Transcript Synaptic Transmission and Neurotransmitters

Neurotransmitters
Chemical communicators
Again: Three Steps for firing
•
Resting potential: voltage is about -70mV
– Dendrites receive incoming signals
– If sufficient, cell goes into firing mode
•
Action potential
–
–
–
–
•
Voltage changes from -70mV to +40mV
Ions exchange places
Repeats itself rapidly down axon
Only in places where myelin sheath doesn’t cover: Nodes of Ranvier
Refractory Period:
–
–
–
–
below resting or lower than -70mV
Cell recovers from firing
Absolute refractor period: Brief time period when cannot fire again
Relative refractory period: Brief time period when difficult for it to fire again.
The Neuron Fires
• Action potential causes nearby Na+ channels to open, so another
action potential is triggered right next to first one, and this continues
all the way down the axon
– Chain reaction
– Like a bunch of dominoes
• Action potential ≠ local potential in several important ways:
– Local potential = graded potential- it varies in magnitude depending on
strength of stimulus that produced it; action potential is ungraded
– Action potential obeys all or none law: occurs at full strength or not at all
– Action potential is nondecremental: does NOT lose strength at each
successive point (local potentials do degrade)
The Neurotransmitter
• Neurotransmitter is chemical
– Several specific kinds- each act on certain neurons
– Most neurons respond to and release one kind of neurotransmitter
• Neurotransmitter stored in synaptic vesicles
• The synaptic vesicles move to and fuse to end of membrane
– Action potential opens channels that allow Ca+ ions to enter terminals
from extracellular fluid
– Ca+ ions cause vesicles nearest the membrane to fuse with membrane
– Membrane then opens and transmitter is dumped into synapse
– Diffuses across synapse to postsynaptic neuron and attaches to
chemical receptor
Action in the Synapse
•
Neurotransmitter is released into the synapse
–
–
•
diffuses across synapse to next neuron’s dendrite
This “next dendrite” is post-synaptic
Neurotransmitter is attracted to the POST-synaptic
side:
–
–
receptor sites on the next neurons dendrites
neurotransmitter must match molecular shape of
receptor site
– Activation of receptor causes ion channels in
membrane to open
Two kinds of Receptor Action
• Ionotropic receptors open channels directly
to produce immediate reactions required for
motor and sensory processing
• Metabotropic receptors open channels
indirectly
– slower: but produce longer-lasting effects
– Sets off graded potentials for next action
potential
• Movement across the synapse is relatively
slow: several milliseconds
Excitation and Inhibition
• The NT opens ion channels on dendrites and soma
• Two effects on local membrane potential:
– shifts in positive direction (towards 0), partially
depolarizing
– Shifts in negative direction (away from 0):
hyperpolarization
• Thus two effects:
– Excitatory: depolarization (moves toward and past 0)
– Inhibitory: hyperpolarization (moves away from 0)
Two kinds of postsynaptic potentials:
• EPSPs: excitatory postsynaptic potentials
– Excitatory effect: increases likelihood of action potential
– Opens Na+ channels
• IPSPs: inhibitory postsynaptic potentials
– Inhibitory effect: decreases likelihood of action potential
– Opens K+ channels
• Thus: bidirectional effects
– Summative effects
– Overall change must be sufficient to produce action
potential
Postsynaptic integration
• Summation across all the IPSPs and EPSPs
– Summates algebraically
– Adds both positive and negatives together
• Two kinds:
– Spatial summation:
• Sum of all IPSPs and EPSPs occurring simultaneously at different locations
along dendrites and cell body
• Must be sufficient number of “hits”
– Temporal summation
• Sum of all IPSPs and EPSPs occurring within a short time
• Must occur within a few milliseconds
• Must get sufficient number of “hits” within certain time
• Neuron is an information integrator!
– A decision maker
– Small microprocessor
•
Remember: Many axons
may be near and
stimulating a neuron
It is the TOTAL
SUMMATION of this that
creates an action potential
Terminating synaptic activity
• Not all neurotransmitter is attached to postsynaptic receptor sites
– Extra must be destroyed or repackaged
– If not: could not limit effects
– LSD is such a drug that does NOT degrade
• Mimics the effects of a neurotransmitter
• “wanders” around in the brain for up to 28 hours
• Neurons are efficient: gets rid of extra
neurotransmitter through
– reuptake
– enzymatic destruction
Destruction via Enzymes
• Enzymes in synapse attack and destroy extra NT
– Specialized enzymes in the synapse seek out and destroy
unused neurotransmitter
– Attach and degradate neurotransmitter
• Examples include:
– e.g., Monoamine oxidase or MAO, acetylcholinesterase
– Drugs such as MAO inhibitors stop this process and
prolong action of dopamine, norepinephrine and serotonin
in synapse:
– e.g., the antidepressant Elavil
Reuptake
• Reuptake: Neuron takes NT back up, recycles it for later use
• There is a specialized autoreceptor that detects how much extra
– Autoreceptors found on the presysnaptic membrane
– That is: on the terminal button
• Specialized transporter attaches to NT and brings it back into cell
• SRI drugs DISRUPT this process: Selective Reuptake INHIBITORS:
– Block reuptake and thus PROLONG the action of the neurotransmitter
–
–
–
–
Serotonin Selective reuptake inhibitors: SSRI
Norepinephrine selective reuptake inhibitors: NSRI
Serotonin/Norepinephrine selective reuptake inhibitors: SNSRI drugs
E.g., prozac, lexapro, wellbutrin, etc.
So: Put it all together
• Neuron receives incoming NT which attaches to receptor sites on
dendrites
– Results in local potentials: excitatory or inhibitory
– If sufficient, produce an action potential
• The action potential involves exchange of ions and opening of cell wall
along axon hillock and nodes of Ranvier
– The action potential is nondecremental or saltatory conduction
– Results in moving down of synaptic vessicles and fusing of synaptic vessicles to
terminal button wall
• Neurotransmitter is released in synapse
–
–
–
–
Most makes it to the next neuron (dendrites)
Some may be degraded by enzymes
Some may be reuptaken
Some may float away
• And so it all begins again, billions of times per minutes.
Neurotransmitters
Two basic kinds of Neurotransmitters
•
Excitatory:
–
–
–
•
Inhibitory:
–
–
–
•
create Excitatory postsynaptic potentials: EPSP's
stimulate or push neuron towards an action potential
effect is merely to produce action potential- no behavioral effect as yet
Create Inhibitory postsynaptic potentials: IPSP's
Reduce probability that neuron will show an action potential
Effect is merely to lessen likelihood of an action potential- again
not talking about behavioral effects just yet!
Some neurotransmitters are both inhibitory and excitatory,
depending upon situation and location
Regulating Synaptic Activity
• Several ways to control synaptic activity
• Three kinds of synapses:
– Axodendritic: targets are dendrites
– Axosomatic: targets are soma
– Axoaxonic synapses
• Most common: Axoaxonic synapses:
– Releases NT onto terminals of presynaptic neuron
– Results in presynaptic excitation or presynaptic inhibition
• This increases or decreases presynaptic neuron’s release of the NT
– Does this by regulating amount of Ca+ entering terminal and thus
increasing/decreasing NT release
Regulating Synaptic Activity
• Several ways to regulate how much neurotransmitter is
released
• Autoreceptor activity:
– Autoreceptors regulate the amount of neurotransmitter
released into the synapse
• Autoreceptors on presynaptic neuron detect amount of
transmitter in cleft; regulate reuptake
– Like a thermostat
– If “temperature” is too low- release more NT
– If “temperature” is too high- release less NT
Glial cells also regulate NT function
• Remember: Glial cells surround and insulate
neurons
– Prevent NT from spreading to other synapses
– Absorb some NT and recycle it for neuron’s reuse
• Can even release NT themselves: particularly
glutamate
– This stimulates presynaptic terminal to increase or
decrease NT release
– Contradicts Dale’s principle that neurons release one
and only one transmitter at all of their synapses.
At least 6 ways of manipulating
neurotransmitter release!
• Alter rate of synthesis: more or less NT
• Alter storage rate: again, more or less NT
– Leaky vesicles
• Alter release: more or less release
• Alter reuptake: more or less
– SSRI’s
• Alter deactivation by enzymes: MAO inhibitors
• Block or mimic receptor site attachment
– Block and prevent attachment to receptors
– Mimic the NT at the receptor site
Individual Neurotransmitters
and their Effects
Specific Neurotransmitters have
specific effects
Why so many neurotransmitters?
• Not only different neurotransmitters, but different kinds of
sub receptors for the same neurotransmitter
• Sub receptors are slightly different versions of the receptor
site for the neurotransmitter
– Allows more specialization
– Allows more refinement of effects
• E.g. dopamine has at least 5 subtypes and short/long
versions of at least one of those subtypes!
– Each has a different role in the processing dopamine
– Each serves a different function, and often a different behavioral
function
Why so many neurotransmitters?
• Neurons can release more than one kind of
neurotransmitter
– Dale’s principle was wrong!
• But, typically release one dominant kind of NT
– Most neurons release fast and slow acting NTs
• But: some release more than one fast
– Very, very complicated…..no where near
understanding the actions completely
Why so many neurotransmitters?
– Release of Neurotransmitter = sending information signal
– Released in response to sensory information
– Produce reaction to the sensory information
– Thus: producing BEHAVIORAL changes
• Neurons tend to be grouped together by the type of
neurotransmitter they release
– Not necessarily “areas”, but often highways
– E.g., a dopamine pathway is composed of mostly dopamine neuronst
which travel from one part of the brain to another
– Neurons travel in groups:
– In the CNS: these are called TRACTS
– In the PNS: these are called NERVES
Behavior vs. Neural Effects
• An “excitatory” neurotransmitter INCREASES the
likelihood of an action potential
• An “inhibitory” neurotransmitter DECREASES the
likelihood of an action potential
• This is different than the behavioral effect:
– An inhibitory neurotransmitter or drug may cause
EXCITATION behaviorally!
– Alcohol: inhibits the inhibitory parts of the brain
• The part that says “don’t do that”
• The effect is EXCITATION of stupid behavior
Substance P
Neuropeptide Y
Acetylcholine or ACh
•
•
Location
–
–
primarily in brain, spinal cord
target organs of autonomic nervous system
Two kinds of receptors
–
–
•
•
•
–
–
–
•
•
•
•
Nicotinic:
nicotine stimulates
Excitatory; found predominately on neuromuscular junctions
Muscarinic
Muscarine (mushroom derivative) stimulates
Both excitatory AND Inhibitory; found predominately in brain
Indicated effects:
excitation or inhibition of target organs
essential in movement of muscles
important in learning and memory
Too much: muscle contractions- e.g. atropine poisoning
Too little: paralysis: curarae and botulism toxin
Norepinephrine or NE
•
Called epinephrine in peripheral nervous system
–
–
•
Also a hormone in peripheral system: adrenalin
Chemically extremely similar to Dopamine, serotonin
Located in
–
–
brain, spinal cord
certain target organs (heart, lungs)
•
At least two kinds: NE alpha and NE beta
•
Indicated effects:
–
–
Primarily excitatory
Fear/flight/fight system
•
•
Too much: overarousal, mania, cardiac issues
Too little: underarousal, depression, cardiac issues
•
Drugs such as sudafed may affect NE
Dopamine or DA
•
•
•
–
–
–
–
–
–
–
–
•
•
•
•
–
–
Location:
primarily in brain
frontal lobe, limbic system, substania nigra
At least 5 subtypes in two groupings:
D1-like: D1 and D5
D2-like: D2, D3 and D4, with D2-short and D2-long
Indicated effects:
inhibitory: reduces chances of action potential
involved in voluntary movement, emotional arousal
reward learning and motivation to get reward
•
•
Critical for modulating movement and reward motivation
Primary task is to inhibit unwanted movement
Responsible for motivation to get reward: movement and initiative
Too little: Parkinson's disease:
Treatment: INCREASE available DA via L-Dopa
Too much: schizophrenia
Treatment: REDUCE available DA via antidopaminergics/antipsychotics
Amphetamines mimic this neurotransmitter
Serotonin or 5HT
•
Located in brain and spinal cord
–
–
–
5-hydroxy-tryptomine
Lots of 5HT receptors in the gut!
Again at least three subtypes:
•
•
5-HT1A, 5-HT1C and 5-HT2
Indicated effects
–
–
–
Both inhibition and excitation
Important in depression, sleep, digestion and emotional arousal
chemically very similar to NE and DA
•
Too little is linked to depression and sleep disorders
•
Too much: Serotonin syndrome: confusion, twitching and trembling, dilated pupils,
shivering, goosebumps, headache, sweating and diarrhea., irregular and fast heartbeat
•
Many antidepressants are specific to this NT
–
–
SSRI’s
Block reuptake of 5HT in the synapse
Amino Acids
• Gamma-aminobutryic Acid or GABA
– Predominant inhibitory NT
– GABA deficiency related to epilepsy, seizure disorders
– Receptors respond to alcohol
• At first is increased sedative effect
• Gradually alcohol kills the GABA receptors, then the neurons
• Alcohol also acts on DA, NE and 5HT
– Benzodiazepines mimic or act like GABA
– Too much: oversedation, over-relaxing of muscles (including heart,
respiration)
– Too little: anxiety! (so why does Valium reduce anxiety?)
Amino Acids
• Glutamate:
– Principal excitatory NT in central nervous system
– Critical for learning: it is Glutamate and the NMDA receptors that allow for
long term potentiation
– May play significant role in schizophrenia: disrupts regulation of DA, NE, Ach,
5HT.
• Affects memory formation
• Affects arousal
• Affects processing of emotions
• Glycine:
– Inhibitory NT in spinal cord and lower brain (brain stem)
– Regulates motor activity by inhibiting unwanted movement
– Strychnine poisoning: alters glycine activity and results in death
Neuromodulators:
Neuropeptides and Gases
• Neuromodulators:
• do not directly excite or inhibit postsynaptic neuron
• increase or decrease release of NT by altering response of postsynaptic cells to
various inputs
• In a way, are helpers to neurotransmitters
• Peptides = chains of amino acids
– Endorphins: related to regulation of pain and feeling of reinforcement
– Substance P: transmitter involved in sensitivity to pain; may also be
important in schizophrenia
– Neuropeptide Y: critical for regulating metabolic functions, especially eating
• Gases such as Nitric Oxide:
– serves as retrograde NT (that is, a backwards NT)
– influences presysnaptic membrane’s release of NT
– Viagra: increases nitric oxide’s ability to relax blood vessels
– produce penile engorgement
– But, moves blood from head, chest to penis
– Related to eye problems and can cause heart arrhythmias
Take home lesson
• Many, many Neurotransmitters
• Neurotransmitters interact with one another, affect one
another
• Your diet, drugs, behavior lead to changes in the
neurotransmitters changes in body function and
behavior
• Be aware of what you eat, what drugs (including OTC or
herbal) you take, how your behavior may change your
brain.