Download Forget It! The role of alpha-2 Agonists in Fear Conditioning

Forget It! The Role of a2
Adrenergic Agonists in Fear
Conditioning
M. Frances Davies, Ph.D
Stanford University
Dept of Anesthesia
Common molecular and cellular
substrates of addiction and
memory
. “Drugs of abuse cause long-lasting changes in the brain that
underlie the behavioral abnormalities associated with drug
addiction. Similarly, experience can induce memory formation by
causing stable changes in the brain. Over the past decade, the
molecular and cellular pathways of drug addiction, on the one
hand, and of learning and memory, on the other, have
converged. Learning and memory and drug addiction are
modulated by the same neurotrophic factors, share certain
intracellular signaling cascades, and depend on activation of the
transcription factor CREB. They are associated with similar
adaptations in neuronal morphology, and both are accompanied
by alterations in synaptic plasticity (e.g., long-term potentiation,
long-term depression) at particular glutamatergic synapses in
the brain. “
Nestler EJ. Neurobiol Learn Mem. 2002 Nov;78(3):637-47
Can addiction be treated by
blocking learning or memory?
Strategies to treat addiction:
•
•
inhibit neuroplastic changes
reverse established memories
The noradrenergic system in
fear learning
•
•
•
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Intimately involved in vigilance and alertness
NE activates a1, a2 and b adrenergic receptors
NE plays a role in the learning of fear
a2 agonist dexmedetomidine reduces the activity
of the central and peripheral noradrenergic system
Reduction of fear is desirable for many anesthetic
and ICU procedures
Supporting Evidence
Blockade of b and a1 adrenoceptors
reduces fear learning
 Stimulation of the a2 adrenoceptors tends
to:

– reduce activity of the central noradrenergic
system
– may also reduce the learning of fear

This hypothesis has not been rigorously
tested
Fear Conditioning: Training
Fear Conditioning: The
Concept
Day 1
Training
Tone:
Conditional
stimulus-CS
Shock:
Unconditional
stimulus-US
Central
Fear State
Freezing:
Unconditional
Response-UR
Day 2
Testing
Tone:
Conditional
stimulus-CS
Central
Fear State
Freezing:
Unconditional
Response-UR
Taken from Michael Davis in Neurobiology of Fear Responses: The Role of the Amygdala. Journal of
Neuropsychiatry 1997 Summer 9(3):382-402.
Fear Conditioning: Discrete
Cue Assessment
The Effect of
Dexmedetomidine on
Discrete Cue Memory
Dexmedetomidine Injection
and Testing Schedule
Day 1
Training
Encoding
Consolidation
Dex
Dex
Day 2
Testing
Retrieval
Reconsolidation
Dexmedetomidine (10 µg/kg) given
before training reduced discrete
cue fear conditioning
Dexmedetomidine (20 µg/kg) had
no effect on consolidation of
discrete cue fear conditioning
Does dexmedetomidine reduce
biochemical markers of learning?
Amygdala is important in discrete cue
memory
 Discrete cue fear conditioning causes
expression of c-Fos and P-CREB in the
amygdala
 Can dexmedetomidine affect this
expression?

Dexmedetomidine reduced cFos and P-CREB in amygdala
Lateral
Nucleus
Basolateral
Nucleus
Central
Nucleus
What a2 receptor subtypes are
involved in fear conditioning?
Adrenergic receptors
ALPHA-2 ADRENERGIC RECEPTORS
ALPHA-2 A
* Antihypertension
* Sedation
*Analgesia
* Anesthetic sparing effect
ALPHA-2 B
ARTERIAL CONSTRICTION
ALPHA-2 C
*Analgesia
*Mood
Dexmedetomidine (20µg/kg) did not
affect encoding of discrete cue fear
conditioning in a2A AR KO mice
ACTIVITY
INITIAL EXPLORATION
DISCRETE CUE
Dexmedetomidine did not
affect discrete cue fear
conditioning in D79N mice
Summary
•
•
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•
a2 receptor activation during training
reduces discrete cue fear conditioning
a2 receptor activation after training does
not
Dexmedetomidine reduced P-CREB and
Fos production in amygdala
The effect of a2 agonists on addiction is
unknown
The role of the a2A AR in
intrinsic fearfulness of mice
Mice deficient in a2A AR are more
fearful in the discrete cue test
Is there any difference in the
noradrenergic system in a2A AR
deficient mice?
LC and nucleus tractus solitarius (NTS)
project to the amygdala
 Are activated by the footshock
(unconditioned stimulus)

a2A AR KO mice have a longer
locus coeruleus
The LC cell bodies are bigger
in a2A AR KO mice
There are more TH positive
neurons in the LC of a2A AR
KO mice
There are more large neurons
in the LC of a2A AR KO mice
Conclusions
a2A adrenergic agonists block the creation of
discrete cue fear conditioning memory
 Block expression of transcription factors that have
been linked to memory in critical area (amygdala)
 a2A adrenergic receptor knockout mice

– are very sensitive to discrete cue fear conditioning
– lose amnestic effect of dexmedetomidine
– have hypertrophied central noradrenergic system
Relevance to Addiction

Do individuals differ in their expression of a2A
AR?
– Yes known differences in promotor region
– Linked to changes in memory, indirect hostility,
irritability, negativity, and verbal aggression

Do individuals differ in their susceptibility to
learning to fear??
 Do individuals differ in their susceptibility to
becoming addicted because of an altered
noradrenergic system??
Contributors

Stanford University
– Janet Tsui
– Judy Flannery
– Xiangqi Li
– Brian Hoffman
Molecular
Research
Institute
–Tim DeLorey