Transcript war, terrorist attacks, natural disasters, familial violence, forced

1/22
What is PTSD?
PTSD = Post-Traumatic Stress Disorder
An anxiety disorder that develops in response to strong stressors
"Incubation" phase
Trauma
(1-6 month)
Early response
Acute
Stress
Disorder
~1 month
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Silent period
The development
of persistent symptoms
How does it look like? Is it simply anxiety?
DSM-IV criteria for PTSD
Number of symptoms "required" within a cluster
Triggering factor (Cluster A): traumatic event 2
(1) life threatening
(2) helpless
Reexperiencing the trauma (Cluster B)
2
(1) distressing recollections
re-experiencing
(2) distressing dreams
(3) reliving the experience by illusions, hallucinations, and dissociative flashbacks
(4) psychological distress when faced with trauma-related cues
(5) psychological
distress when faced with trauma-related cues
Trauma
avoiding cue-associated cues
Avoidance
and
numbing
(Cluster C)
3
(life-threatening stress)
(1) avoiding trauma-related thoughts, feelings, or conversations
(2) avoiding trauma-related activities, places, or people
(3) inability to recall an important aspect of the trauma
(4) diminished interest in significant activities
hyperarousal
(5) detachment from others
(6) restricted range of affect
+ psychosis
(7) sense
of a foreshortened future
A single exposure to a traumatic stress induces a dramatic worsening
depression
Hyperarousal (Cluster D) of in psychological functioning
2
violence
(1) sleep problems
drug addiction
A remarkable example of neuronal plasticity
(2) irritability
anxiety, etc.
(3) difficulty concentrating
(4) hypervigilance
(5) exaggerated startle response
Duration is more than 1 month (Cluster E)
1
It usully lasts years or decades
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How important it is? Risk factors and risks
Prevalence of PTSD (%)
Risk factor
0
10
20
30
40
50
60
70
80
90
100
Prevalence in the general population
Terrorist attack
Natural disaster (earthquake)
Forced migration
Assaultive violence
Prevalence of PTSD in the general population (%)
Combat
10
8
6
similar to the prevalence of other anxiety disorders
Family violence
Trafic accidents, children
and in their mothers
Diabetes, children
and in their mothers
AIDS
4
2
0
1
2
3
5 46
7
8 Average
Study Nr.
Unemployment
Certain profesions (ambulance)
Trauma in mothers, PTSD in child likelyhood
Factors leading to PTSD are parts of daily life
Certain stressors predictably lead to PTSD
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General perception:
People in general are not at risk. I'm safe.
Factors
prenatal stress
early life stress
traumatic stressors in adulthood
Breslau et al., 1991; Breslau et al., 1999; Clohessy and Ehlers, 1999; Creamer et al., 2001; Goowin and Davidson, 2004; Kessler et
al., 1995; Landolt et al., 2005; Marshall et al., 2005; Olley et al., 2005; Perkonnig et al., 2000; Resnik et al., 1993; Rosenman, 2002;
Seedat et al., 2005; Shalev and Freedman, 2005
How does it develop? Glutamatergic plasticity
plasticity of
Trauma
Behavioral deficits
glutamatergic neurotransmission
300
200
a
a
b
100
b
0
Kontroll 0
0.05 0.1 mg/kg MK-801
electric shock
24 hours earlier
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Haller et al., 2006
open arm exploration (%time)
opponent time (sec)
The blockade of NMDA receptors by MK-801 blocks the development of trauma-related deficits
15
10
*
5
0
Kontroll 0
0.05 0.1 mg/kg MK-801
cat exposure
24 h earlier
Adamec et al., 1999
Treatment
NMDA blockers are highly debilitating and addictive ("angel dust")
SSRIs
Problems with these treatments
less well tolerated than placebo
efficacy: significant but often poor
certain symptoms respond less well
effects are often gender-dependent
serotonin
-plasticity of
Trauma
Behavioral deficits
Behavioral
deficits
glutamatergic neurotransmission
+
opponent time (sec)
alpha 1
or beta blockers
There are better ways
to control
glutamatergic plasticity
300
a
a
200
b
100
0
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noradrenalin
b
Serotonin
c and noradrenaline
modulate
Sham but
5-HTx
NAxmediate
xx
not
trauma-induced deficits
Theory-based approach
Developing a behavioral model
Detailed maping of
neuronal activation patterns
Department
of functional and
cellular neuroanatomy
(T.F. Freund)
Detailed analysis
of activated neurons
(e.g. chemotype identification,
network analysis, etc.)
Detailed functional maping
of cortical networks
Unbiased approach
Theory on the role
of particular neurons
Testing the theory by
behavioral pharmacology
Department
of Behavioral
Neurobiology
(J. Haller)
Describing the neural
control of the behavior
in question - new treatment approaches
7/22
Unbiased approach
(applied earlier in identifying
the neural background
of violent forms of aggression
and proposing NK1 blockers for treatment)
If the theory is right:
new treatment approaches
Theory driven approach
The theory: a neuron made for anxiety
Specifically involved in anxiety
Calretinin
cell
CCK - B
receptors
CCK
basket
cell
Parvalbumin
basket cell
CB1
cannabinoid
receptors
CB1
M2 muscarinic
receptors
8/22
GABAA receptors
mainly with α1 subunits
cannabinoid
receptorokNicotinic receptors
with α4 and α7
subunits
GABA
receptorok
GABAAA receptors
α2 alegységgel
mainly
with α2 subunits
5-HT3
receptors
Cannabinoid signaling and anxiety
Specifically involved in anxiety
Endocannabinoids
Calretinin
cell
CCK - B
receptors
CB1 receptors
GABA
GABA
CCK
basket
cell
Parvalbumin
basket cell
Axon terminal
M2 muscarinic
receptors
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GABAA receptors
mainly with α1 subunits
CB1
Postsynaptic
cannabinoid
receptors
membrane
CB1
cannabinoid
receptorokNicotinic receptors
with α4 and α7
subunits
GABA
receptorok
GABAAA receptors
α2 alegységgel
mainly
with α2 subunits
5-HT3
receptors
Testing the hypothesis and ...strange findings with endogenous cannabinoids
Open arm exploration (% time)
Coward
40
*
30
20
10
*
Open arm exploration (% time)
*
*
*
*
Brave
0
WT CB1-KO
Saline
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No changes in locomotion
40
WT CB1-KO
WIN-55,212
WT CB1-KO
AM-251
WT CB1-KO
AM+WIN
mice called
by phone
CD1 mice
30
*
20
10
0
Sal
Ana
1 2 3 4 5
minutes
1 2 3 4 5
minutes
Saline
Andamide
Sal
Ana
1 2 3 4 5
minutes
1 2 3 4 5
minutes
Saline
Andamide
Subtle changes in endogenous cannabinoid signalling
change the response of mice to environmental stimuli
PTSD and the response to environmental stimuli
re-experiencing
Trauma
(life-threatening stress)
(e.g. exaggerated responses to cues)
avoiding cue-associated cues
hyperarousal
(e.g. hypervigilence)
Trauma-related deficits are glutamate-dependent
CB1/x receptors
Glutamate receptors
Cannabinoids
(i) control the response to stimuli
(neurobehavioral evidence)
(ii) control glutamatergic discharges
(neurophysiological evidence)
Cannabinoids must have
a role in PTSD
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CB1
cannabinoid
receptors
The conditioned fear test as model of PTSD
Exploration (%time)
100
80
60
40
20
*
*
*
*
0
24 hours
Resting (%time)
100
1 2 3 4 5 6 7 8 9 10
Time (min)
80
60
40
20
***
*
0
Model of post-traumatic stress disorder
Symptom modelled
Cluster "B"
re-experiencing the trauma by
symptom 4
intense psychological distress in response to trauma-associated cues
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Freezing (%time)
100
1 2 3 4 5 6 7 8 9 10
Time (min)
80
60
40
20
**
o
0
1 2 3 4 5 6 7 8 9 10
Time (min)
The interaction between cannabinoid signaling and conditioned fear
CB1 gene disruption
abolishes conditioned freezing
freezing (%time)
(mice shocked 24h earlier)
counts
300
200
100
40
30
*
*
1
2
20
10
0
0
WIN0 WIN03
WIN1
WIN3
30
20
10
*
0
1
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#
2
3
4
time (min)
5
5
KO-control
KO-shock
CB1 activation
increases conditioned freezing
freezing (%time)
freezing (%time)
*
3
4
time (min)
WT-control
WT-shock
CB1 blockade slightly
decreases conditioned freezing
40
AM-251 had
no effect on locomotion
up to 55 mg/kg
(literature)
*
100
80
60
40
20
0
#
#
#
#
#
*
1
#
2
*
3
time (min)
*
4
*
5
The antagonist blocks
the effects of the agonist
freezing (%time)
Open-field
400
100
80
60
40
20
0
#
#
#
#
3
4
5
#
1
2
time (min)
control
shock AM251 1mg/kg
control
shock WIN55,212 1mg/kg
shock
shock
shock AM251 3mg/kg
shock
shock WIN55,212 3mg/kg
shock WIN03
shock WIN03AM1
shock WIN3
shock WIN3AM1
Cannabinoids and contextual and cue-induced conditioned fear
Contextual
conditioned fear
(hippocampus-specific)
Cue-induced
conditioned fear
(amygdala-specific)
Cannabinoids promote behavioral dysfunctions induced by traumatic experience
this appears to be valid
for behaviors
largely
Different
distribution
of controlled by the hippocampus
Haller et al., 2006
Marsicano et al., 2002
CB1 receptors in,
Cannabinoids promote the extinction
of aversive
memories
and/or
different
roles
this is apparent in behaviors
largely
controlled
by the amygdala
of cannabinoids in
Specific controlling the, Unpecific
involvement
effect
amygdala and hippocampus?
in trauma?
(consequence of
The involvement of cannabinoids in
trauma-related
behavioral dysfunctions suggests that
memory-releted
Involvement of other
cortical
effects)? stress disorder
cannabinoid signalingstructures
is involved
in post-traumatic
(e.g prefrontal
cortex)
in the differential effects?
Cannabinoids promote the
expression of fear
14/22
Cannabinoids promote the
extinction of fear
(no effect on expression)
Interactions between 5-HT3 and CB1 receptors in conditioned fear
5-HT3
receptors
CB1
cannabinoid
receptors
15/22
The effects of the 5-HT3 agonist mCPBG on anxiety
40
Elevated plus-maze
30
Sal
1 mg/kg
20
The 5-HT3 agonist does not affect
plus-maze anxiety (natural fear)
3 mg/kg
10 mg/kg
10
#
0
#
#
#
#
Closed
entries
% time
open arms
% open
entries
Conditioned fear
vehicle, no shock
shock, vehicle
The same agonist prolongs
the conditioned fear response
without affecting amplitude
freezing (% time)
35
shock, 3 mg/kg mCPBG
30
shock, 10 mg/kg mCPBG
25
20
15
10
5
0
1
2
3
4
5
6
min
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7
8
9
10
Concurrent 5-HT3 agonism and CB1 blockade abolishes conditioned fear
Conditioned fear
Freezing (%time)
35
30
vehicle, no shock
25
shock, vehicle
20
mCPBG 3mg/kg
Cannabinoids -alone orshock,
in
combinationshock, mCPBG 3 mg/kg + AM-251 0.3 mg/kg
are potentially important shock,
in the
treatment
of1 mg/kg
mCPBG
3 mg/kg + AM-251
trauma-induced behavioral deficits
15
10
5
0
1
2
3
4
5
6
7
8
9
10
min
freezing (%time)
For comparison: the effects of AM-251
40
*
30
Conclusion
Theremodel
is an unexpectedly
interaction between mechanisms
One problem: was the
goodstrong
enough
mediated by 5-HT3 and CB1 receptors, that may be involved in
to draw this
therconclusion?
control of behavioral dysfunctons induced by trauma exposure
20
10
*
#
anxiolytic
0
1
2
3
4
time (min)
5
control
shock AM251 1mg/kg
shock
shock AM251 3mg/kg
CCK
interneuron
GABA
CCK
anxiogenic
17/22
The usual way of modeling psychiatric disorders
(1) Tearing symptoms apart (depression is just an example)
Glucocorticoid
excess
(3) Bringing the bits together - theoretical perfection
Helplessness
(3) What often happens in practice
Behavioral
suppression
Mania
Anhedonia
Despair
A better solution: modeling the disorder.
Is this possible?
Etc.
This may be feasible in PTSD
where all symptoms have one single cause:
the trauma
(2) Building models for each symptom
Learned
helplessness
18/22
Forced
swimming
Chronic
mild stress
Bulbectomy
/open field
Chronic
restraint
Forced
submission
Etc.
A symptom by symtom analysis of a PTSD model
"New pharmacological approaches need new behavioral methods"
Traumas employed in the laboratory
Electric shocks of various strength, durations, aggravated or not with cue reminders
Cat exposure
Suffocation stress
Restraint + forced swim + halothane or ether
Behavioreal deficits investigated
Limited number (usually one), often after a limited time interval
Can a complex disorder be modelled simply?
Question asked: can we create a rat in which PTSD can be DIAGNOSED?
19/22
Deficits seen in rats receiving 10, 1 sec long, 0.8 or 3 mA shocks over 5 min
380
Closeed arm entries
Heart rate
% time
time
%(%time)
Duration
(exploration)
crossingschamber
opponent's
% time in Line
DSM-IV criteria for PTSD
Number of symptoms "required" within a cluster
Triggering factor (Cluster A): traumatic event 2
(1) life threatening
(2) helpless
Reexperiencing
the trauma
B)jumps 2
Group
Freezing(Cluster
Escape
Vocalizations
(1) distressing recollections
(seconds)
(counts)
duration (sec) latency (sec)
(2) distressing dreams
100
(3)
relivingcontrol
the experience
flashbacks
Unshocked
0.0±0.0 by illusions,
0.0±0.0 hallucinations,
0.0±0.0 and dissociative
300±0†
(4)
psychological
distress
when
faced
with
trauma-related
cues
0.8 mA shocks
1.0±1.0
2.5±0.6
24.6±6.6*
76.7±12.8*
(5) psychological
distress when faced with trauma-related cues
80
1 day
after
shock
days
100shocks
3 mA
44.3±15.1
* 2814.4±6.2
*# shock 8.3±0.3
*#
6.8±4.6*#
Avoidance
and
numbing
(Cluster
C)after
3
Heart
compared to thoughts,
baseline
unshocked or conversations
(1)
avoiding
trauma-related
feelings,
80 rate changes
unshocked,
60
0.8 mA
shocks object 1
*
*
*
(2)
avoiding
trauma-related
activities,
places,
or people
unshocked
3
mA
shocks
12060
unshocked object 2
0.8 mA shocks
*
(3) inability to recall
an
important
aspect
of
the
trauma
*
* * 3 mA shocks
*
40
40
shocked (3 mA) object 1
(4)80diminished
interest in significant
activities
*
(5) detachment
from
others
shocked (3 mA) object 2
* control
4020
12 Elevated
plus-maze
*
400 Openrange
field of affect
3mA
(6) restricted
*
200
10
0sense
(7) 25
ofintr.
a foreshortened
future
Freezing Escape
Freezing
Escape
300
Rez.
100
Hyperarousal
(Cluster
D)
+ 8
jumps 2
*
jumps
Average
-5 T 5 10
20
30
200200
*
6
120
*
(1) sleep
80 problems
minutes
* Object +4
Object
*
#
+
*
(2) 15
irritability
100 manipulation
80
*
*
burying
2 + +
60
*
(3)
difficulty
concentrating
unshocked
25
days
after
The10duration
of theshocks
deficits is at0least
4shocks
weeks * shocks
0 1 day before
0.8 mA
40
460
40
6
12
24
6
12
24
(4) hypervigilance
* 12 the life-span of
Also consider
rats
3 mA
shocks
eD= early dark phase
5
Days
after
shock
Days
after
shock
days after
shockresponse
(5) exaggerated
startle
20
mD = mid dark phase
0 *#
420
Duration
1
0 is more than 1 month (Cluster E)
lD= late dark phase
0SOC AGO
1 day
after shock
-5 T 5 10
28 days
after shock
20
30 Average
eL= early light phase
mL = mid light phase
lL= late light phase
Unshocked control
Rats shocked with 3 mA currents
340
20/22
300
eD mD lD eL mL lL
Average
eD mD lD eL mL lL
Average
Can the disorder be modelled as a whole?
DSM-IV criteria for PTSD
Number of symptoms "required" within a cluster
Triggering factor (Cluster A): traumatic event 2
(1) life threatening

(2) helpless

Reexperiencing the trauma (Cluster B)
2
(1) distressing recollections
(2) distressing dreams
(3) reliving the experience by illusions, hallucinations, and dissociative flashbacks
(4) psychological distress when faced with trauma-related cues

(5) psychological distress when faced with trauma-related cues

Avoidance and numbing (Cluster C)
3
Ratsfeelings,
shocked
3 mA currents reach a state
(1) avoiding trauma-related thoughts,
or with
conversations
that can places,
be considered
an animal variant of PTSD
(2) avoiding trauma-related activities,
or people
(3) inability to recall an important aspect of the trauma
(4) diminished interest in significant activities

(5) detachment from others

(6) restricted range of affect

(7) sense of a foreshortened future
Hyperarousal (Cluster D)
2
(1) sleep problems

(2) irritability
(3) difficulty concentrating
(4) hypervigilance

(5) exaggerated startle response
Duration is more than 1 month (Cluster E)
1

21/22
The next step
Sound theory supported by experimental evidence
Good model
22/22
GO!