The relation between
withdrawal-potentiated
startle and morphine
self administration in
rats
Mari Gades
CCS Spring Research Day
April 25, 2017
Withdrawal-Potentiated
Acoustic Startle
• Spontaneous Withdrawal
• Precipitated Withdrawal
• Percent change in startle
amplitude from baseline
to withdrawal
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1
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1
% Change from Baseline
100dB % Change - MOR/NAL
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200
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95dB % Change - SAL/SAL
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% Change from Baseline
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95dB % Change - MOR/NAL
105dB % Change - MOR/NAL
300
200
100
0
-100
Day
Day
100dB % Change - SAL/SAL
105dB % Change - SAL/SAL
300
200
100
0
-100
Self Administration
• Acquisition
Acquisition
50
Active Lever
Inactive Lever
n = 25
30
N=25
*
25
40
Infusions
Responses
20
30
20
10
10
0
15
5
0
1
2
3
4
5
6
Session
7
8
9
10
** Different from Inactive Responses at that session, p < 0.01
1
2
3
4
5
6
Session
7
8
9
10
Self Administration
• Acquisition
• Behavioral
Economics/Demand
Demand
Individual Demand
108
Group Demand Curve
10
106
Log Consumption
Log Consumption
N=17
104
102
100
1
1000
100
10
Unit Price (FR/unit dose)
r2 = 0.98
1
0.1
0.01
1
1000
100
10
Unit Price (FR/unit dose)
Self Administration
• Acquisition
• Behavioral
Economics/Demand
• Extinction
Extinction
Extinction
40
n = 13
Infusions
30
20
10
0
R
1
2
3
4
5
6
Session
7
8
9
10
Self Administration
• Acquisition
• Behavioral
Economics/Demand
• Extinction
• Drug-Induced
Reinstatement
• Stress-Induced
Reinstatement
Reinstatement
Stress-induced
Reinstatement
Morphine-induced
Reinstatement
60
50
40
30
20
50
40
30
20
10
10
0
0
VEH
+
NO CUE
MOR
+
NO CUE
VEH
+
CUE
MOR
+
CUE
VEH = Vehicle (Saline), MOR = Morphine (1.0 mg/kg, s.c.)
Active
Inactive
n = 11
Responses
Responses
60
Active
Inactive
n = 12
VEH
+
NO CUE
YOH
+
NO CUE
VEH
+
CUE
YOH
+
CUE
VEH = Vehicle (Deionized water), YOH = Yohimbe (2.5 mg/kg, i.p.)
Spontaneous Withdrawal-Potentiated
Startle and Self Administration
20
105dB Startle vs Demand
0.008
n=10
n=10
15
Alpha
0.006
10
5
0.004
0.002
0
0
50
100
% Change from baseline
Spontaneous
150
0.000
0
50
100
% Change from baseline
Spontaneous
105dB Startle vs Extinction Infusions
Avg Infusions EXT First 10
Avg Infusions First 10 Days
105dB Startle vs Acquisition Infusions
n=6
p=0.02
20
15
10
5
0
0
50
100
% Change from baseline
Spontaneous
150
150
Results from
Collaborating Lab - ICSS
A
#
**
ICSS Threshold
(% of Baseline)
160
#
**
#
**
#
**
140
*
120
100
80
MOR + NX (n = 21)
MOR + SAL (n = 6)
SAL + NX (n = 7)
SAL + SAL (n = 8)
130
B
MOR (n = 27)
SAL (n = 15)
120
ICSS Threshold
(% of Baseline)
180
*
110
100
90
1
2
3
Session
4
5
80
6
26
30 50 54 74 98 170
Hours After Injection
40
C r = -0.48, p = 0.038
30
20
10
0
-40 -20
0
20 40 60 80
Precipitated Withdrawal Escalation
(Change in withdrawal, Sessions 1-5)
Acquisition
(Infusion rate, Sessions 1-10)
Acquisition
(Infusion rate, Sessions 1-10)
ICSS Predicts Acquisition
30
D
r = -0.64, p = 0.009
20
10
0
2.0
2.1
2.2
Peak spontaneous withdrawal
(ICSS thresholds, log % baseline)
Conclusions
• Recap
o We can get animals to startle and to self administer morphine
o Startle may be able to predict specific aspects of morphine self
administration
o ICSS negatively predicts morphine self administration acquisition
• Future Directions
o Larger sample sizes with complete control groups
o Look into other early effects of morphine use (e.g. gene expression)
Thank you!
Jonathan Gewirtz
Tatyana Matveeva
Xin Song
Bunchung Ly
Jake Jeong
Cameron Gray
Elsa Mattson
Ali Ruminsky
Laura McGuigan
Andy Harris
Jack Smethells
Bruce Kennedy
NIH DA037728
PharmacoNeuroImmunology
Training Program (4T32
DA007097-35)
UMN Psychology Department
Center for Cognitive Sciences