Article

Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers

Psychopharmacology Section, University of Nottingham, Division of Psychiatry, Nottingham, UK.
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 12/2007; 64(5):591-602. DOI: 10.1111/j.1365-2125.2007.02938.x
Source: PubMed

ABSTRACT

To investigate the effects of the D2-receptor agonist pramipexole with and without the co-administration of the peripherally acting D2-receptor antagonist domperidone on measures of alertness, autonomic and endocrine function.
Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg, domperidone 40 mg, their combination, and placebo administered according to a balanced, double-blind design. Alertness (visual analogue scales (VAS), critical flicker fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine (prolactin, thyroid-stimulating hormone (TSH), growth hormone (GH)) functions were assessed. Data were analyzed with anova with multiple comparisons.
The pre-post treatment changes in VAS alertness were reduced by pramipexole with and without domperidone (mean difference from placebo (95% confidence interval), mm): pramipexole -15.75 (-23.38, -8.13), combination -11.84 (-20.77, -2.91). Treatment condition significantly affected pupil diameter measured in different ways (resting pupil diameter (F(3,45) = 8.39, P < 0.001), initial diameter of the light reflex response (F(3,42) = 3.78, P < 0.05), and light (F(3,45) = 5.21, P < 0.005) and dark (F(3,45) = 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole without domperidone consistently increased pupil diameter on all measures (P < 0.05), whereas with domperidone only the increase in resting and dark diameters reached significance. Pramipexole reduced light reflex amplitude and increased latency, whereas the combination affected latency only. Concentrations of prolactin and TSH were increased by domperidone. Pramipexole reduced prolactin and increased GH concentrations.
The attenuation of the central pupillary effects of pramipexole by domperidone indicates that domperidone had access to some central D2-receptors.

Full-text

Available from: Ruihua Hou
Comparison of pramipexole with and without
domperidone co-administration on alertness,
autonomic, and endocrine functions in
healthy volunteers
Ebony R. Samuels, Ruihua H. Hou, Robert W. Langley, Elemer Szabadi & Christopher M. Bradshaw
Psychopharmacology Section, University of Nottingham, Division of Psychiatry, Nottingham, UK
What is already known about this subject
It is known that the dopamine receptor agonist
pramipexole, used for the treatment of Parkinson’s
disease, often causes nausea that can be treated in
patients by the co-administration of an antiemetic, for
example domperidone.
In experimental studies of pramipexole it may be
necessary to administer domperidone alongside
pramipexole to alleviate nausea, and as such it is
necessary to know how the co-administration of
domperidone may alter the observed effects of
pramipexole.
What this study adds
Results from our study indicate that the co-administration of
pramipexole and domperidone may reduce the likelihood of
observing an effect that is present when pramipexole is
administered alone.
Although domperidone is mainly a peripherally acting drug, it
appears that a high enough concentration of the drug crosses
the blood–brain barrier to partially antagonize some of the
autonomic actions of pramipexole.
Therefore, this repor t provides a cautionary note to the use of
domperidone alongside pramipexole where the results of
interest are those from pramipexole alone.
Correspondence
Professor E. Szabadi,
Psychopharmacology Section,
Division of Psychiatry, University of
Nottingham, Medical School (Room
B109), Queen’s Medical Centre,
Nottingham, NG7 2UH, UK.
Tel.: + 44(0)115 8230219
Fax: + 44(0)115 8230220
E-mail:
elemer.szabadi@nottingham.ac.uk
.............................................................................................................................
Keywords
alertness, darkness reflex,
domperidone, light reflex,
pramipexole, pupil
.............................................................................................................................
Received
19 October 2006
Accepted
12 March 2007
Published OnlineEarly
19 June 2007
Aims
To investigate the effects of the D
2
-receptor agonist pramipexole with and without the
co-administration of the peripherally acting D
2
-receptor antagonist domperidone on
measures of alertness, autonomic and endocrine function.
Methods
Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg,
domperidone 40 mg, their combination, and placebo administered according to a
balanced, double-blind design. Alertness (visual analogue scales (VAS), critical flicker
fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and
darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine
(prolactin, thyroid-stimulating hormone (TSH), grow th hormone (GH)) functions were
assessed. Data were analyzed with anova with multiple comparisons.
Results
The pre-post treatment changes in VAS alertness were reduced by pramipexole with
and without domperidone (mean difference from placebo (95% confidence interval),
mm): pramipexole -15.75 (-23.38, -8.13), combination -11.84 (-20.77, -2.91).
Treatment condition significantly affected pupil diameter measured in different ways
(resting pupil diameter (F
3,45
= 8.39, P < 0.001), initial diameter of the light reflex
response (F
3,42
= 3.78, P < 0.05), and light (F
3,45
= 5.21, P < 0.005) and dark
( F
3,45
= 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole
without domperidone consistently increased pupil diameter on all measures
( P < 0.05), whereas with domperidone only the increase in resting and dark diameters
reached significance. Pramipexole reduced light reflex amplitude and increased
latency, whereas the combination affected latency only. Concentrations of prolactin
and TSH were increased by domperidone. Pramipexole reduced prolactin and
increased GH concentrations.
Conclusions
The attenuation of the central pupillary effects of pramipexole by domperidone
indicates that domperidone had access to some central D
2
-receptors.
DOI:10.1111/j.1365-2125.2007.02938.x British Journal of Clinical Pharmacology
© 2007 The Authors
Journal compilation © 2007 Blackwell Publishing Ltd
Br J Clin Pharmacol 64:5 591–602 591
Page 1
Introduction
Pramipexole, a nonergot dopamine D
2
/D
3
receptor
agonist, is prescribed for the treatment of the motor
deficits associated with Parkinson’s disease (PD), which
include muscular rigidity, bradykinesia, tremor, postural
instability, and hypokinesia [1–4]. However, the toler-
ability of pramipexole is reduced by a side-effect profile
that includes sedation [5–10], dizziness [8–12], and
nausea [8–11,13, 14]. Nausea is a common side-effect of
dopamine receptor agonists in general (for example,
apomorphine [15], piribedil and bromocriptine [16], and
ropinirole [17]), and the co-administration of an anti-
emetic is often necessary to alleviate this symptom.
Domperidone is a frequently utilized antiemetic that
acts as an antagonist at D
2
-dopamine receptors [18–20]
and has been widely co-administered with a variety of
dopamine receptor agonists (for example, apomorphine
[21], bromocriptine [22], lisuride [23], pergolide [24],
piribedil [25], and pramipexole [26]). The antiemetic
action of domperidone results from the blockade of
dopamine receptors in the chemoreceptor trigger zone,
which is believed to lie outside the blood–brain barrier
[18–20]. It is believed that domperidone acts almost
exclusively in the periphery due to its inability to cross
the blood–brain barrier [18–20].
In two previous experiments using single oral doses of
pramipexole 0.5 mg in healthy volunteers we observed
changes in central nervous system activity that included
reduced alertness, increased pupil diameter, and reduced
amplitude of the light reflex response following prami-
pexole administration [9, 10]. In both of these experi-
ments nausea was reported as a side-effect. In the future,
it may be necessary to make use of an antiemetic such as
domperidone to alleviate this nausea in experimental
research, as already practised in drug treatment regimes
for patients with PD. Before routinely coadminister-
ing domperidone with pramipexole, however, it is
important to verify the exclusively peripheral action of
domperidone.
Therefore, the aim of this paper was to compare
the effects of pramipexole administered with and with-
out domperidone and domperidone administered alone
on measures of alertness, autonomic (pupillary activity,
cardiovascular functions, core temperature, and sa-
livary output), and endocrine (blood concentrations of
prolactin, thyroid stimulating hormone, and growth
hormone) functions. The peripheral activity of domperi-
done suggests that on measures of central nervous system
activity (alertness and some autonomic functions) the
effect of pramipexole administration will be the same
regardless of the presence or absence of domperi-
done co-administration. In contrast, domperidone may
be expected to alter the effects of pramipexole on mea-
sures that reflect an interaction with D
2
-dopamine recep-
tors outside the blood–brain barrier (hormone
concentrations).
Methods
Subjects
Sixteen healthy male volunteers aged 18–27 years
(mean SEM 20.75 0.6 years), 167–189 cm (mean
SEM 180.3 1.9 cm) in height and weighing 52.4–
86.8 kg (mean SEM 70.0 2.3 kg) participated in
the study. Subjects were all medication free for at least
3 months prior to the start of the study and completed
a brief medical history and physical examination be-
fore inclusion in the study. Of the 16 volunteers, 14
were nonsmokers and two were occasional smokers
(less than five cigarettes a day). All volunteers were
requested to avoid drinking alcohol, coffee and other
caffeine-containing beverages for at least 24 h be-
fore each experimental session and to avoid taking any
medication for the duration of the study. Women were
excluded from the study due to the slower renal
clearance of pramipexole in this population [27]. The
study protocol was approved by the University of Not-
tingham Medical School Ethics Committee, and all
volunteers gave their written consent after reading a
detailed information sheet.
Drugs
Matching capsules of pramipexole 0.5 mg, domperidone
20 mg, pramipexole 0.5 mg and domperidone 20 mg,
and placebo were prepared for double-blind, oral admin-
istration. The time required to attain peak plasma con-
centration (t
max
) following pramipexole administration is
approximately 2 h [27], whilst the t
max
following domp-
eridone administration is approximately 1 h [28]. There-
fore, a double-dummy procedure was used to ensure the
assessment of drug effects at peak plasma concentra-
tions: pramipexole was administered 2 h and domperi-
done 1 h prior to testing for drug effects. An additional
dosage of domperidone was administered 2 h prior to
testing in order to provide protection against nausea
while the blood concentration of pramipexole was still
rising. Thus the total dosage of domperidone adminis-
tered was 40 mg split into two. Volunteers were required
to ingest two capsules; the contents of the two capsules
in the four experimental sessions are summarized in
Table 1. The doses were chosen on the basis of the
current literature available (pramipexole: Wright et al.
[27], domperidone: Huang et al. [28]). Furthermore,
single doses of pramipexole 0.5 mg have been used in
two recent studies in our laboratory [9, 10].
E. Samuels et al.
592 64:5 Br J Clin Pharmacol
Page 2
Design
Subjects participated in four sessions at weekly inter-
vals, returning to the laboratory at the same time each
week. Subjects were allocated to drug conditions
according to a double-blind, balanced, cross-over
design. The time course of the sessions was designed
with regard to the pharmacokinetic profile of the two
active drugs (see above).
Tests and apparatus
All tests used were conducted as in Samuels et al.
[9, 10].
Measures of alertness A computerized battery of 16
visual analogue scales (VAS, mm [29]), the critical
flicker fusion frequency test (CFFF, Hz [30]), and the
pupillographic sleepiness test (PST, total power of pupil
diameter fluctuations, pupillary unrest index mm min
-1
[31]) were used for the assessment of alertness level.
Pupillary functions A binocular infra-red video pupil-
lometer (Procyon Ltd, London, UK) was used to obtain
resting pupil diameter measurements (static pupillom-
etry) in darkness and at three luminance levels (6, 91 and
360 cd m
-2
). A binocular infra-red television pupillom-
eter (TVC 1015b Applied Science Laboratories,
Waltham, Mass., USA) was used to record pupillary
reflexes (dynamic pupillometry): light reflex responses
were evoked by four light flashes of incremental lumi-
nance levels (5.2, 41, 320 and 2050 cd m
-2
) and darkness
reflex responses by switching off an illuminated screen
of 1370 cd m
-2
luminance.
Non-pupillary autonomic functions Blood pressure and
heart rate, measured in both standing and supine
positions, temperature, and salivation were recorded
conventionally.
Endocrine functions A 10 ml blood sample was taken
and analyzed for concentrations of the hormones prolac-
tin and TSH by enzyme immunoassay and for GH by che-
miluminescence immunoassay in the Clinical Chemistry
Laboratory of Queen’s Medical Centre, Nottingham.
Procedure
The pre- and post-treatment testing sessions consisted of
standing and supine heart rate and blood pressure, tem-
perature, salivation, CFFF, VAS, resting pupil diameter,
light and darkness reflex responses, and PST measure-
ment. After a 15 min acclimatization period of resting in
the laboratory, subjects completed the pretreatment tests
over a 45 min period. Two hours after ingestion of the
first capsule the post-treatment tests were conducted
over 45 min. A blood sample was collected following the
post-treatment testing session.
Data analysis and statistics
Self-rated values of ‘alertness’, ‘calmness’ and ‘content-
edness’ were derived from the VAS scores after weight-
ing on these factors [29]. Pre-treatment/post-treatment
differences for these ratings and for the CFFF and PST
(power of pupillary fluctuations, pupillary unrest index
[PUI]) values were calculated for further analysis. An
increase in self-rated values of ‘alertness’ on the VAS
and an increase in CFFF indicate an increase in alert-
ness, whilst increases in PST values indicate a reduction
in alertness (see Samuels et al. [9, 10]).
Pre-treatment/post-treatment differences were ana-
lyzed for all the autonomic measures (pupillary and non-
pupillary) with the exception of the light dependent
measures of resting pupil diameter and light reflex
response. Pre-treatment/post-treatment differences were
not calculated for these pupillary functions since mea-
surements were taken at different luminance levels, and
calculating the difference would have eliminated the
effect of luminance on the measures studied. All pupil
data were averaged across the left and right eyes. For the
light reflex response the parameters studied were: initial
diameter (diameter of the pupil before the light stimulus
was presented, mm), latency (time from the onset of the
light stimulus to the onset of the pupil response, s), and
amplitude (change in pupil diameter from maximum to
minimum diameter in response to presentation of the
light stimulus, mm). For the darkness reflex, the param-
eters studied were: ‘light diameter (diameter of the
pupil whilst the screen was illuminated, mm), ‘dark
diameter (maximum diameter of the pupil when all
illumination is removed, mm), latency (time from the
offset of the light to the onset of the pupil response, s),
amplitude (change in pupil diameter from minimum to
Table 1
Summary of treatments administered in experimental
sessions
Capsule I Capsule II
(i) Placebo Placebo
(ii) Pramipexole 0.5 mg Placebo
(iii) Pramipexole 0.5 mg and
domperidone 20 mg
Domperidone 20 mg
(iv) Domperidone 20 mg Domperidone 20 mg
Comparison of pramipexole and domperidone
Br J Clin Pharmacol 64:5 593
Page 3
maximum diameter as a response to the removal of the
background luminance, mm), and initial velocity (calcu-
lated on the basis of the time required to obtain 25% of
the maximum response following the onset of the
response, mm s
-1
)
Prolactin, TSH, and GH effects were analyzed using
post-treatment plasma concentration values.
All data were analyzed using repeated measures
anova. The data were initially checked for skew, and
subjected to a transformation where indicated. Pre-
treatment values were analyzed using one- or two-way
anova (treatment, or luminance ¥ treatment) to find
any session effects within the results. No significant
pretreatment session effects were found, and so
pretreatment/post-treatment differences were taken as
the dependent variable where appropriate (see above).
One-way anova with drug condition (four levels) as
the within-subjects factor was used to compare the
effects of drug condition on all measures except pupil
diameter and light reflex responses, where two-way
anova with drug condition (four levels) and luminance
(four levels) as the within-subjects factors was used.
Where there was a significant interaction, one-way
anova were conducted for each luminance level sepa-
rately. Where the interaction term was not significant,
one-way anova were conducted on values averaged
across luminance level. All significant main effects
were further analyzed using Dunnett’s corrected t-test
(d.f. = 45, k = 4): active treatment conditions were
compared with placebo (criterion of significance
P < 0.05). In addition, where the overall anova was
significant, Fisher’s least significant difference (LSD)
test was used to compare the combination administra-
tion of pramipexole and domperidone to the individual
administration of the drugs ( d.f. = 45; criterion of
significance P < 0.05).
Results
Alertness
The VAS, CFFF, and PST data are shown in Table 2. A
significant effect of treatment condition was observed on
the VAS measure of alertness (F
3,45
= 7.35, P < 0.001),
where pramipexole and the combination of pramipexole
and domperidone reduced alertness compared with
placebo. The mean (95% confidence interval (CI)) dif-
ferences from the placebo condition were: pramipexole
-15.75 (-23.38, -8.13) mm, combination -11.84
(-20.77, -2.91) mm. A significant effect of treatment
condition on contentedness was also found (F
3,45
= 6.24,
P = 0.001), where pramipexole and the combination of
pramipexole and domperidone reduced contentedness
compared with placebo. Fisher’s LSD showed that the
combination of pramipexole and domperidone was not
significantly different from pramipexole administered
alone on either alertness or contentedness. There was no
effect of treatment condition on calmness (square root
transformation; F
3,45
= 2.17, NS). Pramipexole and the
combination of pramipexole and domperidone also
appeared to reduce measures of CFFF and increase PUI
and power measures of the PST, indicating reduced
alertness level (see Table 2), but these effects failed
to reach significance (CFFF: F
3,45
= 1.18, NS; PUI:
F
3,45
= 2.45, P = 0.08; power: F
3,45
= 1.83, NS).
Pupillary functions
Resting pupil diameter at different luminance levels is
shown in Figure 1. Pre-treatment data show a significant
Table 2
Pretreatment/post-treatment differences in alertness (mean (95% confidence intervals))
Placebo Pramipexole Domperidone Combination
VAS
Alertness (mm) -1.84 (-5.86, 2.19) -17.59 (-24.45, -10.73)* -1.73 (-10.26, 6.80) -13.67 (-22.08, -5.27)*
Calmness (mm) -1.97 (-10.66, 6.71) -0.16 (-5.71, 5.40) -2.90 (-10.87, 5.08) -2.94 (-9.97, 4.09)
Contentedness (mm) 0.07 (-2.74, 2.87) -8.04 (-12.96, -3.12)* -1.70 (-7. 41 , 4.01) -7.71 (-13.40, -2.01)*
CFFF (Hz) -0.39 (-1.11, 0.33) -0.84 (-1.61, -0.08) -0.25 (-1.13, 0.62) -1.08 (-2.02, -0.15)
PST
PUI (mm min
-2
)1.61(-0.47, 3.69) 3.05 (0.49, 5.62) 1.17 (-0.21, 2.54) 4.25 (1.08, 7.41)
Power (arbitrary units) 663 (173, 1154) 947 (256, 1637) 499 (92, 905) 1284 (383, 2186)
Pupil diameter (mm) -0.20 (-0.48, 0.08) -0.25 (-0.72, 0.22) -0.33 (-0.61, -0.06) -0.50 (-0.91, -0.08)
*significant effect compared with placebo (P < 0.05).
E. Samuels et al.
594 64:5 Br J Clin Pharmacol
Page 4
effect of luminance (F
3,45
= 446.0, P < 0.001), but no
effect of session (F
3,45
= 0.19, NS) and no significant
interaction (F
9,135
= 1.24, NS). Post-treatment data (log
10
transformation) show a significant effect of treatment
condition (F
3,45
= 8.39, P < 0.001) and luminance level
(F
3,45
= 325.23, P < 0.001), and a significant interaction
(F
9,135
= 2.34, P < 0.05). One-way anova conducted at
each luminance level show significant effects of treat-
ment condition at 6 cd m
-2
(F
3,45
= 7.79, P < 0.001),
91 cd m
-2
(F
3,45
= 5.90, P < 0.005), and 360 cd m
-2
(F
3,45
= 7.10, P = 0.001), but no significant effect in the
dark (F
3,45
= 2.19, NS). Multiple comparisons indicate
that the significant effect of treatment condition is due to
an increase in pupil diameter following pramipexole
administration at 6 cd m
-2
, and both pramipexole and the
combination of pramipexole and domperidone adminis-
tration at 91 cd m
-2
, and 360 cd m
-2
. The mean (95% CI)
differences from the placebo condition were: 6 cd m
-2
pramipexole -0.62 (0.12, -1.35) mm; 91 cd m
-2
prami-
pexole -0.56 (0.15, -1.27) mm, combination -0.43
(0.22, -1.07) mm; 360 cd m
-2
pramipexole -0.32 (0.16,
-0.80) mm, combination -0.23 (0.26, -0.72) mm. In
addition, at 6 cd m
-2
, Fisher’s LSD found that the com-
bination condition significantly increased pupil diameter
in comparison with domperidone administered alone,
but that this pupil dilatation was significantly less than
the increase in pupil diameter following pramipexole
administered alone. At 91 cd m
-2
and 360 cd m
-2
, the
combination condition was not significantly different
from the pramipexole condition.
Light reflex measures are shown in Figure 2. The data
from one volunteer were excluded due to corruption of
the data due to technical difficulties. For pretreatment
measures of initial diameter, averaged across the eight
measurements (i.e. two measurements at each luminance
level), there was no effect of session (F
3,42
= 0.19, NS).
Post-treatment data show a significant effect of treat-
ment condition (F
3,42
= 3.78, P < 0.05), where pramipex-
ole increased pupil diameter compared with placebo.
The combination condition also increased pupil diam-
eter, but this effect failed to reach statistical significance.
For pretreatment measures of amplitude, there was
a significant effect of luminance (F
3,42
= 234.63,
P < 0.001) but not of session (F
3,42
= 2.05, NS) and there
was no interaction (F
9,126
= 1.00, NS). Post-treatment
data (square root transformation) show a significant
effect of treatment condition (F
3,42
= 7.85, P < 0.001)
and luminance level (F
3,42
= 62.82, P < 0.001), but no
interaction (F
9,126
= 0.80, NS). Analysis of light reflex
amplitude averaged across luminance levels revealed a
significant effect of treatment condition (F
3,42
= 7.85,
P < 0.001), where pramipexole reduced light reflex
amplitude. Fisher’s LSD showed that the combination
condition significantly reduced light reflex amplitude
compared to domperidone alone, but was significantly
less effective at reducing light reflex amplitude com-
pared with pramipexole alone. For pretreatment mea-
sures of latency, there was a significant effect of
luminance (F
3,42
= 106.84, P < 0.001) but not of session
(F
3,42
= 0.39, NS) and there was no interaction
Pre-Treatment
Pupil Diameter, mm
3
4
5
6
7
8
Post-Treatment
Luminance, cd m
–2
Luminance level, cd m
–2
0 6 91 360
0
6
91
360
Pupil Diameter, mm
3
4
5
6
7
8
*
*
*
+
+
I 2SED
I 2SED
Figure 1
Resting pupil diameter: relationship between level of luminance and
pupil diameter pretreatment (top) and post-treatment (bottom). The
four treatment conditions are indicated by different symbols (see
below). Ordinate: absolute pupil diameter (mm); abscissa: level of
luminance (cd m
-2
). Each point corresponds to the mean obtained for
the group (n = 16). Vertical bars represent two standard errors of the
difference (2SED) obtained from the interaction term of the analysis of
variance. Pramipexole (*) and the combination of pramipexole and
domperidone (+) increased pupil diameter (P < 0.05; Dunnett’s test:
comparison with placebo condition). Placebo, (
); Pramipexole, ( );
Domperidone, (
); Combination, ( )
Comparison of pramipexole and domperidone
Br J Clin Pharmacol 64:5 595
Page 5
PRE-TREATMENT
Pl Prami
Dom
Combi Pl Prami
Dom
Combi
Pupil Diameter, mm
7.0
7.2
7.4
7.6
7.8
8.0
8.2
8.4
POST - TREATMENT
Pupil Diameter, mm
7.0
7.2
7.4
7.6
7.8
8.0
8.2
8.4
Initial Diameter
Luminance, cd m
–2
Amplitude, mm
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Luminance, cd m
–2
Amplitude, mm
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Amplitude
Latency
*
Luminance, cd m
–2
5.0 41.0 320.0 2050.0 5.0 41.0 320.0 2050.0
5.0 41.0 320.0 2050.0
5.0 41.0 320.0 2050.0
Latency, s
0.26
0.28
0.30
0.32
0.34
0.36
Luminance, cd m
–2
Latency, s
0.26
0.28
0.30
0.32
0.34
0.36
*
I 2SED
I 2SED
I 2SED
I 2SED
*
Figure 2
Pupillary light reflex responses: pretreatment (left) and post-treatment (right) measures of initial diameter in the dark (top), latency (middle), and light
reflex amplitude (bottom). Initial diameter: columns correspond to mean changes in the initial diameter for the group (n = 15). Treatment condition is
indicated at the bottom of the g raphs: Pl = placebo, (); Prami = pramipexole, (
); Dom = domperidone, ( ); Combi = combination, ( ). Vertical bars
represent standard errors of the mean (SEM). Pramipexole increased initial pupil diameter. *P < 0.05 (Dunnett’s test: comparison with placebo condition).
Latency: relationship between light stimulus intensity and the latency of the response. The four treatment conditions are indicated by different symbols (see
below). Ordinate: time to respond to the light stimulus (s); abscissa: level of luminance (cd m
-2
). Each point corresponds to the mean obtained for the
group (n = 15). Vertical bars represent two standard errors of the difference (2SED) obtained from the interaction term of the analysis of variance.
Pramipexole and the combination of pramipexole and domperidone increased the latency of the light reflex (*P < 0.05; Dunnett’s test: comparison with
placebo condition). Amplitude: relationship between light stimulus intensity and the amplitude of the response. The four treatment conditions are indicated
by different symbols (see below). Ordinate: maximal change in pupil diameter in response to the light stimulus (mm); abscissa: level of luminance (cd m
-2
).
Each point corresponds to the mean obtained for the group (n = 15). Vertical bars represent two standard errors of the difference (2SED) obtained from
the interaction term of the analysis of variance. Pramipexole (*) reduced light reflex amplitude (P < 0.05; Dunnett’s test: comparison with placebo
condition). Placebo, (
); Pramipexole, ( ); Domperidone, ( ); Combination ( )
E. Samuels et al.
596 64:5 Br J Clin Pharmacol
Page 6
(F
9,126
= 0.78, NS). Post-treatment data (reciprocal trans-
formation) showed a significant effect of treatment
condition (F
3,42
= 9.54, P < 0.001) and luminance level
(F
3,42
= 90.48, P < 0.001), but no interaction (F
9,126
=
0.42, NS). Analysis of latency averaged across lumi-
nance levels revealed a significant effect of treatment
condition (F
3,42
= 8.05, P < 0.001), where pramipexole
and the combination of pramipexole and domperidone
increased the latency of the light reflex response. Fish-
er’s LSD showed a trend for the increase in latency
following pramipexole to be greater than the increase in
latency following the combination condition.
Darkness reflex measures are shown in Figure 3. A
significant effect of treatment condition is shown on
‘light diameter (F
3,45
= 5.21, P < 0.005) and ‘dark diam-
eter (square root transformation; F
3,45
= 3.36, P < 0.05).
Multiple comparisons show that pramipexole increased
‘light diameter and tended to increase ‘dark diameter’,
whilst the combination of pramipexole and domperidone
increased only ‘dark diameter’. Fisher’s LSD showed a
trend for the pramipexole-induced increase in ‘light
diameter to be greater than the increase following the
combination condition. There were no significant effects
of treatment condition on latency (log
10
transformation;
F
3,45
= 0.32, NS), amplitude (square root transformation;
F
3,45
= 1.65, NS), or initial velocity (log
10
transforma-
tion; F
3,45
= 0.44, NS).
Non-pupillary autonomic functions
The data for nonpupillary autonomic functions are
shown in Table 3. There was a significant effect of treat-
ment condition on systolic blood pressure in the supine
position (F
3,45
= 2.85, P < 0.05), where domperidone
tended to reduce blood pressure, and in the standing
position (F
3,45
= 4.19, P < 0.05), where pramipexole
tended to reduce blood pressure. There was also a sig-
nificant effect of treatment condition on orthostatic
change (F
3,45
= 3.05, P < 0.05), where domperidone
increased the change in systolic blood pressure between
the supine and standing positions. Fisher’s LSD showed
a significant difference between the effects of the com-
bination treatment and pramipexole on systolic blood
pressure in the supine and standing positions. There was
a significant effect of treatment condition on diastolic
blood pressure in the standing position (F
3,45
= 4.74,
P < 0.01), where pramipexole tended to reduce blood
pressure, but there was no effect of treatment condition
in the supine position (F
3,45
= 1.48, NS) and no effect of
treatment condition on orthostatic change (F
3,45
= 2.33,
NS). Fisher’s LSD showed a significant difference
between the effects of the combination treatment and
pramipexole alone on diastolic blood pressure. Heart
Light Diameter
Δ
Pupil Diameter, mm
–0.4
–0.2
0.0
0.2
0.4
Dark Diameter
Δ
Pupil Diameter, mm
–0.4
–0.2
0.0
0.2
0.4
Amplitude
Δ
Amplitude, mm
4.6
4.8
5.0
5.2
5.4
*
*
PL Prami
Dom
Combi
PL Prami
Dom
Combi
PL Prami
Dom
Combi
Figure 3
Pupillary darkness reflex responses: pre/post treatment differences in
measures of light diameter (top), dark diameter (middle), and amplitude
(bottom). Columns correspond to mean changes for the group (n = 16).
Treatment condition is indicated at the bottom of the graph:
Pl = placebo, (); Prami = pramipexole, (
); Dom = domperidone, ( );
Combi = combination, (
). Vertical bars represent standard errors of the
mean (SEM). Ordinate (light diameter): pre/post treatment change in the
diameter of the pupil under illumination (mm); ordinate (dark diameter):
pre/post treatment change in the diameter of the pupil in the dark (mm);
ordinate (amplitude): pre/post treatment change in the maximal difference
in pupil diameter in response to removal of the light stimulus (mm).
Pramipexole increased light diameter and the combination of pramipexole
and domperidone increased dark diameter (*P < 0.05; Dunnett’s test:
comparison with placebo condition)
Comparison of pramipexole and domperidone
Br J Clin Pharmacol 64:5 597
Page 7
rate in the standing position showed an effect of treat-
ment condition (F
3,45
= 3.16, P < 0.05), where multiple
comparisons showed a trend for domperidone to reduce
heart rate. There was no effect of treatment condition on
heart rate in the supine position (F
3,45
= 0.95, NS), but
there was a significant effect of treatment condition on
orthostatic change in heart rate (F
3,45
= 3.24, P < 0.05),
where domperidone reduced the change in heart rate
between the lying and standing positions. There was no
effect of treatment condition on salivation (F
3,45
= 1.29,
NS) or temperature (F
3,45
= 1.35, NS).
Endocrine functions
Plasma concentrations of prolactin, TSH, and GH are
shown in Figure 4. Data from three subjects were
excluded from the analysis due to missing samples. A
significant effect of treatment is shown on prolactin
concentrations (log
10
transformation; F
3,36
= 209.8,
P < 0.001), where domperidone and the combination of
pramipexole and domperidone increased prolactin
secretion and pramipexole reduced prolactin secretion.
Fisher’s LSD showed that the combination treatment
had a significantly different effect on prolactin concen-
trations to pramipexole but not to domperidone. A
significant effect of treatment is shown on TSH concen-
trations (log
10
transformation; F
3,36
= 11.02, P < 0.001),
where domperidone and the combination of pramipexole
and domperidone increased TSH secretion. Fisher’s
LSD showed that the combination treatment had a sig-
nificantly different effect on TSH concentrations to
pramipexole but not to domperidone. A significant effect
of treatment was also shown on GH concentrations
(square root transformation; F
3,36
= 17.55, P < 0.001),
where pramipexole and the combination of pramipexole
and domperidone increased GH concentrations. Fisher’s
LSD showed that the effect of the combination treatment
was not significantly different from the effect of prami-
pexole on GH concentration.
Discussion
In agreement with previous reports from our laboratory
[9, 10], a single dose of pramipexole 0.5 mg produced
sedation in a group of 16 healthy male volunteers as
evidenced by a significant reduction in subjectively rated
alertness on the VAS (see Table 2). Pramipexole also
reduced the subjective rating of contentedness: this is
consistent with reports that an increase in sedation is
usually perceived as an unpleasant experience [32], and
in the case of pramipexole the nausea associated with the
drug is likely to have enhanced the unpleasantness of the
drug experience. It has been proposed that pramipexole
has a biphasic dose–response curve in relation to the
Table 3
Pre-treatment/post-treatment differences in autonomic functions (mean (95% confidence interval))
Placebo Pramipexole Domperidone Combination
Heart rate
(beats min
-1
)
Supine -12.00 (-16.22, -7.78 ) -12.31 (-17 .14, -7.48) -10.69 (-15.33, -6.05) -8.88 (-13.66, -4.09)
Standing -8.81 (-16.27, -1.35) -7.19 (-13.31, -1.06) -16.69 (-22.47, -10.91)T -5.88 (-14.57, 2.82)
Orthostatic change 3.19 (-3.74, 10.11) 5.13 (0.77, 9.48) -6(-11.09, -0.91)* 3 (-3.55, 9.55)
Systolic BP
(mm Hg)
Supine -1.88 (-8.94, 5.19) -7.8 8 (-13.38, -2.37) -9.88 (-15.85, -3.90)T 0.31 (-5.80, 6.43)
Standing -0.19 (-8.32, 7.94) -9.13 (-16.93, -1.32)T 4.25 (-1.61, 10.11) 4.94 (-0.75, 10.63)
Orthostatic change 1.69 (-7.70, 11.08) -1.25 (-8.54, 6.04) 14.13 (5.11, 23.14)* 4.63 (
-1.49, 10.74)
Diastolic BP
(mm Hg)
Supine 1.75 (-0.85, 4.35) -0.88 (-4.20, 2.45) 1.69 (-1.33, 4.70) 2.88 (-0.06, 5.81)
Standing 2.25 (-1.30, 5.80) -2.94 (-9.01, 3.13)T 4.25 (0.56, 7.94) 6.94 (3.31, 10.57)
Orthostatic change 0.5 (-2.56, 3.56) -2.06 (-7.74, 3.62) 2.56 (-1.54, 6.67) 4.06 (1.93, 6.20)
Salivation (g) -0.05 (-0.46, 0.37) 0.20 (-0.23, 0.64) -0.01 (-0.18, 0.15) 0.34 (0.07, 0.60)
Temperature (°C) 0.04 (-0.10, 0.17) -0.15 (-0.33, 0.03) -0.07 (-0.25, 0.11) 0.03 (-0.17, 0.23)
*significant effect compared with placebo (P < 0.05) T trend for significance compared with placebo.
E. Samuels et al.
598 64:5 Br J Clin Pharmacol
Page 8
modulation of alertness level [33, 34]: low doses are
sedative while high doses are alerting. This effect is
attributed to an action of pramipexole at presynaptic
dopamine receptors at low doses and postsynaptic
dopamine receptors at high doses. Inhibitory presynaptic
D
2
dopamine receptors have been identified on the cell
bodies of neurones in the ventral tegmental area (VTA)
of the midbrain [35], which sends a tonic excitatory
projection to the noradrenergic locus coeruleus (LC) in
the pons, a major wakefulness-promoting nucleus [36,
37]. The activation of the presynaptic dopamine re-
ceptors in the VTA by pramipexole may ‘switch off’
this mesocoerulear pathway, leading to a reduction in
LC activity and consequently in alertness level [9, 10,
33, 38].
Administration of domperidone 40 mg had no effect
on alertness level (see Table 2). The dosage adminis-
tered was within the range commonly used (50 mg:
Quinn et al. [22]; 40 mg: Lesser & Bateman [39];
10–40 mg: Huang et al. [28]; 60 mg Jansen et al. [24])
and this lack of effect on alertness is consistent with the
peripheral mode of action proposed for the drug [18–20]
(see Introduction). In addition, the pramipexole-induced
sedation was not antagonized by the concomitant admin-
istration of domperidone. On measures of alertness
therefore the co-administration of domperidone with
pramipexole did not appear to alter the sedative effects
observed following the administration of pramipexole
alone.
Pupil diameter was increased by pramipexole on a
number of measures of pupillary function (resting pupil
diameter at different levels of luminance, initial diam-
eter of the light reflex response, ‘light diameter and
‘dark diameter of the darkness reflex response; see Fig-
ures 1, 2 and 3). Mydriasis following the administration
of pramipexole has been found previously [9] and is in
contrast to the usual observation of miosis following the
administration of a sedative drug (see pp 786–788 in
Loewenfeld [40]). We have suggested that the adminis-
tration of pramipexole may attenuate the influence of a
tonic excitatory dopaminergic output from the VTA to
the Edinger-Westphal nucleus (EWN), a parasympa-
thetic nucleus involved in pupil constriction, resulting
in mydriasis [9, 10]. The presence of this putative
meso-pupillomotor pathway is supported by evidence
of a projection from the VTA to the periaqueductal
grey matter (PAG) [41], and evidence of cells with-
in the ventral PAG expressing D
2
receptor mRNA [42],
where the occulomotor complex (incorporating the
EWN) is situated. Furthermore, alterations in the light
reflex response following pramipexole administration
(increased latency and reduced amplitude) reflect a para-
sympatholytic action of the drug that is consistent with
removal of the effect of an excitatory input to the EWN.
Although domperidone on its own had no effect on
any of the measures of pupillary function (resting pupil
diameter, light reflex and darkness reflex responses; see
Figures 1, 2 and 3), when co-administered with prami-
pexole it attenuated some of the pupillary effects of
pramipexole. Thus the mydriatic effect of pramipexole
at6cdm
-2
and the pramipexole-induced increase in the
‘light diameter of the darkness reflex response were
reduced by domperidone, together with a reduction in
the effects of pramipexole on light reflex amplitude and
Prolactin
Blood Concentration, mIU/L
0
200
400
600
800
1000
TSH
Blood Concentrations, mIU/L
0
1
2
3
4
5
GH
Blood Concentration, mIU/L
0
20
40
60
80
100
*
*
*
*
*
*
*
Pl Prami Dom Combi Pl Prami Dom Combi Pl Prami Dom Combi
Figure 4
Post-treatment plasma concentrations of prolactin (left), thyroid-stimulating hormone (TSH; centre), and growth hormone (GH; right). Columns
correspond to mean plasma concentrations for the group (three samples missing: n = 13). Treatment condition is indicated at the bottom of the
graphs: Pl = placebo, (); Prami = pramipexole, (
); Dom = domperidone, ( ); Combi = combination of pramipexole and domperidone, ( ). The ordinate
axis represents the plasma hormone concentration (mIU l
-1
). Vertical bars represent standard errors of the mean (SEM). Domperidone increased plasma
concentrations of prolactin and TSH whilst pramipexole increased plasma concentrations of GH and reduced concentrations of prolactin. *P < 0.05
(Dunnett’s test: comparison with placebo condition)
Comparison of pramipexole and domperidone
Br J Clin Pharmacol 64:5 599
Page 9
latency. These observations suggest that domperidone
can gain access to some central dopamine receptors,
since the pupillary effects of pramipexole are likely to be
centrally mediated. It should be noted, however, that a
contribution to the pupillary effect of pramipexole by a
peripheral mechanism cannot be entirely discounted
since dopamine and/or dopaminergic mechanisms have
been identified in ciliary ganglia [43] and the retina [44].
Pramipexole had relatively minor effects on measures
of nonpupillary autonomic functions (see Table 3). Both
systolic and diastolic BP tended to be reduced in the
standing position following drug administration, consis-
tent with reports of a reduction in BP in response to
dopamine receptor agonists [45–48]. Indeed, it has been
reported that dopamine receptor agonists may cause
orthostatic hypotension and subjective dizziness [8–12,
14, 46]. This propensity of these drugs is consistent with
a reduction in sympathetic activity which may be caused
by central [47, 49, 50] and/or peripheral [51–53] mecha-
nisms. Although the location of the central dopamine
receptors mediating the sympatholytic effect of dopam-
ine receptor agonists has not been established, it is
likely that the VTA is involved since there is evidence
that activation of the VTA results in an increase
in BP in experimental animals [54]. Therefore, the
hypotensive, sedative, and mydriatic effects of prami-
pexole may all be related to the ‘switching off’ of VTA
activity via stimulation of inhibitory D
2
autoreceptors on
VTA neurones. Heart rate and core temperature were not
affected by pramipexole in the present study, although
small increases in heart rate [9] and decreases in core
temperature [10] have been reported previously. In
agreement with previous reports, pramipexole did not
alter the rate of salivation [9, 10]. Domperidone had only
minor effects on cardiovascular function (see Table 3),
in agreement with previous reports [55, 56]. Domperi-
done, like pramipexole, was without any effect on core
temperature and salivation.
In addition to alertness and autonomic measures,
plasma concentrations of prolactin, TSH, and GH were
analyzed, since the secretion of these hormones is modu-
lated by the hypothalamic dopaminergic system. The
secretion of prolactin and TSH is inhibited by the
tuberoinfundibular dopaminergic neurones which exert
an inhibitory influence on the secretion of these hor-
mones via the activation of D
2
dopamine receptors situ-
ated on the lactotropes and thyrotropes of the pituitary
gland [57]. It is generally accepted that these postsyn-
aptic inhibitory D
2
dopamine receptors lie outside of the
blood–brain barrier [57] and thus they were expected to
be sensitive to both pramipexole and domperidone.
Indeed, we have found that pramipexole and domperi-
done had opposite effects on the secretion of these
hormones, pramipexole reducing and domperidone
increasing prolactin concentrations and domperidone
increasing TSH concentrations. The inhibitory effect of
pramipexole on prolactin secretion has been reported
before by ourselves [9, 10] and others [58], and although
the TSH concentration was not affected by pramipexole
in the present study, there are some reports describing an
inhibitory effect of pramipexole [9, 58]. The opposite
effects of pramipexole and domperidone are consistent
with enhancement of the inhibitory effect of dopamine
on prolactin and TSH secretion by pramipexole and
attenuation of this inhibition by domperidone. The
pattern observed by comparing a D
2
dopamine receptor
agonist and antagonist on the concentration of these
hormones is identical to that observed by us in a previ-
ous study in which pramipexole and amisulpride were
compared [10].
The secretion of GH is also modulated by the hypo-
thalamic dopaminergic system. However, this modula-
tion is indirect via somatostatin, which exerts an
inhibitory influence on the secretion of GH. As the D
2
dopamine receptors involved are not situated on the
somatotropes of the pituitary gland but are on the soma-
tostatin secreting neurones within the hypothalamus,
they may lie inside rather than outside of the blood–
brain barrier. Indeed, pramipexole had a profound facili-
tatory influence on the secretion of GH, presumably by
disinhibiting the somatotropes from the influence of
somatostatinergic neurones, whilst domperidone was
without any effect. The predominant effect of pramipex-
ole was also highlighted by the increased GH concen-
tration recorded after the combination treatment. This is
in contrast with the effect of the combination treatment
on prolactin and TSH secretion where the effect of dom-
peridone superseded any effect of pramipexole.
Overall, the results of this study demonstrate reliable
sedative effects of pramipexole that are maintained in
the presence of domperidone. However, some of the
effects of pramipexole on the pupil (pupil diameter, light
and darkness reflexes) and nonpupillary autonomic
functions (BP, HR) were reduced or eliminated when
domperidone was co-administered. This indicates that a
small concentration of domperidone may enter the
central nervous system when it is co-administered with a
dopamine receptor agonist to prevent nausea. Our results
have practical implications for experimental studies of
dopamine receptor agonists when domperidone may be
used to counteract nausea caused by the dopamine
receptor agonist assuming that the effect of domperi-
done will be restricted to the periphery (for example
Navan et al. [26] and Roesch-Ely et al. [59]). However,
E. Samuels et al.
600 64:5 Br J Clin Pharmacol
Page 10
it is not possible to make a direct comparison with the
clinical situation where both dopamine receptor agonists
and domperidone are administered chronically using
dosage regimens different from that employed in the
present study.
ERS is an Institute of Neuroscience, University of
Nottingham, Scholar.
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    • "Salvinorin-A administered alone increased prolactin plasma concentration, as previously reported for this drug (Johnson et al., 2016) and other KOR agonists such as spiradoline (Ur et al., 1997). Prolactin release is physiologically under inhibitory control by dopaminergic neurotransmission, with amphetamine and other pro-dopaminergic drugs effectively blocking its release (Samuels et al., 2007; Dos Santos et al., 2011 ). The increase in prolactin concentrations induced by salvinorin-A could be secondary to the inhibition of dopamine release in the tuberoinfundibular pathway . "
    Full-text · Article · Mar 2016 · The International Journal of Neuropsychopharmacology
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    • "Salvinorin-A administered alone increased prolactin plasma concentration, as previously reported for this drug (Johnson et al., in press) and other KOR agonists such as spiradoline (Ur et al., 1997). Prolactin release is physiologically under inhibitory control by dopaminergic neurotransmission, with amphetamine and other pro-dopaminergic drugs effectively blocking its release (Samuels et al., 2007; Dos Santos et al., 2011). The increase in prolactin concentrations induced by salvinorin-A could be secondary to the inhibition of dopamine release in the tuberoinfundibular pathway. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A (5-HT2A) receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor (KOR) rather than at the 5-HT2A receptor. Here we assessed the involvement of KOR- and 5-HT2A-agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.Methods: We conducted a placebo-controlled, randomized, double-blind study with two groups of 12 healthy volunteers with experience with psychedelic drugs. There were four experimental sessions. In Group-1 participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50 mg orally. In Group-2 participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo and ketanserin+salvinorin-A. Ketanserin, a selective 5-HT2A antagonist, was administered at a dose of 40 mg orally.Results: Inhalation of 1 mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin.Conclusions: Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans, and rule out the involvement of a 5-HT2A-mediated mechanism.
    Full-text · Article · Feb 2016 · The International Journal of Neuropsychopharmacology
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    • "In the current study, we report tentative findings suggesting that pramipexole reduced the learning rate rather than affecting the reward sensitivity, which might correspond to a direct reduction in the signal reported by phasic DA. Although pramipexole is a non-ergot D 2/D3agonist (and is clinically used as such in Parkinson’s disease, restless leg syndrome, and occasionally in treatment-resistant MDD), it has previously been found to have behavioural effects of a DA antagonist at the low doses (0.5 mg) used in our dataset [72-74]. Similarly, low doses of the D 2 agonist cabergoline have been found to specifically reduce reward go learning [75]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. Methods Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. Results MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. Conclusion Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior.
    Full-text · Article · Jun 2013 · Biology of Mood and Anxiety Disorders
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