L3 Pharmacological Modulation of Memory Flashcards
What is memory?
Memory is a term given to the processes and structures involved in the storage and subsequent retrieval of information
3 stages of memory
- Encoding
- Storage
- Retrieval
2 major forms of memory
- Explicit (declarative) memory - conscious attention necessary for recall
- Implicit (procedural) memory - unconsciously recalled
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
Lesions to the network formed by different neuronal populations within the hippocampus affect…
functional connectivity and cause memory impairment
Relay centre for memory storage
Hippocampus
How was learning and memory linked to the hippocampus?
Patient H.M. had 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
Basically cells that fire together wire together (synaptic efficacy arises from presynaptic cell repeatedly stimulating postsynaptic cell)
A key aspect of memory is __
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 (or low Mg2+)
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 glutamate response
What is 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→activation of Ca/calmodulin-dependent protein kinase→phosphorylation of non-NMDA (AMPA) receptors (to increase sensitivity to glutamate)
- Repeated AP trains activate NMDA receptors, activating AC→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…
PFC tasks
Attention enhancer than inhibits DAT
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
True or False: Environmental effects modify learning
True
