forget it! the role of a 2 adrenergic agonists in fear conditioning
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Forget It! The Role of a 2 Adrenergic Agonists in Fear Conditioning. M. Frances Davies, Ph.D Stanford University Dept of Anesthesia. Common molecular and cellular substrates of addiction and memory. - PowerPoint PPT PresentationTRANSCRIPT
Forget It! The Role of Forget It! The Role of 22
Adrenergic Agonists in Fear Adrenergic Agonists in Fear ConditioningConditioning
Forget It! The Role of Forget It! The Role of 22
Adrenergic Agonists in Fear Adrenergic Agonists in Fear ConditioningConditioning
M. Frances Davies, Ph.D
Stanford University
Dept of Anesthesia
Common molecular and Common molecular and cellular substrates of cellular substrates of addiction and memoryaddiction 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 Can addiction be treated by blocking learning or memory?blocking learning or memory?
Strategies to treat addiction:• inhibit neuroplastic changes • reverse established memories
The noradrenergic system in The noradrenergic system in fear learningfear learning
The noradrenergic system in The noradrenergic system in fear learningfear learning
• Intimately involved in vigilance and alertness
• NE activates 1, 2 and adrenergic receptors
• NE plays a role in the learning of fear
• 2 agonist dexmedetomidine reduces the activity of the central and peripheral noradrenergic system
• Reduction of fear is desirable for many anesthetic and ICU procedures
Supporting EvidenceSupporting Evidence Supporting EvidenceSupporting Evidence
Blockade of and 1 adrenoceptors reduces fear learning
Stimulation of the 2 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: TrainingFear Conditioning: Training
Fear Conditioning: The Fear Conditioning: The ConceptConcept
Fear Conditioning: The Fear Conditioning: The ConceptConcept
Day 1 Training
Day 2 Testing
Taken from Michael Davis in Neurobiology of Fear Responses: The Role of the Amygdala. Journal of Neuropsychiatry 1997 Summer 9(3):382-402.
Tone: Conditional stimulus-CS
Shock: Unconditional stimulus-US
Central Fear State
Freezing: Unconditional Response-UR
Tone: Conditional stimulus-CS
Central Fear State
Freezing: Unconditional Response-UR
Fear Conditioning: Discrete Fear Conditioning: Discrete Cue AssessmentCue Assessment
The Effect of The Effect of Dexmedetomidine on Dexmedetomidine on Discrete Cue MemoryDiscrete Cue Memory
Dexmedetomidine Injection Dexmedetomidine Injection and Testing Scheduleand Testing Schedule
Dexmedetomidine Injection Dexmedetomidine Injection and Testing Scheduleand Testing Schedule
Day 1 Training
Day 2 Testing
Reconsolidation
Dex Dex
Encoding Retrieval
Consolidation
Dexmedetomidine (10 µg/kg) given Dexmedetomidine (10 µg/kg) given before training reduced discrete before training reduced discrete
cue fear conditioningcue fear conditioning
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ACTIVITY DISCRETE CUE
Dexmedetomidine (20 µg/kg) had Dexmedetomidine (20 µg/kg) had no effect on consolidation of no effect on consolidation of
discrete cue fear conditioningdiscrete cue fear conditioning
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ACTIVITY DISCRETE CUE
Does dexmedetomidine reduce Does dexmedetomidine reduce biochemical markers of learning?biochemical markers of learning?Does dexmedetomidine reduce Does dexmedetomidine reduce
biochemical markers of learning?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 c-Dexmedetomidine reduced c-Fos and P-CREB in amygdalaFos and P-CREB in amygdala
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A B C
D E F
Lateral Nucleus
Basolateral Nucleus
Central Nucleus
What What 22 receptor subtypes are receptor subtypes are
involved in fear conditioning?involved in fear conditioning?What What 22 receptor subtypes are receptor subtypes are
involved in fear conditioning?involved in fear conditioning?
Adrenergic receptorsAdrenergic receptors
* Antihypertension* Sedation*Analgesia* Anesthetic sparing effect
ALPHA-2 A
ARTERIAL CONSTRICTION
ALPHA-2 B
*Analgesia*Mood
ALPHA-2 C
ALPHA-2 ADRENERGIC RECEPTORS
Dexmedetomidine (20µg/kg) did not affect encoding of discrete cue fear
conditioning in 2A AR KO mice
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ACTIVITY INITIAL EXPLORATION DISCRETE CUE
Dexmedetomidine did not Dexmedetomidine did not affect discrete cue fear affect discrete cue fear
conditioning in D79N miceconditioning in D79N mice
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ACTIVITY DISCRETE CUEINITIAL EXPLORATION
SummarySummary
• 2 receptor activation during training reduces discrete cue fear conditioning
• 2 receptor activation after training does not
• Dexmedetomidine reduced P-CREB and Fos production in amygdala
• The effect of 2 agonists on addiction is unknown
The role of the The role of the 2A2A AR in AR in
intrinsic fearfulness of miceintrinsic fearfulness of mice
Mice deficient in Mice deficient in 2A2A AR are more AR are more
fearful in the discrete cue testfearful in the discrete cue test
WT 2A AR KO D79N
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Is there any difference in the Is there any difference in the noradrenergic system in noradrenergic system in 2A2A AR AR
deficient mice?deficient mice?
LC and nucleus tractus solitarius (NTS) project to the amygdala
Are activated by the footshock (unconditioned stimulus)
2A2A AR KO mice have a longer AR KO mice have a longer
locus coeruleuslocus coeruleus
WT 2A KO
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The LC cell bodies are bigger The LC cell bodies are bigger in in 2A2A AR KO mice AR KO mice
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There are more TH positive There are more TH positive neurons in the LC of neurons in the LC of 2A2A AR AR
KO miceKO mice
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There are more large neurons There are more large neurons in the LC of in the LC of 2A2A AR KO mice AR KO mice
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Soma Volume (µm3)
ConclusionsConclusions
2A 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)
2A 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 Relevance to Addiction
Do individuals differ in their expression of 2A 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??
ContributorsContributors
Stanford University– Janet Tsui – Judy Flannery– Xiangqi Li– Brian Hoffman
Molecular Research Institute
–Tim DeLorey