Download Buspirone and Pindolol Effects on the EEG Frequency Spectrum in

Buspirone and Pindolol Effects on the EEG Frequency Spectrum in
Healthy Men
R.H. McAllister-Williams* and A.E. Massey
Department of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK
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Introduction
"Lightheaded" (mm)
50
Plac/Plac
Plac/Busp
Pin/Plac
Pin/Busp
40
l
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5-HT1A receptors may be of central importance
in the pathophysiology and treatment of
affective disorders 1
Current methods of examining their functional
integrity in man are limited:
30
l
l
0
0
60
90
0
30
Time
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EEG
Temp
Blood
VAS
EEG
Temp
Blood
VAS
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10 min EEG recording:
F
F
F
F
2
3
29 scalp electrodes
referenced to left mastoid, rereferenced off-line to linked
mastoids
band width 0.1 - 100 Hz
blink corrected using VEOG
10 s epochs generated
rejected if voltage deflection
>  75 mV (including HEOG)
FFT generated with bin width
of 0.1 Hz
Post-hoc analysis used 8
colored sites to examine
ant/post and left/right
differences
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4
5
6
7
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Buspirone and pindolol effects on the EEG frequency
spectrum
F
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Relative Power (P7)
Centroid
Plac/plac
Plac/busp
Pind/plac
Pind/busp
5.0
2.5
60
1.5-6
90
6-8.5
8.5-10.5
10.5-12.5
Prolactin response to buspirone and pindolol
Main effect of drug (F(1.7,26.3) = 15.80, p < 0.001)
Main effect of buspirone (F(1.0,20.7) = 27.85, p <
0.001)
Trend for effect of pindolol (F(1.0,16.6) = 4.61, p =
0.053)
Pindolol + buspirone significantly less than buspirone
(F(1.0,18.6) = 20.07, p < 0.001)
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Frequency spectrum analysis by bands
F
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NS
Restless
-0.352
p < 0.01
Using bands determined by factor analysis6
Analysis of theta band
Drug X AP effect for buspirone ( F(1,13) = 4.64, p = 0.051)
and pindolol (F(1,13) = 18.24, p < 0.001)
F No significant difference between pindolol+ buspirone and
buspirone alone
6
Centroid frequency shift (6-10.5 Hz)
FP1
FP2
F3
FZ
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F8
F4
FC3
FT7
FCZ
FC4
FT8
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C3
T7
CZ
C4
Prolactin
-0.354
p < 0.01
-0.275
p < 0.05
0.487
p < 0.001
0.543
p < 0.001
0.416
p < 0.005
Temp
NS
Nausea
NS
lighthead
NS
-0.275
p < 0.05
0.487
p < 0.001
NS
0.543
p < 0.001
NS
NS
NS
NS
0.701
p < 0.001
0.701
p < 0.001
NS
Restless
-0.352
p < 0.01
0.416
p < 0.005
NS
NS
0.250
p = 0.063
0.250
p = 0.063
Weak correlation between shift in centroid (P7) and
restlessness and prolactin response
Strongest correlation between prolactin response and
nausea and lightheadedness
Conclusions
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10 Hz.min
36.0
T8
Buspirone (30 mg) causes a leftward shift of the EEG
frequency spectrum between 6 and 10.5 Hz in healthy
subjects
Pindolol (20 mg) causes a similar effect
The relative effects of buspirone and pindolol on the
EEG are different to the prolactin response which is
known to reflect postsynaptic 5-HT1A activation
Pindolol has been shown to be a partial agonist at
somatodendritic 5-HT1A receptors in rodents7
The shift in EEG spectrum with buspirone and
pindolol may reflect somatodendritic 5-HT1A receptor
activation
References
35.5
TP7
CP3
CPZ
CP4
TP8
P7
P3
PZ
P4
P8
35.0
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lighthead
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F
Plac/Plac
Plac/Busp
Pin/Plac
Pin/Busp
36.5
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NS
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37.0
l
Nausea
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Frequency Bands (Hz)
Body Temperature (C)
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Temp
-0.354
p < 0.01
NS
Prolactin
-2.5
3
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Correlation between effects
Centroid
30
60
90
Time
Range
18.8 – 38.0
19.0 – 30.8
90 – 113
13 – 20
0–3
0-4
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Drug
Drug X AP
F(1.9,25.2) = 3.84
p < 0.05
F(2.4,31.3) = 5.40
p < 0.01
F(1,13) = 18.53
p < 0.001
F(1,13) = 7.03
p < 0.05
F(1,13) = 3.30
p = 0.093
F(1,13) = 7.01
p < 0.05
NS
NS
Significant effect of buspirone and pindolol
Effect greater at posterior sites
Pindolol + buspirone not significantly different from
buspirone alone
0.0
0
Mean  SD
23.0  5.2
24.7  4.6
102  9
15  2
0.3  0.8
1.3  1.5
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Relative power between 0.5 and 30Hz calculated from FFT (plotted to
15Hz)
F7
Subjects
Busp vs pind/busp
9 10 11 12 13 14 15
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Time
EEG
Temp
Blood
VAS
F
1
Frequency
0
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F
0
250
3:00
F
0.00
Plac/Plac
Plac/Busp
Pin/Plac
Pin/Busp
30
Drug
Drug X AP
7.5
0
Drug
Busp vs plac
Pind vs plac
500
2:30
Drug X AP
Drug X AP
5
750
Effects
Drug
0.01
Prolactin (mIU/l)
2:00
F
90
Subjective effects rated using VAS scales
No main effect of buspirone or pindolol on depressed,
drowsy or restless VAS
Significant buspirone X time effect, but not pindolol,
on ‘nausea’ (F(2.52,30.23) = 4.86, p < 0.01) and
‘lightheaded’ (F(2.06,26.82) = 10.32, p < 0.001)
Pindolol + buspirone significantly less than buspirone
(F(2.26,27.11) = 4.80, p < 0.05 and F(2.42,29.08) =
3.03, p = 0.055 respectively)
2
Buspirone 30 mg
or placebo
1:30
60
Time
1000
EEG
Temp
Blood
VAS
Age (years)
BMI (kg/m2)
NART
Yrs of education
HAMD
BDI
30
Analysis of centroids - 8 sites
Comparison
All conditions
Plac/Plac
Pin/Plac
Plac/Busp
Pin/Busp
0
0
14 healthy male volunteers
4-way random order cross over, double blind
experiment
Resting EEG recorded, plus temperature,
prolactin levels and VAS for ‘depressed’,
‘drowsy’, ‘restless’, ‘nausea’ and ‘lightheaded’
Pindolol 20 mg
or placebo
0.02
10
Methods
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20
7
Relative Power (P7)
Plac/Plac
Plac/Busp
Pin/Plac
Pin/Busp
10
The neuroendocrine response to l-tryptophan and 5-HT 1A
agonists may reflect postsynaptic hypothalamic 5-HT 1A
receptor activation 2
agonists is believed to
F The hypothermic effect of 5-HT1A
reflect a combination of somatodendritic and postsynaptic
5- HT1A receptor activation3
The 5-HT1A agonist buspirone causes a leftward
shift of the EEG frequency spectrum4,5 which is
hypothesised to reflect somatodendritic 5-HT1A
receptor activation
30
20
F
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4
"Nausea" (mm)
Temperature response to buspirone and pindolol
Main effect of drug (F(2.0,60.0) = 6.30, p < 0.01)
Main effect of buspirone (F(1.3,30.8) = 7.65, p < 0.05)
Main effect of pindolol (F(1.3,31.6) = 6.67, p < 0.05)
Pindolol + buspirone not significantly different to
buspirone alone
O1
O2
10 Hz.min
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Centroid analysis of FFT between 6 and 10.5 Hz
1. McAllister-Williams R.H. & Young A.H. (1998) The pathology of depression. A synthesis of
the role of serotonin and corticosteroids. In New models for depression (ed. Ebert D. and
Ebmeier K.), Vol . 19, pp. 170-198. Karger, Basel.
2. Smith C.E., Ware C.J., & Cowen P.J. (1991) Pindolol decreases prolactin and growth hormone
responses to intravenous L-tryptophan. Psychopharm. 103, 140-142.
3. Blier P., Seletti B., Young S.N., Benkelfat C., & de Montigny C. (1994) Serotonin 1A receptor
activation and hypothermia: Evidence for a postsynaptic mechanism in humans.
Neuropsychopharm. 10, 92S (O-229-360).
4. Bogdanov N.N. & Bogdanov M.B. (1994) The role of 5-HT1A serotonin and D2 dopamine
receptors in buspirone effects on cortical electrical activity in rats. Neurosci. Lett. 177, 1-4.
5. Anderer P., Barbanoj M.J., Saletu B., & Semlitsch H.V. (1993) Restriction to a limited set of
EEG-target variables may lead to misinterpretation of pharmaco-EEG results. Neuropsychobiol.
27, 112-116.
6. Herrman W.M., Fichte K., & Kubicki S. (1980) Definition of EEG frequency bands based on the
interpretation of factor analysis with EEG power spectrum parameters. In Factor analysis and
EEG variables (ed Kubicki S., et al.), pp 61-74. Gustav Fischer, Stuttgart.
7. Clifford E.M., Gartside S.E., Umbers V., Cowen P.J., Hajos M., & Sharp T. (1998)
Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5HT(1A) autoreceptor in vivo. Brit. J. Pharmacol. 124, 206-212.
Acknowledgements
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This work was supported by an MRC (UK) Clinician
Scientist Fellowship award to RHMcAW