5 - CNS Neurotransmitters Flashcards
Small Molecule Neurotransmitter Synthesis
- Made within presynaptic terminal via enzymatic conversion from existing precursor and then packaged into vesicles
- Slow axonal transport because enzyme to make the NT is made in the cell body then transported to the terminal
- Rapid response because once the enzyme is in the presynaptic terminal, precursors a re quickly converted into new NTs
CNS Neurotransmitter Classification
- Small Molecules
- ACh
- Amino Acids (Glutamate, GABA, Glycine)
- Biogenic Amines
- Catecholamines (Dopamine, Norepinephrine, Epinephrine)
- Serotonin
- Neuropeptides (Nonclassical)
- More than 100, typically 3-36 amino acids long
Neuropeptide Neurotransmitter Synthesis
- Neuropeptide precursors made in the cell body and are a packaged into vesicles before moving into the presynaptic terminal
- Fast Axonal transport because of microtubule tracts down axon
- Slow response to increased demand because precursors have to be made in the cell body and transported to the terminal before being converted to NTs within their vesicles
- Individual propeptides in the vesicles can give rise to multiple active peptides during final processing in the vesicles
- Often co-released with Small Molecule NTs
Neurotransmitter Receptors
- Ionotropic: ligand-gated ion channels
- 4-5 subunits with 3-4 transmembrane passes allows large diversity of Ionotropic receptors
- Metabotropic: G-protein coupled receptor that modulates ion channels either directly or indirectly via intracellular enzymes
- Monomeric proteins with 7 transmembrane domains
- G-protein coupling allows excitatory or inhibitory post-synaptic potentials
Acetylcholine (ACh)
PNS: Neuromuscular Junction (Nicotinic, Ionotropic)
Parasympathetic (Muscarinic, Metabotropic)
CNS: Brainstem + Forebrain Interneurons
Large neurons in basal forebrain to cerebral cortex
–> Associated with attention, reward plasticity, & memory
-Removed from synaptic cleft via breakdown by Acetylcholinesterase into Acetate and Choline, which are then transported back into the presynaptic terminal
-Organophosphatases (Sarin Gas, Insecticides) inhibit Acetylcholinesterase, causing ACh to accumulate in synaptic cleft, making postsynaptic cell refractory to subsequent ACh release, resulting in muscle paralysis
-ACh Antagonists for therapeutic benefit
-Atropine for pupil dilation
-Scopolamine for motion sickness
-Myasthenia Gravis
-Autoimmune disease against NMJ nicotinic ACh receptors, causing decreased concentration of ACh receptors in postsynaptic membrane and so are/shallow junctional folds
-Results in muscle fatiguability/weakness, diplopia, & ptosis
-End plate Potentials are reduced during repeated stimulation, so compound APs in the muscles decrease in size
-Treat with acetylcholinesterase-inhibitors and thymectomy
Glutamate
- Can’t cross the blood-brain barrier (glutamine can)
- Synthesized from glutamine or by transom inaction of α-ketoglutarate (product of glycolysis)
- Removed by glutamate receptors on emerge terminal and nearby glial cells that convert glutamate to glutamine
- Most prominent NT for brain function
- Nearly all excitatory neurons in the brain use glutamate as the NT
- Excitotoxicity: Too much glutamate is toxic, leads to neuron death
- Though to cause neuronal damage during strokes because oxygen deprivation slows glutamate reuptake
- Ionotropic receptors are all Na+ selective
- NMDA - also passes Ca2+, Voltage-dependent because of Mg2+ gating (requires depolarization), and glycine binding is required to open channel
- AMPA - does not pass Ca2+, is not voltage-gated, but acts faster than NMDA
- Metabotropic receptors can be excitatory or inhibitory
GABA & Glycine
-Major inhibitory NT of the CNS
-GABA is widely distributed through brain and brain stem
-Used by local Interneurons and purine cells of the cerebellum
-Glycine primarily used at synapses in the spinal cord
-Glycine is synthesized from serine in presynaptic nerve terminals and removed from the synaptic cleft by glial cells with specific transporters
-Excess glycine due to transporter defects cause son neonatal disease characterized by lethargy and mental retardation
-Ionotropic Receptors
-GABAa, GABAc, Glycine receptors
-Inhibitory Cl- channels
-Agonists: Benzodazepines (Vallium) are tranquilizers
Barbiturates are an esthetics for epilepsy patients
-Antagonists: Strychine blocks Glycine receptors causing seizures
-Metabotropic Receptors
-GABAb
Biogenic Amines (Catecholamines, Serotonin)
- Aminergic neurons project widely in brain to modulate the intensity of specific nerve signals
- Very important to mental health but used by relatively few neurons in the brain
- Synthesized in nerve terminals, packaged by vesicular membrane transporter (VMAT), and removed from synaptic cleft by reuptake directly into the nerve terminal
- Receptors are all metabotropic (except serotonin also has ionotropic receptors)
Distribution of Dopamine Neurons
1: Source: Substantia Nigra, sends projections to striatum (caudate + putamen)
Function: Copordination of body movements
–> In Parkinson’s disease, these neurons degenerate. Treated with dopamine precursor to increase dopamine levels in the striatum
- Source: Midbrain (Ventral tegmentum), sends projections ventral striatum
Function: Motivation, reward and reinforcement, emotional behavior
–>Addictive drugs raise dopamine levels by interfering with reuptake transporters
Catecholamine Receptors
- Source: Local Coeruleus, sends projections to forebrain and brainstem
Function: influences sleep, wakefulness, attention, & feeding behavior
- All catecholamine receptors are metabotropic
- Dopamine receptors activate or inhibit adenylyl cyclase
- Norepinephrine receptors have α- and β- adrenergic receptors
- Catecholamine reuptake is facilitated by glial cells into nerve terminals by transmitter-specific plasma membrane transporters
- ->Cocaine inhibits dopamine transporter, increasing dopamine levels in the synaptic cleft
- ->Amphetamines inhibit both dopamine and norepinephrine transporters (Speed)
Distribution of Serotonin Neurons
- Source: Raphe Nuclei in brain stem, sends projections to forebrain and brain stem
Function: Regulati on of sleep, eating, and arousal
-Norepinephrine = “Mood Elevating”
Serotonin = “Mood Altering”
-Reuptake is by Specific Serotonin Transporter (SERT)
-Metabotropic receptors for emotions, circadian rhythm, motor, mental
-Activation mediates satiety and decreased food consumption
-Ionotropic receptors are non-selective excitatory cation channels
