L5: CNS Neurotransmitters Flashcards
There are 2 groups of NTs: Small molecule transmitters and peptide transmitters. Compare & contrast their synthesis and packaging.
1) Small molecule NTs (eg. ACH, NE)
- synthesis of ENZYMES in cell body
- slow axonal transport of enzymes
- at pre-synaptic terminal, enzymes synthesize NTs from precursors already there
- packaged into vesicles w/ help of transport proteins
2) peptide NTs (VIP, opiods)
- synthesis of ENZYMES & PRECURSORS in cell body
- fast axonal transport
- at pre-synaptic terminal, enzymes modify NT precursors
Why can’t peptide NTs respond quickly to increased demand?
Although the transport down the axon from cell body to pre-synaptic terminal is fast, the fact that the precursors are made at the cell body make it hard for peptide NTs to respond quickly to increased demand. Unlike small molecule NTs, they have precursors at the terminal boutin ready to be synthesized by enzymes.
Compare and contrast the 2 groups of NT receptors
1) ionotropic
- fast
- ligand gated ion channels
- formed by 4-5 subunits
- selective for size
* *very complex b/c many combinations of subunits give rise to diff affinity, selectivity of ion channels
2) metabotropic
- slower
- g-protein coupled receptors
- monomeric
* *similar to ionotropic receptors, these receptors vary with different properties
Acetylcholine is synthesized in the pre-synaptic terminal when enzymes catalyze the rxn btw acetyl-coA & choline. How is ach removed from the synpatic cleft?
acetylcholinesterase into acetate & choline. Choline is re-taken up again
How does Sarin gas (Organophosphates: insecticides) lead to muscle paralysis?
inhibit acetylcholinesterase causing a build up of acetylcholine in the synaptic cleft leading to continued depolarization of post-synaptic cell making it refractory to sub ACH release = muscle paralysis
Describe Ach receptors
1) ionotropic/nicotinic Ach receptors
2) Metabotropic/muscarinic Ach receptors
* **mediate most of Ach effects in brain
Atropine
sympathomimetic leading to pupil dilation by antagonizing AchR
Scopolamine
for motion sickness and is a AchR antagonist
Myasthenia Gravis
autoimmune condition when autoantibodies attack ionotropic/nicotinic AcHr in NMJ. Symptoms include fatigue, diplopia, droopy eyelids (ptosis), difficulty in speaking, swallowing, chewing.
Treatment - acetylcholinesterase inhibitors
Glutamate is the major excitatory NT in CNS. Explain the phenomenon of Excitotoxicity
high extracellular concentration of glutamate is toxic to neurons. During strokes, O2 deprivation, glutamate re-uptake is slow causing more glutamate to remain in synapse, which can cause neuronal damage. Therefore, drugs are targeting glutamate receptors to prevent neuronal damage in such cases.
What is the precursor to glutamate in the pre-synaptic terminal?
glutamine
How is glutamate removed from synaptic cleft?
Mainly by glial cells. Once in glial cells, glutamate is converted back to glutamine b/c glutamine is less toxic and then glutamine is transported back into nerve terminal
What are the 3 types of ionotropic glutamate receptors?
NMDA, AMDA, Kainate = all excitatory Na+ channels
What makes NMDA receptors unique?
Unlike the other ionotropic glutamate receptors (AMDA, Kainate), NMDA receptors are unique:
- Ca2+ can pass thru
- mandatory glycine binding
- Mg2+ blocks receptor which is released by depolarization
Hence, to activate NMDA receptors, you need glutamate, glycine & depolarization to get Mg2+ off
Are there both metabotropic and ionotropic glutamate receptors?
yes
GABA is the major inhibitory NTs in CNS. How is GABA removed from cleft?
glial cells
Epilepsy is related to increase or decrease GABA levels?
decrease GABA
What is the precursor to make glycine in the terminal bouton?
serine
How is glycine removed from cleft?
Glial cells
Increase glycine can be due to defects in glycine transporter, which can lead to what types of problems?
lethargy, mental retardation (neonatal disease)
GABAa, GABAc and glycine receptors are ionotropic receptors. What kind of channels are they?
inhibitory Cl- channels
List some drugs that are GABA receptor agonists
1 - benzodiazepines (Valium) used as tranquilizer
2 - barbiturates (phenobarbital) used as anesthetics for epilepsy
What is strychnine?
rat poison
-glycine receptor antagonist will lead to overreactivity in spinal cord & brainstem leading to seizures
There are both ionotropic and metabotropic GABA receptors. List them
Ionotropic = GABAa and GABAc metabotropic = GABAb -widely distributed in brain
Within the small molecule NT group, there are amino acids and biogenic amines. Biogenic amines (e.g. dopamine) not used by a lot of neurons in brain, but impt in maintaining
mental health
Which transporter is used to package biogenic amines (e.g. dopamine)?
vesicular monoamine transporter
How are biogenic amines removed from cleft?
nerve terminals
Do biogenic amines have both ionotropic and metabotropic receptors?
No, only metabotropic receptors
In Parkinsons disease (an example of hypokinesia, a basal ganglia d/o), why are patients treated with L-Dopa?
b/c the dopamine containing neurons degenerate leading to motor dysfunction.
Briefly describe dopamine’s actions/effects in CNS
- coordination of body movements (in corpus striatum: caudate & putamen)
- motivation, reward & reinforcement (midbrain)
- addiction pathway
- emotional behavior
In the CNS, the biogenic amine, NE works to do what?
NE projects from Locus Coerulus to forebrain & brainstem, influencing sleep & wakefulness, attention, and feeding behavior
What can be used to treat nausea & vomiting
“anti-emetic”
dopamine receptor antagonists
What is the effect of cocaine on dopamine re-uptake?
Dopamine is taken up into nerve terminals and glial cells. Cocaine inhibits this re-uptake, causing more dopamine to stay in the cleft.
Amphetamine (used to treat ADHD & narcolepsy) works by
inhibiting both dopamine and NE transporters leading to increased dopamine & NE.
Serotonin (5-HT) is in which nuclei in brain?
Raphe Nuclei in upper brainstem
What does serotonin do?
regulation of sleep, eating, arousal & wakefulness
What are SSRIs?
Selective Serotonin Reuptake Inhibitors -used to treat depression & anxiety increasing serotonin in cleft
Are there both ionotropic & metabotropic serotonin receptors?
Yes, majority are metabotropic; some ionotropic (5-HT3 clss).
impairment with serotonin metabotropic receptors disorders is implicated in causing what types of diseases?
psychiatric d/os
activation of serotonin metabotropic receptors will result in
satiety and decreased food consumption
Anti-psychotic drugs block which receptors? What are the implications?
-block dopamine receptors
this implies that maybe higher levels of dopamine result in certain psychoses
anti-anxiety drugs
- selective serotoninin reuptake inhibitors (SSRIs to increase serotonin helps with anxiety)
- MAO inhibitors = block breakdown of biogenic amines
Anti-depressants
- MAO inhibitors
- SSRI
Generally describe what peptide NTs do?
-modulate emotions, perception of pain, response to stress
What determines peptide NTs’ activity?
- biological activity dependent on amino acid sequence
* **due to differences in a.a. sequences, there are 5 catergories of peptide NTs.
How are peptide neurotransmitters synthesized?
1 - pre-propeptides made in cell body
2 - in ER, pre-propetides are cleaved into propeptides
**individual propeptides can become MANY active peptides w/in a single vesicle
3 - final processing to active peptides occurs in vesicles AFTER they bud
What are the 5 categories of peptide NTs?
1 - Brain-gut peptides 2 - Opioid peptides 3 - Pituitary peptides 4 - Hypothalamic-releasing peptides 5 - Miscellaneous peptides
How are peptide NTs dealt with in the synaptic cleft?
broken down by peptidases
T/F: Peptide NTs are often co-released with small molecules
True
Are there both ionotropic and metabotropic peptide NT receptors?
No, just metabotropic
What enzyme is used to further activate some peptide NTs in the cleft?
endopeptidases
What are 3 examples of opioid peptides?
endorphins
enkephalins
dynorphins
***all differ in a.a. sequences
morphine is an opiod and is used for?
used as an analgesic
Opioid peptides are widely distributed in the brain and act as ______ & ________.
depressants and analgesics
Which neurotransmitters only use metabotropic receptors?
Dopamine
Norepinephrine
Neuro peptides
