Exam 1 Week 2: ppt 10 Synaptic Pharmacology, Plasticity & Pathophysiology Flashcards
Steps in chemical synaptic transmission that drugs can act on (5)
- Transmitter Synthesis
- Transmitter Reuptake
- Transmitter Release
- Transmitter-receptor interaction
- Inhibition of Breakdown - Enzyme inhibitors
Eample of drug acting at transmitter synthesis
L-DOPA is a dopamine (DA) precursor & given when DA lacking such as in Parkinson’s Disease
Examples of drugs that work on transmitter reuptake
- –Reuptake inhibitors
- –Selective serotonin reuptake inhibitors (SSRIs)
- –Serotonin & Norepinephrine reuptake inhibitors (SNRIs)
Transmitter Re-uptake– commonly Reuptake inhibitors such as Selective serotonin reuptake inhibitors (SSRIs) which as their name implies block the reuptake of serotonin and leaves more in the synaptic gap and Serotonic Norepinephrine Reuptake Inhibitors (SNRIs) which as their name implies block the reuptake of serotonin and norepinephrine and leaves more in the synaptic gap. Both of these agents are used in the treatment of depression which has been related to low levels of both serotonin and norepinephrine
Examples of drugs that affect Transmitter release
–Amphetamine stimulates DA release
–Botox (botulinus toxin) blocks ACh release
Examples of drugs that affect Transmitter-receptor interaction
- –“Blockers” or “antagonists” - beta-blockers
- –“Agonists” or “mimetics” – DA agonists
- –Enhance affinity of transmitter for receptor – benzodiazepines affect GABA receptors
Transmitter–receptor interaction
“Blockers” or “antagonists” such as beta-blockers which block beta-adrenergic receptors for norepinephrine and are used in a variety of cardiovascular conditions and as an drug to prevent stage fright
“Agonists” or “mimetics” such as dopamine agonists used in Parkinson’s disease
Enhance affinity of transmitter for receptor – such as the tranquilizers/anti-anxiety medications the benzodiazepines which increase the affinity of GABA for its receptors
Examples of drugs that affect Inhabigion of Breakdown - Enzyme inhibitors
- –Acetylcholinesterase inhibitors block breakdown of ACh
- –MAO inhibitors affect NE & DA breakdown
Acetylcholinesterase inhibitors block breakdown of ACh which are used in memory disorders
Monoamine oxidase inhibitors (MAOIs) which block the breakdown of catecholamines such as norepinephrine and dopamine. Used in the treatment of depression which has been related to low levels of norepinephrine and in Parkinson’s disease due to low levels of dopamine
Snyaptic Plasticity
- Change in synaptic function and structure secondary to experience (sensory input) or repetitive activities
- Long-term experienced alterations in the strengths of synaptic relationships may underlay plasticity to some degree
Synaptic plasticity is a Change in synaptic function and structure secondary to experience (sensory input) or repetitive activities
Long-term experienced alterations in the strengths of synaptic relationships may underlay plasticity to some degree
Post-Tetanic Potentiaion
- –A form of short-lived synaptic plasticity
- –Involves increased transmitter release by a single action potential following repetitive stimulation of a synapse
- –Requires seconds to develop and lasts tens of seconds to several minutes after cessation of tetanic stimulation
- –PTP occurs PNS & CNS
- –May be mechanism of short-term memory
- –Involves increase Ca++ influx & activation of calmodulin with a subsequent increased activation of myosin light chain kinase (MLCK)
- –This activates increased release of both fast transmitter pool & slow pool
One form of short-term synaptic plasticity is Post-Tetanic Potentiation (PTP) it Involves increased transmitter release by a single action potential following repetitive stimulation of a synapse. Requires seconds to develop and lasts tens of seconds to several minutes after cessation of tetanic stimulation. Post-Tetanic Potentiation occurs PNS & CNS
Post-Tetanic Potentiation (PTP) May be mechanism of short-term memory when seen in the CNS
Involves increase Ca++ influx & activation of calmodulin with a subsequent increased activation of myosin light chain kinase (MLCK) which produces more release of neurotransmitter from pre-synaptic endings when they are activated
Long-term potentiation
- •Long-term potentiation (LTP)
- –Long-lasting enhancement in signal transmission between two neurons that results from synchronous stimulation
- –Enhanced strength of linkage from synaptic plasticity
- –Memories are perhaps encoded by this modification of synaptic strength – memory consolidation
- –Produced by application of a series of tetanic bursts to a neural pathway.
- –Produces a long lasting enhancement of activity in the pathway
Long-term potentiation (LTP) is a Long-lasting enhancement in signal transmission between two neurons that results from synchronous stimulation which occurs as a result of synaptic plasticity. Memories are perhaps encoded– memory consolidation - by this modification of synaptic strength
Long-term potentiation (LTP) is a long lasting enhancement of activity in the pathway Produced by application of a series of tetanic bursts to a neural pathway.
Long-Term Potentiation: reasons linking LTP with learning/memory
- Development of added dendritic spines – increased number & strength of synaptic connections
- Both develop added neurotransmitter receptors on dendritic spines to strengthen synaptic connections
- Both associated with glutamate binding to NMDA receptors & non-NMDA receptors such as metabotropic glutamate receptors or AMPA receptors
- Strengthened by neurotrophic factors such as brain derived neurotrophic factor (BDNF)
- Similar time course of development
- Tetanic burst most effective in producing LTP is at the same frequency a theta electroencephalographic (EEG) frequency
- Memory consolidation is best accomplished during activities when the brain is in theta rhythms such as in REM sleep
There are several reasons that a physiological change like Long-term potentiation (LTP) has ben linking with learning/memory. For instance with Long-term potentiation there is the Development of added dendritic spines which is related to the increased number & strength of synaptic connections seen with memory consolidation
In both Long-term potentiation (LTP) and memory consoliation there are added neurotransmitter receptors on the added dendritic spines which further strengthens synaptic connections
Both Long-term potentiation (LTP) and memory conslidation are associated with glutamate binding to NMDA receptors & non-NMDA receptors such as metabotropic glutamate receptors or AMPA receptors
Both Long-term potentiation (LTP) and memory conslidation are associated with Strengthening by neurotrophic factors such as brain derived neurotrophic factor (BDNF). Oth have a similar time course of development and one of the common patterns of Tetanic burst most effective in producing LTP is at the same frequency a theta electroencephalographic (EEG) frequency that is associated with memory consolidation.
Theta EEG rhythms are those seen in REM sleep which has been associated with memory consolidation.
Cellular Mechanisms that enhance strength of synaptic transsiion
- –Increased fraction of available presynaptic vesicles released (25% to 50%) – no structural changes seen with this mechanism
- –Number of synaptic vesicles available for release increased (fast & slow pool)
- –Number of release sites along the presynaptic membrane – requires enchanced RNA and protein metabolism
- –Increased sensitivity of post-synaptic receptors – also does not require an anatomical change
- –Increased number of post-synaptic receptor sites
- –New synaptic contacts between cells - synaptogenesis
As mentioned previously, there are several Cellular Mechanisms that enhance strength synaptic transmission, These including the following pre-synaptic mechanisms:
Increased fraction of available presynaptic vesicles released (25% to 50%) – no structural changes seen with this mechanism just more presynaptic transmitter is available for immediate release
Number of synaptic vesicles available for release increased (increases in both the fast & slow pool of vesicles)
Number of release sites along the presynaptic membrane – requires enchanced RNA and protein metabolism
Also as mentioned previously, there are post-synaptic changes that enhance strength synaptic transmission
Increased sensitivity of post-synaptic receptors – also does not require an anatomical change
Increased number of post-synaptic receptor sites – seen as an enhancement of the post-synaptic density
New synaptic contacts between cells - synaptogenesis
Two things that produce increased number & strength of synaptic connections
- •Development of added dendritic branching density
- •Development of additional dendritic spines
____________________ may also contribut to plasticity.
•Silent synapses activation may also contribute to plasticity
Silent synapses activation may also contribute to plasticity. Seen in glutaminergic synapses with the addition of AMPA receptors in the post-synaptic neuron as a result of the activation of normally “silent” NMDA receptors. Activation of the NMDA receptors will generate the production of more AMPA receptors and enhance the post-synaptic effect.
Reversal of any of these may lead to long-term depression (LTD)
Silent synapses activation may also contribut to plasticity. Where this this seen? How? Waht happens if there is reversal?
- •Silent synapses activation may also contribute to plasticity
- –Seen in glutaminergic synapses with the addition of AMPA receptors in the post-synaptic neuron
- –Glutaminergic synapses with only NMDA receptors may be electrically slient
- •Reversal of any of these may lead to long-term depression (LTD)
Silent synapses activation may also contribute to plasticity. Seen in glutaminergic synapses with the addition of AMPA receptors in the post-synaptic neuron as a result of the activation of normally “silent” NMDA receptors. Activation of the NMDA receptors will generate the production of more AMPA receptors and enhance the post-synaptic effect.
Reversal of any of these may lead to long-term depression (LTD)
Parkinson’s Disease (PD)
•In PD there is a degeneration of dopamine (DA) producing cells in the substantia nigra and a substantial reduction in the synthesis of DA
