Neurotransmitter Systems Flashcards
Monoamines
Epinephrine, norepinephrine, dopamine, serotonin, histamine
Norepinephrine
Locations: locus ceruleus, pontine/medullary areas
Role: wakefulness/alertness
Epinephrine
Locations: medulla
Role: modulatory role
Epinephrine and Norepinephrine Synthesis
- derived from tyrosine
- tyrosine > dopamine > NE > epinephrine
- Tyrosine Hydroxylase converts tyrosine to DOPA = rate-limiting
- moved into vesicles then conversion to NE
- Phenolethanolamine-N-methyl transferase converts NE to epinephrine once NE leaves vesicles
- epinephrine moves back into vesicles
Vesicular Monoamine Transporter
moves epinephrine and norepinephrine into vesicles
VMAT1 and 2
blocked by reserpine = synaptic failure
Limitation of NE and E actions
- reuptake
- degradation by MOA: mitochondria outer surface
- degradation by COMT: glial cells/post-synaptic membrane
Monoamine Receptor Classes
Alpha adrenergic
Beta adrenergic
many places in brain; both serpantine
Dopamine
basal ganglia (motor control) hypothalamus and limbic system (endocrine and emotions)
Dopamine Synthesis
precursor to NE and E
Limitation of Dopamine Actions
reuptake
catabolism by MOA and COMT and released to ECF
Dopamine Receptors
5 Metabotropic and G Protein Receptors
D1 and D5: increase cAMP via Gs = excitatory neurons
D2: decreases cAMP = via Gi/o = potassium efflux > cell hyperpolarization > inhibition
D3 and D4: decreases cAMP via Gi/o
Serotonin
Hypothalamus and Limbic System: mood
Cerebellum: motor activity
Brainstem Raphe Nuclei: modification of motor and sensory activity esp nociception
Serotonin Synthesis and Termination
tryptophan precursor
made by tryptophan hydroxylase
catabolized by MAO and COMT
Serotonin Receptors
7 receptor types
5HT3 ionotropic receptor = Na influx and depolarization; present in area postrema
5HT6 ionotropic receptor = anti-depressant effects
5HT7 = limbic system and mood
Histamine
tuberomamillary nucleus and hypothalamus
roles in wakefulness
Histamine Synthesis
histidine precursor
histidine decarboxylase enzyme
Histamine Termination
reuptake
catabolism by diamine oxidase and COMT
Histamine Receptors
3 receptor types
H1: PLC activation via Gq pathway; wakefulness
H2: increase cAMP; gastric acid release; least in brain
H3: pre-synaptic; decrease histamine release
Anti-Histamines
H1 receptor blockers
Inhibitory Amino Acids
GABA
Glycine
GABA
major inhibitory AA in brain
more present in higher areas of CNS
least in spinal cord
GABA Function
consciousness, motor control, vision
GABA Synthesis
from glutamate glutamate decarboxylase (target of autoimmune responses = neuro sx)
GABA Termination
VGAT: transports into vesicles
GAT1: remove from synapse; located on pre-synaptic terminal
GAT2: remove from synapse; located on glial cells
GAT1
GABA repackaged into vesicles as is
GAT2
- GABA converted to glutamate and then glutamine by glial cell
- must be converted to glutamine bc glutamate has excitatory effects
- released to ECF and taken up by pre-synaptic terminal and recycled to GABA
GABA A Receptors
-ionotropic; Cl conduction for cell entry and hyperpolarization to create IPSPs
Benzo binding site: more Cl- entry and cell inhibition
Ethanol and steroid binding sites: cause bigger IPSPs
extra GABA A receptors in the synapse respond to anesthetics like propofol
GABA B Receptors
metabotropic and Gi/Go coupled
activate GIRK K+ channel for K to leave cell
Inhibit Ca ++ channel and reduce Ca
Pre-synaptic location: regulates release of GABA
Post-synaptic location: inhibits post-synaptic cell
Glycine
Locations: spinal cord, medulla, less in higher areas
Function: mediates spinal inhibition
Production: unmodified amino acid
Termination: GAT proteins and recycling
Glycine Receptors
- ionotropic allow Cl influx cause IPSP
- potentiated by alcohol and anesthetics = more Cl and more inhibition
- blocked by strychine which causes convulsions via increased excitatory activity
Purines
- all vesicles have ATP
- Location: everywhere in CNS esp cortex, cerebellum, hippocampus, basal ganglia
- Production: ATP by mitochondria, stored in vesicles, released
- conversion of ATP to adenosine occurs in synaptic trough
P1 Purine Receptors
bind adenosine
post-synaptic locations: sleep induction, general inhibition of neural function
pre-synaptic locations: inhibit NT release
P2 Purine Receptors
P2X: bind ATP, ionotropic, allow Ca and Na in
P2Y: bind ATP, ADP, UTP, UDP, metabotropic, Gi/Gs coupled
Function: learning and memory (co-release with EAA), locomotor pathway modification
Opioids
endorphins, enkephalins, dynorphins, nociceptins
Location: basal ganglia, hypothalamus, pontine and medullary sites
Function: modify nociceptive inputs, mood
Opioid Pre-Cursors
Proopiomelanocortinin: pre-cursor to B-endorphines and ACTH
Pro-Enkephalin: met-enkephalin, leu-enkephalin
Pro-Dynorphin: dynorphin
Orphanin: nociceptin
Opioid Synthesis and Termination
standard protein synthesis in cell body
removed via reuptake and destruction by enkephalinase and aminopeptidase
Mu Receptors
opioid receptor
metabotropic
Gi/Go
increased K efflux and hyperpolarization = inhibit
role in analgesia, respiratory depression, euphoria, constipation, sedation
Kappa Receptors
opioid receptor
serpentine
Gi/Go
reduced calcium influx = indirect inhibition
produces analgesia, dysphoria, diuresis, miosis
Delta Receptors
opioid receptor
Gi/Go
serpentine
analgesia
Endocannabinoid Active Ingredients
anandamide, 2-arachidonylglycerol
Endocannabinoids
Basal ganglia: mood, motor performance
Spinal cord: modulation of nociception
Cortex: neuroprotection
Hippocampus and Hypothalamus
Endocannabinoid Synthesis
from arachidonic acid lipids in presynaptic terminal
Anandamide Synthesis: from NAPE
2-AG: from PIP2; 2 AG is major source of arachidonic acid in brain so manipulation pharmacologically has wide range effects
CB1 Receptor
- neurons
- psychoactive response
- Gi coupled
- binds AEA and 2-AG with high affinity
- locations: striatum, thalamus, hypothalamus, cerebellum, brainstem (uniformly); cortex, amygdala, hippocampus (non-uniform)
- largely pre-synaptic in EAA and GABA releasing synapses to reduce their release
CB2 Receptor
- in microglia
- neuronal locations associated with nerve injury
- high response to injury/inflammation
Anandamide Hydrolysis
via Fatty Acid Amide Hydrolase
2-AG Hydrolysis
via mono-acyl glycerol lipase
Oxidation of Endocannabinoids
via cyclooxygenase and lipooxygenase (both AEA and 2-AG)
EAA
glutamate
aspartate: NT in visual cortex and pyramidal cells
widely in CNS
NMDA Receptor
ionotropic and voltage gated
EAA receptor endogenously
activated by NMDA exogenously
Ca influx
Glycine binding site for modulation; required for channel to open but doesn’t open channel on its own; needs EAA
Mg binding site within channel blocks channel at resting membrane and prevents calcium influx; leaves channel when cell is depolarized
PCP binding site blocks channel when hallucinogen PCP binds and prevents Ca entry
AMPA Receptor
activated by AMPA exogenously asp/glut endogenously ionotropic sodium influx Benzo site: benzos reduce Na influx and decreases excitation
Kainate Receptor
opened by Kainic acid to allow Na influx and some Ca
Non-NMDA Receptor Activation
short EPSP due to Na
NMDA Receptor Activation
long latency (bc kicking Mg out) and long duration (bc of Ca influx and how long channel is open)
EPSP
- EAA binds to NMDA and non-NMDA receptors
- Na flows into non-NMDA
- Ca can’r enter NMDA due to Mg
- non-NMDA receptor activity induces EPSP
- EPSP causes enough depolarization to cause Mg to leave NMDA channel
- Ca enters NMDA channel and longer lasting EPSP occurs
Non-NMDA Receptor Functions
- sensory afferents
- upper motor neurons
NMDA Receptor Functions
short-term and long-term memory formation
synaptic plasticity
EAA Metabotropic Receptors
Group 1: Gq
Group 2 and 3: Gi
Pre-synaptic: control NT release via feedback
Post-Synaptic: learning, memory, motor systems
EAA Control
EAA in high concentrations = toxic
Glial cells take EAA in via active transport Na/K pump and convert to glutamine
glutamine diffuses out and is taken into pre-neuron again
NMDA Receptors and NO
EAA binds to NMDA receptors and allows Ca ++ into cell
Ca activates calcineurin which activates Nitric oxide synthase
NOS takes arginine and cleaves NO leaving NO and citruline
NO = very lipid soluble and diffuses across cleft
Neuronal Functions of NO
Memory: long term potentiation in hippocampus and cerebellum
CV and resp control: pons and medulla
high concentrations of NO is toxic to neurons bc half life is short and free radicals are produced which harm neurons
Non-Neuronal Functions of NO
- released by macrophages bc toxic to bacteria
- EDRF = vasodilator
