CNS neurotransmission - Craviso Flashcards
Regions of the brain are specialized based on what?
Function.
Describe some characteristics of neurons.
- are the individual signaling elements of the CNS
- mediate signaling via neurotransmitters
- the average neuron forms 1000 synaptic connections and receives even more
- their activity is dependent on the ratio of excitatory to inhibitory inputs to that neuron
Can a nerve cell body have both excitatory and inhibitory inputs?
Yes.
Can nerve terminals receive inputs?
Yes.
Name the main categories of neurotransmitters involved in CNS pharmacology.
- small molecules
- amino acids
- neuropeptides
- endocannabinoids
Name the small molecule type neurotransmitters.
- Serotonin - 5-HT
- Norepinephrine - NE
- Dopamine - DM
- Acetylcholine - Ach
- Histamine
These neurotransmitters mediate higher functions and can be found in the peripheral NS also.
What functions are mediated by Serotonin?
Mood, sleep, arousal, behavioral changes, hallucinations, vomiting and appetite.
What functions are mediated by NE?
Mood, arousal, cardiovascular control and appetite.
What functions are mediated by Dopamine?
Movement (motor control), behavior, mood and perception.
What functions are mediated by Ach?
Arousal, cognition (such as memory and learning).
What functions are mediated by histamine?
Wakefulness and equilibrium.
What do antidepressants modify?
They primarily work on the neurotransmitters that mediate mood.
What can be a consequence of anti-depressant use?
They work on neurotransmitters that mediate mood - but these neurotransmitters also mediate other functions - like appetite and arousal - so antidepressants can effect these functions as well as mood.
What are the amino acid type neurotransmitters?
- Glutamate
2. GABA
What are the main functions of glutamate and GABA?
They are found primarily in the CNS and they mediate major excitatory (glutamate) and inhibitory (GABA) neurotransmission.
Name the neuropeptide type neurotransmitters.
- Methionine
- Leucine enkephalin
- Substance P
These neurotransmitters are found in the peripheral NS also.
What functions do the neuropeptides mediate?
They mediate pain transmission.
What are the Endocannabinoid type neurotransmitters?
- Anadamide
2. 2-arachidonyglycerol
What functions do the Endocannabinoids mediate?
They mediate memory, cognition and pain perception.
What is unique about the Endocannabinoids?
They are produced in the postsynaptic neuron and are involved in retrograde transmission.
What are two main patterns of neuronal connectivity?
- long-heirarchical or relay
2. nonhierarchical projecting
Describe long-heirarchical connections.
- transmission is highly sequential
2. interconnected neurons are related to each other in a hierarchical manner
What is an example of a long-heirarchical connection?
Primary sensory and motor pathways. For example if a pain receptor in the periphery is activated it sends the signal to the brain via neurons in the spinal cord.
Describe nonhierarchical connections.
- Neurons from a single anatomical location extend multiple, divergent connections to target cells outside the region in which the neurons originate.
- most connections in the brain are this type.
Describe serotonin neurons.
- project from the Raphe nucleus with ascending and descending projections
- nonhierarchical type connections
- mediate:
mood, sleep, arousal, behavior and hallucinations - frontal cortex
appetite - hypothalamus
vomiting - brainstem
Describe NE neurons.
- nonheirarchical type connections
- project from the locus coeruleus
- mediate:
mood and arousal - frontal cortex
appetite- hypothalamus
cardiovascular control - brainstem
Describe dopamine neurons.
- nonheirarchical type connections
- project from the midbrain, striatum and hypothalamus
- 3 main pathways:
nigrostriatal - mediates motor control
tuberoinfundibular - mediates neuroendocrine function (such as prolactin secretion)
mesocortical/mesolimbic - mediates mood, behavior changes and vomiting
Describe cholinergic (Ach) neurons.
- nonheirarchichal type connections
- project from the forebrain - basal forebrain pathway and the brainstem- mesopontine pathway
- mediate:
arousal (frontal cortex via basal forebrain pathway), learning and memory (basal forebrain pathway), motor control (in concert with dopamine) - effects via muscarinic (G-protein linked) receptors and via nicotinic (ionotropic) receptors located presynaptically
What are ionotropic receptors?
These are receptors that are ion channels. The neurotransmitter binds directly to this receptor.
Describe histamine neurons.
- nonheirarchichal type connections
- project from hypothalamus via the tuberomammilary nucleus
- mediate arousal wakefulness and equilibrium via the cerebellum
What are some major mechanisms by which the actions of neurotransmitters are modulated?
- pre-synaptic modification
- post-synaptic modification
- neurohormone modification
- neuromodulators
- effects on voltage-gated ion channels
- non selective effects
What are some pre-synaptic modifications to neurotransmitters?
- effects on synthesis
- effects on storage
- effects on release
- effects on reuptake and or degradation
- agonist activity at nerve terminal auto receptors
- antagonist activity at nerve terminal auto receptors
What do nerve terminal autoreceptors do?
They modulate how much neurotransmitter is released.
How is most neurotransmitter action ended?
Via reuptake into nerve terminal.
Where else can neurotransmitter be taken up?
Into glial cells.
What are some post-synaptic modifications to neurotransmitters?
- receptor agonists
- receptor antagonists
- modulatory activity
- degradation of neurotransmitters
If degradation happens in the synaptic cleft, is this pre or post synaptic modification?
Post synaptic.
If degradation of neurotransmitter happens in the neuron, is this pre or post synaptic modification?
Pre synaptic.
What is an example of non selective effect type of neurotransmitter modification?
The use of anesthetics. These drugs are said to have non selective effects because it is unknown which neurotransmitter system or ion channel they work on.
What is one exception to the trend that most neurotransmitter action is ended via reuptake?
Acetylcholine is degraded in the synaptic cleft by acetylcholinesterase instead of being taken back up by the nerve terminal.
What are metabotropic receptors?
They are G-protein coupled receptors. They are the most common type outside of the CNS.
Responses to binding of metabotropic receptors occur within what timeframe?
Within several hundreds of milliseconds and last for seconds to minutes.
What kinds of receptors are metabotropic?
- all known alpha and beta adrenergic receptors (bind E and NE)
- muscarinic acetylcholine receptors
- histamine receptors
- neuropeptide receptors
- endocannabinoid receptors
- some glutamate and GABA receptors
- most serotonin receptors
What type of serotonin receptor is not a metabotropic receptor?
5-HT3 receptors. These receptors are located in the brain and are important in vomiting.
Describe how G-protein coupled receptors work in general.
- neurotransmitter binds to receptor
- binding causes a G protein to be activated
- G protein subunits or intracellular messengers modulate an ion channel
- ion channel opens
What are ionotropic receptors?
These are ligand gated ion channels. They are also found outside the CNS - predominately at the neuromuscular junction.
Responses to ionotropic receptors occur within what timeframe?
Responses occur within a few milliseconds and last for only milliseconds.
Name the two general types of ionotropic receptors.
- those that cause a depolarization of the cell
2. those that cause hyper polarization of the cell
What receptors when bound cause a depolarization of cells?
- AMPA receptors - let Na in
- Kainate receptors - let Na in
- NMDA receptors - predominately let calcium in but can also let sodium in
- nicotinic Ach receptors - primarily let sodium in but can also let calcium in
- 5-HT3 receptors - let in sodium
Receptors in the CNS that cause depolarization when bound respond to what neurotransmitter?
Glutamate.
What receptors when bound cause hyper polarization of cells?
- GABAa receptors - let chloride in
2. glycine receptors - let chloride in
Receptors in the CNS that cause hyper polarization when bound respond to what neurotransmitter?
GABA and glycine.
Excitatory inputs to CNS neurons are mediated by what neurotransmitter?
Glutamate.
Inhibitory inputs to CNS neurons are mediated by what neurotransmitter?
GABA.
GABA is typically released from what type of neurons?
Small interneurons.
Describe the interplay between excitatory and inhibitory inputs to CNS neurons.
- Excitatory transmission is balanced by feed forward and recurrent inhibitory actions of GABA released from interneurons
- inputs t neurons are paired to achieve a coordinated balance between excitatory (EPSP) and inhibitory (IPSP) events but inhibitory neurotransmission predominates
- interference in this balance is disruptive and can lead to extreme conditions like comatose and seizures
Describe feed forward inhibition.
This occurs when glutamate acts on a neuron to cause an EPSP and also acts on a ‘connected’ interneuron. Glutamate causes an excitation of that interneuron which releases GABA that feeds back on the neuron to dampen down the excitatory effects of glutamate.
Describe recurrent inhibition.
This occurs when glutamate excites a neuron. This neuron has a collateral that works on a ‘connected’ interneuron. The interneuron is excited to release GABA that feeds back on the neuron to dampen down the excitatory effects of glutamate.
What type of neurotransmission predominates?
Inhibitory transmission mediated by GABA.
Describe some characteristics of GABA.
- synthesized from glutamate by glutamic acid decarboxylase
- pyridoxal phosphate is required for the synthesis of GABA
- metabolized by GABA-amino transferase found in the mitochondria of neurons and glial cells
- can bind to both ionotropic and metabotropic receptors
How are the actions of GABA terminated?
Reuptake via the nerve terminal and glial cells.
What is the therapeutic strategy for seizures?
Enhance GABAergic transmission and attenuate glutanergic transmission.
Describe GABA-A receptors.
- ionotropic receptors
- found on postsynaptic neurons
- cause hyperpolarization of the cell
Describe GABA-B receptors.
- metabotropic receptors
- found at the nerve terminal - functions to decrease the amount of GABA that is released
- Also found on the postsynaptic membrane - modulates the action of GABA
GABA-B receptors on the nerve terminal act how?
They decrease calcium influx and hence decrease the release of GABA.
GABA-B receptors on the postsynaptic membrane act how?
They work by a couple different mechanisms. One is that some are coupled to activation of potassium channels that mediate the production of slow inhibitory synaptic currents. The other is that some cause a decrease in calcium conductance which tends to cause hyper polarization. They also regulate IP3 production and/or inhibit cAMP production. All of these mechanisms work to modulate the actions of GABA.
What is special about GABA-B receptor modulation?
It extends beyond the modulation of GABA alone. This receptor is also on the nerve terminals of glutamate neurons. GABA that diffuses away from the synaptic cleft where it is released can bind to these receptors and cause a decrease in the release of glutamate, leading to a smaller excitatory effect.
What is Baclofen?
This drug is an analog of GABA that acts as an agonist at GABA-B receptors in the spinal cord. It is used to treat spasticity in individuals with amytrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Another name is Lioresal.
What is another name for Baclofen?
Lioresal
Which receptors mediate the majority of effects mediated by GABA?
GABA-A receptors. These are ion channels that conduct chloride leading to the hyper polarization (IPSP generation) of a postsynaptic cell.
What are the two types of GABA neurotransmission?
Phasic and Tonic.
Describe phasic GABA neurotransmission.
- GABA binds to the postsynaptic membrane at the synaptic cleft
- binding results in the rapid, synchronous opening of chloride channels and hyper polarization and inhibition occur
- GABA is taken back up (some but not all) and its actions at the synaptic cleft are terminated
Describe tonic GABA neurotransmission.
- GABA diffuses outside of the synaptic cleft and binds to extra synaptic receptors
- this binding results in a continuous activation
Describe inhibitory neurotransmission via glycine.
- actions are identified primarily in the spinal cord and involve control of motor rhythm generation, coordination of reflex responses and processing of sensory signals
- there are some actions also in the brain stem and reticular formation
- these receptors are chloride conduction channels that lead to hyper polarization
- there are no metabotropic glycine receptors
Are there therapeutic agents currently in use that can act at glycine receptors?
No
What is strychnine?
This is a natural ingredient of certain seeds that is the active ingredient of rat poison. It is an antagonist of glycine receptors and a powerful convulsant (blocking inhibitory transmission leads to seizures).
Describe glutamate neurotransmission.
- is excitatory
- glutamate works on both metabotropic and ionotropic receptors
- termination of action involves reuptake
Describe how the actions of glutamate are terminated.
- glutamate is taken up by the nerve terminal or glial cells (astrocytes)
- it is converted to glutamine and if in a glial cell the glutamine is pumped out for the neuron to take up for formation of more glutamate
What is the dominant place for glutamate uptake?
The majority of glutamate is taken up by astrocytes to be metabolized.
What are the types of metabotropic receptors for glutamate?
- there are three types that are located on the nerve terminal (Group I), the postsynaptic membrane (Group II) and on astrocytes (Group II)
- Group I augment the responses of glutamate
- Group II decrease responses to glutamate
What are the 2 types of ionotropic glutamate receptors?
- NMDA receptors
2. NON-NMDA receptors - AMPA receptors and Kainate receptors
Describe AMPA receptors.
- primarily conduct sodium but some are permeable to calcium
- mediate the majority of excitatory synapses
- play a major role in neural plasticity
Describe Kainate receptors.
- primarily conduct sodium but some are permeable to calcium too
- located both pre and post synaptically
- physiologic role not known but do play a role in neural plasticity
Describe NMDA receptors.
- ionophores that primarily conduct calcium but can also conduct sodium
- are essential mediators of neural plasticity and are capable of converting specific patterns of neuronal activity into long term changes in synapse structure and function - therefore play a role in memory and learning
- contain external binding sites for glutamate and glycine (acts as a co-agonist here)
- contain an internal binding site for magnesium
- at membrane potentials more negative than -50 mV the Mg binds inside the receptor pore and blocks it
- requires a strong stimulus to open
How are NMDA receptors opened?
Activation requires a strong depolarizing stimulus such as repetitive stimulation or coordinated input from many synapses. It also requires the binding of both glutamate and glycine simultaneously. If these conditions are met then the Mg is displaced and the channel opens.
How do NMDA receptors mediate neural plasticity?
Via long-term potentiation or long-term depression.
Describe long term potentiation.
- happens in time frame of hours to days
- lots of glutamate action leads to activation of NMDA receptors
- this allows calcium to go through the pore
- early effects of calcium lead to an increase in AMPA receptors at the membrane and thus an increase in the cell’s sensitivity to glutamate
- long term effects of calcium lead to gene expression including an up regulation of the production of AMPA receptors
- LTP actually changes the structure of the synapse
Describe long term depression.
- long, sustained, low grade depolarization of NMDA receptors leads to a decrease in the number of AMPA receptors at the membrane and thus a decrease in the sensitivity of the neuron to glutamate
- this is a way for connections to be pruned
What can happen with excessive activation of NMDA glutamate receptors?
Excitotoxicity.
Excessive activation of NMDA receptors can result from what?
- ischemia
- stroke
- head injury
- hypoglycemia
- repeated intense seizures
What are the mechanisms of excitotoxicity?
- large increases of neuronal calcium (due to NMDA receptors and voltage gated calcium channels) over-activate a variety of cellular process controlled by calcium
- NO alone or in combination with superoxide free radicals contributes to the death of the neuron
- NMDA receptors can also let sodium in and the cell will swell in response to this contributing to neuronal death
Excitotoxicty is thought to play a role in what?
Neurodegenerative disorders such as Alzheimer’s.
