Pharmacological Modulation of Memory Flashcards
What is memory?
the term given tot he process and structures involved in storage and subsequent retrieval of information
3 stages of memory
- Encoding: - sensory input is relayed into the brain (thalamus - processing centre) and is subsequently relayed into e.g., occipital lobe towards the visual cortex or amygdala for fear responses → determine how we will interpret that experience (i.e., if that information is attended to or not) SUBJECTIVE
- Storage: - associated with neural networks, in short term can be quite plastic → through rehearsal these memories are maintained - consolidates memory, which can lead to long term encoding which can be easily retrieved
- Retrieval
Explicit (Declarative) Memory
Facts, Events, People, Places and object
→ mainly mediated in the hippocampus
→ conscious attention is necessary for recall
Implicit (Procedural) Memory:
Unconsciously recalled
→ Skill & Habits: Striatum, affected in PD - affecting motor functions
→ Associative learning: Amygdala (Emotional response) & Cerebellum (Movement skills)
→ Non-associative learning: Habituation and sensitisation - reflex pathways which we can’t consciously control but can affect attention
What is meant by “Semantics”?
to make meaning of something - is it a good or bad memory - i.e., is it a good or bad experience, depending on the impact it made determines whether or not it gets processed into a longer term memory
Factors which can affect memory in a negative way
- Old age
- Stress
- ADHD
- Schizophrenia (Negative Symptoms)
- Anxiety/Depression
- Sleep Deprivation
How does electroshock therapy affect memory?
Has a serious negative impact on retrograde memory
ADHD is believed to be due to…
a lack of connection between neurons in the prefrontal cortex
Relay centre for memory storage
Hippocampus
How was learning and memory linked to the hippocampus?
Patient H.M.
→ intractable temporal lobe epilepsy. Bilateral removal of H.M.’s temporal lobe & hippocampus cured his epileptic seizures. Declarative memory was impaired. Procedural memory was intact.
Age-associated hippocampal atrophy corresponds to..
cognitive decline
Hebb’s Rule
Cells that fire together wire together (synaptic efficacy arises from presynaptic cell repeatedly stimulating postsynaptic cell)
A key aspect of memory depends on
Glutamate
NMDA glutamate receptor
-heteromeric ion channel
- 4 subunits (2x NR1, 2x NR2)
- glutmate binds NR2
- glycine (co-agonist) binds NR1
NMDA receptor antagonists
Memantine, Amantadine, Ketamine, PCP (angel dust)
Overactivation of glutamate receptors can induce
Excitotoxicity
What minerals can inhibit the NMDA receptor
Zinc and magnesium
Resting membrane potential of a neuron
-40mV
Competitive inhibitor of the active site of the NMDA receptor
APV
Selective competitive AMPA receptor antagonist
CNQX
What is the net result of administering APV and CNQX together?
No Glutamte Response
Long term potentiation
A lasting, activity-dependent increase in synaptic efficacy (repeated firing of neurons strengthens synaptic connections)
Molecular changes in LTP
- Glutamate activation of NMDA receptors allow Ca influx which activated Ca/calmodulin-dependent protein kinase, causing phosphorylation of non-NMDA receptor channels to increase sensitivity to glutamate
- Repeated AP trains activate NMDA receptors, activating AC and a sensitisation cascade
- Late LTP is thought to give rise to growth of new synaptic connections
What is a potential target for novel memory enhancers, and why?
CREB transcription factor - transcribes genes involved in forming new synaptic connections
NMDA antagonists in the amygdala block acquisition, but not expression, of….
fear learning
What is the name given to drugs that enhance cognition (in clinical development)?
Nootropics
Examples of nootropics
- AMPakines
- MEM1414 prolongs CREB activity (PDE inhibitor)
- GABAb receptor antagonists
- Estrogen (anabolic steroid)
- 5-HT6 receptor antagonists
What can act as a partial agonist at the glycine site of NMDA receptors to facilitate extinction of fear memories?
D-cycloserine (combined with CBT)
How does nicotine act as a cognitive enhancer
- Stimulation of nAChRs leads to enhanced NT release in brain areas
- Low conc of nicotine can enhance performance in individuals with compromised nicotinic function, however, when an individual’s performance is already at optimum levels, nicotine impairs performance
Most robust effects of nicotine are seen in tasks that have…
a high attentional requirement
Increased smoking in patients with…
ADHD and schizophrenia
Sensorimotor gating inhibition deficit in schizophrenia has been linked to
nAChα7 subunit gene (reduced number in hippocampus of patients)
What are in development for improving cognitive symptoms of schizophrenia
α7-nicotinic agonists
Examples of pharmacological agents that can regulate PFC function
- D1 receptor agonist (A77636) - improves (low dose) and impairs (high dose) working memory in monkey
- Guanfacine (agonist at postsynaptic α2A-adrenoceptors) - improves working memory in WT mice, but no benefit in α2A-KO mice
Most effective treatments for ADHD facilitate
catecholamine transmission
Drug treatments for ADHD
- Methylphenidate (Ritalin) - blocks DA & NA transporters (approved)
- Amphetamines (e.g. Adderall) - block DA & NA transporters (approved)
- Atomoxetine (inhibits NA transporters)
- Guanfacine (NA mimetic)
Methylphenidate improves performance of
Prefrontal cortex tasks
Attention enhancer than inhibits dopamine transmission
Modafinil (approved drug treatment for individuals with attention deficit)
What is Caffeine?
An adenosine receptor antagonist that interacts with GABAergic and dopaminergic neurotransmission
Potential MCI therapeutics
- AChE inhibitors
- Anti-oxidants
- Anti-inflammatories
- Glu receptor modulators
- Nootropics
- Immunomodulators
