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TRANSCRIPT
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Pharmacological and Deep Brain Stimulation Treatments in a Rodent Model of Post-Traumatic Stress Disorder1 2 3 4 5 6 Eric Janezic , Ryan LaHood , David A. Stidd , Jean-Philippe Langevin , Edward French , and Jean-Marc Fellous
1: Program in Neuroscience, University of Arizona, Tucson AZ - 2: Program in Molecular and Cellular Biology, University of Arizona, Tucson AZ - 3: Division of Neurosurgery, University of Arizona, Tucson AZ -4: Department of Neurosurgery, University of California, Los Angeles CA - 5: Department of Pharmacology, University of Arizona, Tucson AZ - 6: Department of Psychology and Program in Applied Mathematics, University of Arizona , Tucson AZ
1. Introduction
2. Methods
3. Results 4. Conclusions
5. References
Refs,etc.
6. Acknowledgements
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Avoidance of the shock compartment is increased by chronic nicotine suggesting its possible role in memory consolidation. Chronic nicotine increases long term anxiety in the BWBox test but not in the open field test.
Acute administration of OXT immediately after reactivation of the traumatic context may block memory consolidation, and decrease long term anxiety. Chronic OXT post trauma but not during trauma reduces anxiety. Chronic Oxytocin affects touch but not pain sensitivity.
DBS immediately after trauma causes a lasting reduction in anxiety, even after DBS has ceased. The DBS effect can be delayed and still cause reduction in anxiety. DBS affects cue-related anxiety, while paroxetine affects general anxiety.
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Post-Traumatic Stress Disorder (PTSD) has a lifetime prevalence of about 7.8% (Kessler et. al., 1995). SSRIs are the most commonly prescribed drug treatments for PTSD with a full remission rate of 20-30% (Berger et. al., 2009). Deregulation of the amygdala (Liberzon and Sripada, 2007) and decreases in baseline dopamine
have been identified as neurophysiological changes in animal models of PTSD. Oxytocin (OXT) has been shown to reduce baseline anxiety in fear-potentiated startle paradigms (Missig e.t al., 2010). Nicotine (NIC) and OXT are known to interact with the dopaminergic system ( Baskerville et. al., 2010 ). Deep Brain Stimulation (DBS) has emerged as a viable treatment for diseases such as depression in humans and has been shown effective in a rodent model of PTSD (Langevin, et. al., 2010).
(Corral-Frias et. al., 2013)
Yin and French, 2000;
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Baskerville, T. A., & Douglas, A. J. (2010). Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS neuroscience & therapeutics, 16(3), e92-e123.Berger, William, et al., “Pharmacologic Alternatives to Antidepressants in Post-Traumatic Stress Disorder:
A Systematic Review.” Progress in Neuro-psychopharmacology & Biological Psychiatry 33.2 (2009):169Corral-Frias, Nadia S., et al. “Involvement of the Ventral Tegmental Area in a Rodent Model of Post-
Traumatic Stress Disorder.” Neuropsychopharmacology (2012)Kessler RC, et al., “Post-Traumatic Stress Disorder in the National Comorbidity Survery.” Arch Gen
Psychiatry 52:1048-1060. (1995)Langevin, Jean-Philippe, et al. "Deep brain stimulation of the amygdala alleviates post-traumatic stress
disorder symptoms in a rat model." Journal of psychiatric research 44.16 (2010): 1241-1245.
—Missig et al. Oxytocin reduces background anxiety in fear-potentiated startle paradigm. Neuropsychopharmacology 2010; 35:2607-16—Stidd, D. A., Vogelsang, K., Krahl, S. E., Langevin, J. P., & Fellous, J. M. (2013). Amygdala deep brain stimulation is superior to paroxetine treatment in a rat model of posttraumatic stress disorder. Brain stimulation.—Yin, R., & French, E. D. (2000). A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrophysiological study. Brain research bulletin, 51(6), 507-514.
Liberzon, Israel, and Chandra Sekhar Sripada. "The functional neuroanatomy of PTSD: a critical review." Progress in brain research 167 (2007): 151-169.
Thanks to the Fellous lab for helpful input and discussions. Funding in part by NSF grants 1117388 and 1010172, and the Undergraduate in Biology Research Program at the University of Arizona.
Day -1: Pain (Tail Flick) and tactile (Von Frey) sensitivity tests
Day 8: Pain and tactile sensitivity tests
Day 16: Pain and tactile sensitivity tests
Days -5 to -2: Open field test
Day 15: Open field test
Days 3,5,7: Situational reminders
Day 13: Black and white box test (BWBox)
Day 14: Elevated plus maze
Break
Day 1: Inescapable footshock (2 mA, 10s)
Footshock (2 mA, 1s every 30s for 5 min)
Pharmacological experiments DBS experiments
Tra
um
a
Tra
um
a
Sprague Dawley 3-4 month old male rats.Oxytocin SC injections: 0.2 mg/kg in saline.Oxytocin SC pumps: 7-Day & 14-Day osmotic pumps (4.2 mg/hr).Nicotine SC pumps: 28-Day osmotic pumps (0.02ml/hour).All controls were the Saline (Sal) equivalent.
B. Effect of Oxytocin
-14
-7
-1
1
6
8
15
Acclimation
Recovery
Daily DBS: 120ms pulse at 160 Hz and 2.5 V for 4 hoursParoxetine (PRX): 5 mg/kg IP
Implant electrode into right Basolateral amygdala
Burying assessment
Elevated plus maze
Burying assessment
Burying assessment
Time Spent in Shock Side during Situational
Reminders
Latency to Escape White Side in BWBox Test
Total Distance Covered in Open Field Test
Chronic Nicotine Increases Long Term Anxiety
Chronic Nicotine Does Not Affect Touch and Pain Sensitivity
HippocampusAmygdala
Dopamine
Oxytocin
OtherPVN
VTA
Nicotine pre-pump (n = 9)
Saline pre-pump (n = 7)
Saline (n = 7)
Nicotine (n = 9)
Pe
rce
nta
ge
of
time
sp
en
t in
sh
ock
sid
e (
ou
t o
f 1
20
s)
SR1 SR2 SR30%
5%
10%
15%
20%
25%
30%
*
La
ten
cy t
o E
sca
pe
(s)
0
4
8
12
16
20
Both groups are more anxious after trauma (** = p < 0.01). There is no difference between the two groups.
Nicotine animals are more anxious than controls 13 days after shock (* = p < 0.05).
Nicotine brings the animals to maximal avoidance on SR1. This suggests that nicotine increases sensitivity to context (* = p < 0.05).
Post-Shock
Me
an
Dis
tan
ce (
m)
Pre-Shock
10
12
0
2
4
6
8
Pre-shock Post-shock7 days
Post-shock16 days
Von Frey Touch Sensitivity
Shock
0
10
20
30
40
50
60
Sensi
tivity
Thre
shold
(g)
Sensi
tivity
Thre
shold
(g)
Tail Flick Pain Sensitivity
Nicotine pre-pump (n = 11)
Saline pre-pump (n = 11)
ShockNicotine (n = 11)
Saline (n = 7)
Pre-shock Post-shock7 days
Post-shock16 days
0
1
2
3
4
5
6
7
8
9
Late
ncy
for
with
dra
wal (
s)
Late
ncy
for
with
dra
wal (
s)
7-Day Chronic Oxytocin Administration Increases Anxiety in BWBox Test
Entries into White Side
* = p < 0.05
Time Spent in White Side
* = p < 0.05, ** = p < 0.010
20
40
60
80
100
120
140
160
180
200
Tim
e (
s)
0%
10%
20%
30%
40%
50%
60%
Pre-Shock Post-Shock
Time Spent in Center of Open Field
7 Day OXT (n = 11)
14 Day OXT (n = 11)
SC OXT (n = 9)
Sal Pump (n = 8)
SC Sal (n = 9)
Perc
ent of 500 s
eco
nds
Acute administration of OXT immediately after reactivation of the traumatic context may block memory consolidation, and decrease long term anxiety. Chronic OXT post trauma but not during trauma reduces anxiety .(* = p < 0.05, ** = p < 0.01)
Shock
Left: In control conditions, rats do not bury a novel object. Right: After shock, rats bury the item that was present during trauma (Stidd et. al., 2013).
Time (s)
100
200
300
400
500
Pre-Shock Post-Shock DBS-Sham Sham-DBS
Histology shows that the electrodes were correctly placed in the right basolateral amygdala (Stidd et. al., 2013).
Time-lapse of Ball-Burying Behavior Placement of DBS Electrodes
Oxytocin and Dopamine Pathways
A. Effect of Nicotine
C. Effect of DBS of the Amygdala
Num
ber
of E
ntr
ies
0
1
2
3
4
5
6
7
8
9
543.25/ II5
Sham
Sham
DB
S
DB
S
Chronic Oxytocin Increases Touch Sensitivity, But Not Pain Sensitivity
Pre-Shock 7 Days Post-Shock
7 Days Post-Shock
Von Frey Touch Sensitivity
16 Days Post-Shock
16 Days Post-Shock
0
5
10
15
20
25
30
35
Shock
** = p < 0.01
Tail Flick Pain Sensitivity
0
1
2
3
4
5
6
7
8
9
10
Pre-Shock
Shock
***
**
*
*
*
*
*
*
*
*
*
**
****
7 Day OXT (n = 11)
14 Day OXT (n = 11)
SC OXT (n = 9)
Contact Information: [email protected]
Tim
e (
sec)
DBS does not affect general anxiety as shown by the elevated plus maze, but paroxetine does (* = p < 0.05, adapted from Stidd et. al. 2013).
DBS-Sham (n = 10)
Sham-DBS (n = 10)
PRX (n = 10)
Controls (n = 10)
0
50
100
150
200
250
Controls PRX Sham-DBS DBS-Sham
Tim
e (
sec)
DBS for 1 week after trauma shows less anxiety than all other groups, which persists up to 2 weeks after shock even when DBS has stopped. DBS also reduces anxiety even when started one week after initial trauma (* = p < 0.05). Paroxetine is uneffective (Adapted from Stidd et. al., 2013).
0
20
40
60
80
100
120
140
160
180
200
Baseline pre-shock
1 week post-shock
2 weeks post-shock
Shock
Time in Open Arm of Elevated Plus Maze
Time Spent Burying Object
7 Day OXT (n = 11)
14 Day OXT (n = 11)
SC OXT (n = 9)
7 Day OXT (n = 11)
14 Day OXT (n = 11)
SC OXT (n = 9)
7 Day OXT (n = 11)
14 Day OXT (n = 11)
SC OXT (n = 9)
Paro
xetin
e
*
*
**
**
VTA
HCAMG
PVN
Dopamine
Oxytocin
Unknown