CNS Neurotransmission Information Flashcards
The brain is made of
neurons and glia
neurons
Neurons (~100 billion in the brain); each neuron can synapse with many other neurons
o Cell body, dendrites, axon
glia
Glia—largely not well understood; include astrocytes, oligodendrocytes, microglia
o May have roles in inflammation, brain injury, infection, myelination, neurotransmitter uptake, and more
Neurotransmission
- How the neurons in the brain communicate with each other
- Synapse: space between two neurons where neurotransmission occurs
- Neurotransmission between neurons is usually chemical (using neurotransmitters, neuropeptides, etc)
Chemical neurotransmission
- Synthesis of neurotransmitter
- Packaging of neurotransmitter
- Release of neurotransmitter
- Receptors for neurotransmitter
- Reuptake of neurotransmitter from synapse
- Degradation of neurotransmitter
Synthesis of neurotransmitter
! Therapeutics can target production of neurotransmitter
Packaging of neurotransmitter
o Vesicles
o Active transport is needed to concentrate neurotransmitter into vesicle (requires ATP)
o Vesicular monoamine transporter (VMAT) serotonin (5HT), norepinephrine (NE), dopamine (DA)
o Therapeutics can block packaging of neurotransmitter, causing their concentration in the axon terminal space to rise
Release of neurotransmitter
- o Action potential! Turning electrical signal within the neuron into a chemical signal between neurons
- o Action potential induced depolarization of the membrane at the axon terminal causes opening of calcium channels which are essential for vesicular release
- o Classic neurotransmission: neurotransmitter released from axon terminal (presynaptic neuron) acts on either pre- or post-synaptic receptor
- o Retrograde neurotransmission: neurotransmitter is released from post-synaptic neuron and acts on pre-synaptic neuron (like negative feedback), Ex: endocabbinoids
- o Therapeutics can block calcium channels and block neurotransmitter release, or can affect ability of the neuron to carry the action potential (stabilizing the neuron membrane in a non-depolarized state)
Receptors for neurotransmitter
- Post-synaptic vs. pre-synaptic
- Excitatory vs. inhibitory effects
- Ionotropic receptors
- Metabotropic receptors
Therapeutics can be agonists, partial agonists/antagonists, or antagonists at receptors
Post-synaptic vs. pre-synaptic receptors
Pre-synaptic is usually acting as a negative feedback (inhibiting the release of more neurotransmitter from the pre-synaptic neuron)
Excitatory vs. inhibitory effects
Depends on receptor!!!
Ionotropic receptors
Ionotropic receptors (aka ligand-gated ion channels)
- ▪ Fast (directly opens or closes channel)
- ▪ Usually post-synaptic
- ▪ Examples: nicotinic acetylcholine receptors, GABA A receptors, glutamate receptors, glycine receptors, 5-HT3 receptors
Metabotropic receptors
- Metabotropic receptors (aka G-protein coupled receptors)
- Slower than ionotropic receptors because they work by activation of ion channels or signal cascades/second messenger systems
- Can be pre- and post-synaptically located
- Subtype of G protein will determine whether it is excitatory (Gs) or inhibitory (Gi)
- Gs receptor activation:
- Increases adenylyl cyclase activity
- Opens Ca2+ channels
- Inhibits Na+ channels
- Gi receptor activation:
- Inhibits adenylyl cyclase activity
- Closes Ca2+ channels
- Opens K+ channels
- Gq receptor activation:
- Increases phospholipase C activity
- Gs receptor activation:
Reuptake of neurotransmitter from synapse
- o One method for removal of neurotransmitter from the synapse (ending its action), it “recycles” the neurotransmitter back into the pre-synaptic neuron
- o Not believed to be active transport (transports with the concentration gradient from more concentrated in the synapse to less concentrated area in the axon terminal of the pre-synaptic neuron)
- o Examples: serotonin reuptake transporter (SERT), norepinephrine reuptake transporter (NET), dopamine reuptake transporter (DAT), and more
- o Therapeutics can block reuptake transporters, increasing the concentration of neurotransmitter in the synapse
Degradation of neurotransmitter
- o Enzymatic degradation of neurotransmitter can occur in the synapse or in the pre- synaptic terminal
- o In the synapse degradation of the neurotransmitter is one way of terminating the neurotransmitter’s action
- o In the pre-synaptic axon terminal it can decrease the amount of neurotransmitter that is available for packaging into vesicles
Neuroanatomy: Cerebral Cortex
Cerebral cortex
- a. Frontal lobe—planning
- b. Motor lobe
- c. Speech
- d. Somato-sensory
- e. Vision, smelling, hearing
Neuroanatomy: Limbic System
Limbic areas
- Regions include:
- Hippocampus
- Amygdala
- Limbic cortex
- Functions include:
- Memory
- Mood
- Biological needs
Neuroanatomy: Brain Stem
- Brainstem
- Regions include:
- Reticular formation
- Medulla
- Pons
- Functions include:
- Sleep/wake, attention
- Breathing
- Blood pressure maintenance
- Regions include:
Neuroanatomy: Spinal Cord
- Spinal Cord
- Connects body to brain
- Input of peripheral information
- Pain
- Position
- Output of central message
- Movement
- Blood pressure maintenance
- Body temperature maintenance
- Respiration
Neurotransmitters
Monoamine
Amino acids
Acetylcholine
Monoamine Neurotransmitters
Dopamine
Norepinephrine
Serotonin
Dopamine
Dopamine (DA; monoamine AND catecholamine)
- ○ Synthesis→ tyrosine hydroxylase is the rate limiting step in production of dopamine (converts tyrosine to dopa)
- ○ Vesicles→ vesicular monoamine transporter (VMAT) packages all monoamines into vesicles in the presynaptic terminal
- ○ Degradation→ Monoamine oxidase (MAO, found in presynaptic terminal and synapse) and Catechol-O-Methyl tranferase (COMT, found in synapse only)
- ○ Localization
- ■ Cell bodies mostly limited to:
- ● ventral tegmental area (reward, addiction)
- ● substantia nigra (movement)
- ■ Projectionstolimbicareas(emotion, memory), striatum, and cortex
- ■ Cell bodies mostly limited to:
- ○ Reuptake→ Dopamine reuptake transporter (DAT)
- ○ Receptors: Metabotropic
- ■ D1family→coupled to Gs
- ■ D2family→coupled to Gi, may be presynaptic (autoreceptors) or postsynaptic
- ○ Central diseases/conditions associated with dopamine:
- ■ Parkinson’sdisease
- ■ Substanceabuse
- ■ Schizophrenia
- ■ ADHD
- ○ Receptors: Metabotropic
Norepinephrine
- ● Norepinephrine (NE; monoamine AND catecholamine)
- ○ Synthesis→ synthesized from dopamine (dopamine betahydroxylase converts dopamine to norepinephrine)
- ○ Vesicles→ vesicular monoamine transporter (VMAT) packages all monoamines into vesicles in the presynaptic terminal
- ○ Degradation→ Monoamine oxidase (MAO, found in presynaptic terminal and synapse) and Catechol-O-Methyl tranferase (COMT, found in synapse only)
- ○ Localization
- ■ Cell bodies mostly limited to:
- ● locus ceruleus (LC, near brainstem)
- ● brainstem
- ■ Projections to amygdala(partoflimbicsystem-emotion,memory),thalamus and cortex
- ■ Cell bodies mostly limited to:
- ○ Reuptake→ Norepinephrine reuptake transporter (NET)
- ○ Receptors: Metabotropic
- ■ alpha1→coupledtoGq
- ■ alpha2→coupledtoGi,maybe presynaptic (autoreceptors) or postsynaptic
- ■ beta→coupledtoGs
- ○ Central diseases/conditions associated with norepinephrine:
- ■ Cognition
- ■ Depression
- ■ Posttraumaticstressdisorder(PTSD)
- ■ ADHD
Serotonin
- Serotonin (5-HT; monoamine ONLY)
- ○ Synthesis→ synthesized from tryptophan
- ○ Vesicles→ vesicular monoamine transporter (VMAT) packages all monoamines into vesicles in the presynaptic terminal
- ○ Degradation→ Monoamine oxidase (MAO, found in presynaptic terminal and synapse)
- ○ Localization
- ■ Cell bodies mostly limited to:
- ● raphe nucleus
- ■ Projectionstolimbic,midbrain,andcortex
- ■ Cell bodies mostly limited to:
- ○ Reuptake→ Serotonin reuptake transporter (SERT)
- ○ Receptors: 13 different receptor subtypes identified (12 metabotropic, 1 ionotropic)
- ■ 5-HT3→ionotropic;antagonistsat5-HT3receptorsareusedforanti-nausea
- ■ 5-HT1Dand1A→inhibitory,autoreceptors;agonistsareusedformigraine
- treatment
- ■ 5-HT2A→antagoniststothisreceptorareantipsychotics
- ○ Central diseases/conditions associated with serotonin:
- ■ Depression
- ■ Antipsychotics
- ■ Migraine
- ■ Obesity/weightloss
Acetylcholine
- • Synthesis: Choline acetyltransferase combines choline and acetyl coenzyme A to make acetylcholine
- • Vesicles: Vesicular acetylcholine transporter packages Ach into vesicles in axon terminal
- • Degradation: Acetylcholinesterase is very efficient enzyme that breaks down ACh
- • Localization:
- o Cellbodiesinforebrainandbrainstem;interneuronsinstriatum
- o Projectionstolimbicareas,cortex,striatum
- • Reuptake: Choline transporter (transports only choline after it is degraded in synapse)
- • Receptors:
- o Muscarinic G-protei ncoupled receptors found pre- and post-synaptic
- o Nicotinic Ionotropic receptors
- • Central diseases/conditions associated with acetylcholine:
- o Alzheimer’s/Dementia
- o Parkinson’s
- o Depression(?)
Amino acid neurotransmitters
Glutamate-excitatory
GABA-inhibitory
Balance between excitation and inhibition is vitally important in the brain!
Glutamate
Glutamate = Excitatory
○ Uptake by astrocytes with reuptake transporters specific to glutamate
○ Ionotropic receptors (FAST)
■ AMPA,NMDA,Kainate
○ Metabotropic receptors (mGluR, SLOWER)
■ Inhibitory, so coupled to Gi
GABA
- GABA = Inhibitory
- GABA A receptors → Ionotropic receptors
- GABA binding to these receptors causes Cl- to enter cell—hyperpolarizing it
- Receptor where alcohol, barbiturates, benzodiazepines, inhalants all work!
- GABA B receptors → Metabotropic/G-protein coupled receptors
- Can be pre- or post-synaptically located
- GABAB receptors on neurons that release glutamate, dopamine, norepinephrine or serotonin will decrease release of THOSE neurotransmitters
Conditions related to some dysfunction or imbalance with glutamate and/or GABA
- ○ Epilepsy
- ○ Addiction
- ○ Stroke
- ○ Schizophrenia
- ○ Anxiety
- ○ Sleep disorders
- ○ Anesthesia
