses of opioids might help to improve the application of a task rule within the same perceptual dimension. ...
... The modulation of the startle reflex to a noise burst following a prestimulus, a phenomenon called prepulse inhibition, has been shown to be enhanced by a low dose of 10 mg PO morphine in 18 males (Quednow et al., 2008). This suggests that the ability to regulate sensory input by filtering out irrelevant stimuli (in order to prevent sensory overflow) can also be enhanced by opioid agonists. ...
... At first sight, these findings seem difficult to reconcile with the findings reported by Arnsten and colleagues (Arnsten et al., 1983(Arnsten et al., , 1984. As we will discuss more detail later, one possibility is that the task by Quednow et al. (2008) involved increased levels of distress because of the loud auditory noise involved in the task. Opioids might help to downregulate stress responses under such conditions, perhaps improving sensorimotor gating. ...
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The opioid system plays a key role in the regulation of affective processing including pain, pleasure, and reward. However, there is also increasing evidence that this system plays a broader role and can modulate cognitive function. In particular, increasing evidence suggests that the mu-opioid system influences how we choose between actions of different values and how we control our behavior in the face of distracting information. The present paper reviews the available evidence from studies that have used pharmacological manipulations of the mu-opioid system in healthy human volunteers. Our review covers experimental paradigms that have investigated reward-based decision making, impulsivity, neuropsychological tests of executive functioning, attention, inhibition and effort. The reviewed findings provide an emerging picture of how the mu-opioid system influences higher-level cognitive function via modulation of valuation, motivation and control circuits dense in mu-opioid receptors, including orbitofrontal cortex, basal ganglia, amygdalae, anterior cingulate cortex, and prefrontal cortex. The working model we put forward proposes that opioids influence decision making and cognitive control by increasing the subjective value of reward and reducing aversive arousal. The review highlights potential mechanisms that might underlie the effects of mu-opioids on decision making and cognitive control and provides important directions for future research.
... Juvenile Oprm1 -/mice find social interactions less salient (Cinque et al., 2012) Cognitive Systems: Attention Attentional set shifting was enhanced by morphine administration in healthy controls (Quednow, Csomor, Chmiel, Beck, & Vollenweider, 2008) Systems for social processes ...
... (Chelnokova et al., 2016) Perception and Understanding of Self Decreased MOR BP in corticoamygdalar structures and posterior thalamus during a sustained sadness challenge (Kennedy et al., 2006) Greater magnitude of change in subjective self-esteem in depressed subjects in a social rejection challenge, was associated with reduced corticoamygdalar MOR BP (Hsu et al., 2015) Arousal/Regulatory systems Arousal Sensorimotor gating was enhanced by morphine administration in healthy controls. (Quednow et al., 2008) Sleep and Wakefulness ...
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Since the serendipitous discovery of the first class of modern antidepressants in the 1950's, all pharmacotherapies approved by the Food and Drug Administration for major depressive disorder (MDD)have shared a common mechanism of action, increased monoaminergic neurotransmission. Despite the widespread availability of antidepressants, as many as 50% of depressed patients are resistant to these conventional therapies. The significant length of time required to produce meaningful symptom relief with these medications, 4–6 weeks, indicates that other mechanisms are likely involved in the pathophysiology of depression which may yield more viable targets for drug development. For decades, no viable candidate target with a different mechanism of action to that of conventional therapies proved successful in clinical studies. Now several exciting avenues for drug development are under intense investigation. One of these emerging targets is modulation of endogenous opioid tone. This review will evaluate preclinical and clinical evidence pertaining to opioid dysregulation in depression, focusing on the role of the endogenous ligands endorphin, enkephalin, dynorphin, and nociceptin/orphanin FQ (N/OFQ)and their respective receptors, mu (MOR), delta (DOR), kappa (KOR), and the N/OFQ receptor (NOP)in mediating behaviors relevant to depression and anxiety. Finally, putative opioid based antidepressants that are under investigation in clinical trials, ALKS5461, JNJ-67953964 (formerly LY2456302 and CERC-501)and BTRX-246040 (formerly LY-2940094)will be discussed. This review will illustrate the potential therapeutic value of targeting opioid dysregulation in developing novel therapies for MDD.
... Attentional set-shifting measures the ability of subjects to shift between rules. In an attentional set-shifting test conducted in humans, an acute dose of morphine (10 mg) in healthy male participants given 75 min prior to testing reduced the rates of intradimensional and extradimensional errors, but had no effect on reversal learning (Quednow et al., 2008). In rodents, aged male rats performed worse than young rats during the extradimensional shift, but not during the intradimensional shift or during reversal. ...
... However, lower doses of morphine effectively disrupted PPI in SD rats during withdrawal following chronic administration (Lee et al., 2017;Meng et al., 2010), but not when the MOR agonist was present, suggesting a marker of opioid withdrawal. On the other hand, in humans, an acute dose of morphine (10 mg) in healthy male participants given 75 min prior to testing enhanced sensorimotor gating by increasing PPI, but had no effect on ASR and habituation (Quednow et al., 2008). Inconsistencies regarding the effect of KOR agonists on PPI are reflected in the literature. ...
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The failure of traditional antidepressant medications to adequately target cognitive impairment is associated with poor treatment response, increased risk of relapse, and greater lifetime disability. Opioid receptor antagonists are currently under development as novel therapeutics for major depressive disorder (MDD) and other stress-related illnesses. Although it is known that dysregulation of the endogenous opioid system is observed in patients diagnosed with MDD, the impact of opioidergic neurotransmission on cognitive impairment has not been systematically evaluated. Here we review the literature indicating that opioid manipulations can alter cognitive functions in humans. Furthermore, we detail the preclinical studies that demonstrate the ability of mu-opioid receptor and kappa-opioid receptor ligands to modulate several cognitive processes. Specifically, this review focuses on domains within higher order cognitive processing, including attention and executive functioning, which can differentiate cognitive processes influenced by motivational state.
... Finally, sensory-motor gating is also altered in MAP6 KO mice (Fradley et al., 2005;Volle et al., 2013). This effect might be linked to perturbed dopamine-, glutamate-, and serotoninmediated neurotransmission, but could also be related to activation of opioid mu receptors (Quednow et al., 2008) which is altered in MAP6 KO mice (Charlet et al., 2010). ...
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The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs—including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);—were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6’s effect on microtubules, we describe its impact on the actin cytoskeleton, on neuroreceptor homeostasis, and its involvement in signaling pathways governing neuron development and maturation. We also discuss its roles in synaptic plasticity, brain connectivity, and cognitive abilities, as well as the potential relationships between the integrated brain functions of MAP6 and its molecular activities. In parallel, the Collapsin Response Mediator Proteins (CRMPs) are presented as examples of how other proteins, not initially identified as MAPs, fall into the broader MAP family. These proteins bind MTs as well as exhibiting molecular and cellular properties very similar to MAP6. Finally, we briefly summarize the multiple similarities between other classical structural MAPs and MAP6 or CRMPs.In summary, this review revisits the molecular properties and the cellular and neuronal roles of the classical MAPs, broadening our definition of what constitutes a MAP.
... The opioid receptor system (μ) is involved in impaired sensorimotor gating, attentional set-shifting, and other critical cognitive processes in schizophrenia [23]. Dopamine metabolism, reuptake, and release are known to be altered by opioid agonists. ...
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... Research in the past decade has highlighted the strong influence of endocannabinoids on the endogenous opioid system (e.g., Scavone, Sterling, & Van Boeckstaele, 2013). Increased activity of the opioid system has been shown to improve affect (e.g., Boecker et al., 2008) and some aspects of cognitive performance in non-exercising participants (e.g., Quednow, Csomor, Chmiel, Beck, & Vollenweider, 2008). However, because no blood-based biomarker was measured in the present study, further research is needed to substantiate this view in the exercise domain. ...
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A significant number of patients (30%) do not adequately respond to commonly prescribed antidepressants (e.g. SSRIs, SNRIs, and TCAs). Opioid receptors and their endogenous peptides have demonstrated a clear role in the regulation of mood in animal models and may offer an alternative approach to augment existing therapies. Nevertheless, there is an urgent need to find better ways to predict a patient's response to drug treatment, to improve overall drug responding, and to reduce the time to symptom remission using novel diagnostic and efficacy biomarkers. Cognitive processes, such as perception, attention, memory, and learning, are impaired in patients with mood disorders. These processes can be altered by emotions, a phenomenon called cognitive affective bias. Negative affective biases are a key feature of major depressive disorder (MDD) and may present concurrently with other cognitive deficits. Importantly, a significant percentage of patients report residual cognitive impairments even after effective drug treatment. This approach offers a new opportunity to predict patient treatment responses, potentially improving residual cognitive symptoms and patient outcomes. This review will (1) describe the underlying neurocircuitry of affective cognition and propose how negative biases may occur, (2) outline the role of opioid receptors in affective cognition, executive function, and MDD, and (3) present evidence from the published literature supporting a modulatory role for opioid drugs on negative affective bias, with a focus on kappa-opioid receptor antagonists, currently in development for clinical use for treatment-resistant MDD.
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The article which follows this introduction was originally published as a Special (Cover) Article in the American Journal of Psychiatry in the November, 1985 issue, the same month in which the First International Drug Symposium, sponsored by The Bahamas Ministry of Health and The Embassy of the United States of America, was convened to discuss the rock-cocaine epidemic in the Bahamas and other Caribbean Islands. Based on my article, I was invited to participate in the Symposium and to speak about some of my views on the psychological predispositions for drug dependence in general, and in particular, on the psychological predisposition for cocaine dependence. At first, I did not grasp the seriousness and scope of the cocaine problem, but I accepted the invitation, believing I might make a contribution to the Symposium. I was not long in attendance at the Symposium before I realized that the Bahamian citizens, professionals, and health care leaders were facing a major crisis as a consequence of the cocaine epidemic.
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Eighteen patients with early Huntington's disease were compared with age-and IQ-matched control volunteers on tests of executive and mnemonic function taken from the Cambridge Neuropsychological Test Automated Battery. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, spatial planning and visual discrimination learning/attentional set shifting were employed. These tests have previously been found to be sensitive to the later stages of Huntington 's disease. Patients with early Huntington's disease were found to have a wide range of cognitive impairments encompassing both visuo-spatial memory and executive functions, a pattern distinct from those seen in other basal ganglia disorders. In contrast to patients with more advanced Huntington's disease, early Huntington's disease patients were not impaired at simple reversal learning, but were impaired at performing an extradimensional shift (EDS). The results will be discussed in relation to the hypothesized neuropathological staging of Huntington's disease and to the anatomical connectivity of the striatum.
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The "Verbaler Lern- and Merkfaehigkeitstest" (VLMT) (Helmstaedter & Durwen, 1990) is a German version of the "Auditory Verbal Learning Test" (AVLT) (Lezak, 1983). This test requires wordlist learning and allows the assessment of different memory parameters in one testing session. Complementary to recently published data from children (Schweisthal, 1997), the present study provides normative standards based on a sample of 221 healthy subjects aged between 15 and 45 years. The different test parameters were evaluated with regard to sex, age, and intelligence as estimated by vocabulary testing. Significant differences were only found between younger (15-30 years of age) and older (31-45 years of age) subjects in supraspan, learning performance and recognition performance. For these parameters normative standards were calculated depending on age. Taking into account the relevance that wordlist paradigms have gained in memory diagnosis and research, these norms provide a more secure and objective diagnosis of memory deficits in people aged between 15 and 45 years.
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Schizophrenic patients exhibit impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have well-described neurobiologic bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize patients with schizophrenic spectrum disorders. In this context, the startle response is particularly interesting, because it is a cross-species response to strong stimuli that is plastic or alterable using experimental and neurobiologic manipulations. Thirty-nine medicated schizophrenic patients and 37 normal control subjects were studied in a new electromyography based startle response paradigm in which both prepulse inhibition (an operational measure of sensorimotor gating) and habituation (the normal decrease in response magnitude to repeated stimuli over time) can be separated and assessed in one test session. The results indicate that schizophrenic patients have extensive deficits in both intramodal and cross-modal sensorimotor gating and a trend to show acoustic startle habituation deficits. The deficit in prepulse inhibition of startle amplitude exhibited by schizophrenic patients was evident when an acoustic prepulse stimulus preceded either an acoustic or a tactile startle stimulus. No deficit was observed in the prepulse-induced facilitation of startle latencies, indicating that the failure of gating was not due to a failure of stimulus detection. These findings suggest centrally mediated deficits in sensorimotor gating in schizophrenic patients.
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The mossy fibre pathway in the hippocampus uses glutamate as a neurotransmitter, but also contains the opioid peptide dynorphin. Synaptic release of dynorphin causes a presynaptic inhibition of neighbouring mossy fibres and inhibits the induction and expression of mossy fibre long-term potentiation. These findings demonstrate a physiological role for a neuropeptide in the central nervous system, provide a functional basis for the coexistence of a neuropeptide with classic neurotransmitters and demonstrate the very different roles played by these two classes of signalling molecules.
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G*Power (Erdfelder, Faul, & Buchner, 1996) was designed as a general stand-alone power analysis program for statistical tests commonly used in social and behavioral research. G*Power 3 is a major extension of, and improvement over, the previous versions. It runs on widely used computer platforms (i.e., Windows XP, Windows Vista, and Mac OS X 10.4) and covers many different statistical tests of the t, F, and chi2 test families. In addition, it includes power analyses for z tests and some exact tests. G*Power 3 provides improved effect size calculators and graphic options, supports both distribution-based and design-based input modes, and offers all types of power analyses in which users might be interested. Like its predecessors, G*Power 3 is free.