Neurotransmitter Systems Flashcards
Where are neurotransmitters made?
In cell bodies in the brain
Where are the receptors for the NTs located?
Usually outside the CNS (may travel a long distance)
What do the raphe nuclei make?
Serotonin
Meaning the cell bodies that make this NT (serotonergic) are within the raphe nuclei
What are the excitatory amino acids?
Glutamate and Aspartate
What are the different NT systems?
Excitatory amino acids, monoamines, cholinergic, inhibitory amino acids, purines, opioids and endocannabinoids
What is glutamate?
Derived from alpha ketoglutarate
Metabolic and transmitter pool strictly separate
What is Aspartate?
Often co-localized with glutamate
Serves as NT on its own in visual cortex and pyramidal cells
Metabolic and transmitter pool strictly separated
Where are the EAA located?
Most important excitatory NT system in the brain
Widely distributed throughout the CNS
What are the receptors for the EAA?
Both ionotropic (allows ions in) and metabotropic receptors (G-protein coupled) Several kinds of each
What are the ionotropic EEA receptors?
NMDA (N-methyl-D-aspartate) receptor
Non-NMDA receptors including AMPA and kainate (primarily Na influx).
What is the NMDA receptor?
NMDA is an exogenous agent that activates this receptor
Glutamate, aspartate, etc all active them in the body
When activated the channel allows influx of Ca
Has multiple modulators sites (glycine binding site, PCP binding site and magnesium binding site)
Describe the glycine binding site of the NMDA receptor
Is a required co-agonist but it alone cannot open the channel
Both EAA and glycine must be present for the channel to open
Describe the Mg binding site of the NMDA receptor
Within the channel itself
Blocks the channel at resting membrane potentials
Prevents Ca influx when the channel opens
Makes the NMDA receptor both ligand and voltage gated
Describe the PCP binding site on the NMDA receptor
Horse tranquilizer and hallucinogen
Blocks the channel preventing Ca influx
Describe the AMPA (non-NMDA) ionotropic receptor for EAA
Exogenous agent AMPA activated
Glutamate/Aspartate are the endogenous ligands
Modulator sites as well
Na influx when open
Benzodiazepines bind to a site on the extracellular face of the protein
-Reduces the amount of Na that enters
Describe the kainate non-NMDA ionotropic receptor
Allows for Na and some Ca entry
What is the result of EAA ligands binding to ionotropic receptors?
Activation of the non-NMDA receptors produces a typically excitatory synaptic potential (epsp) with a relatively short onset and duration
While activation of the NMDA receptors produces a long latency epsp (due to Na leaving) with a long duration (due to Ca influx)
Describe the co-localization of non-NMDA and NMDA receptors on the post-synaptic membrane (EAA)
EAA released
Binds to both types of receptors
Both non-NMDA and NMDA channels open, Na flows in via the non-NMDA channels and Ca cannot enter the NMDA channel because of the Mg
The non-NMDA receptor activation produces the typical epsp
The epsp can provide a sufficient depolarization to cause the Mg to leave the NMDA channel
Ca now enters the NMDA channel producing the longer lasting epsp
Non-NMDA receptors do exist on post synaptic membranes without what?
NMDA receptors in some systems
What is the function of non-NMDA ionotropic receptors?
Primary sensory afferent
Upper motor neurons (pre-motor neurons)
What are the functions of NMDA ionotropic receptors?
Critical in short and long term memory formation
Synaptic plasticity in many forms
What are the three groups of EAA metabotropic receptors?
Group 1: coupled to Gq
Groups 2 and 3: coupled to Gi
What doe pre-synaptic metabotropic EAA receptors control?
NT release
What are post synaptic metabotropic EAA receptors involved with?
Learning, memory and motor systems
What are the neural functions of NO?
Memory -long term potentiation -in hippocampus and cerebellum -elsewhere Cardiovascular and respiratory control -pons and medulla Potent vasodilator in the CVS
What is the immunological role of NO?
Macrophages -> toxic to bacteria
What is the downside of NO?
Vary unstable - has a short half life
Leads to production of free radicals
In high concentrations it becomes toxic to neurons and kills them
What are the monoamines?
Class of NTs that includes all those that are created by modifying single amino acids
Includes epinephrine, NE, dopamine, serotonin and histamine
Where does norepinephrine synthesis occur and what is its role as a NT?
Locus ceruleus, other pontine/medullary areas
Role: wakefulness/altertness
(Independent of the ANS)
Where does epinephrine synthesis occur and what is its role?
Medulla
Role: modulatory
Describe the synthesis of epinephrine and NE
Derived from tyrosine (along with dopamine)
Tyrosine -> L-DOPA -> dopamine -> NE -> epi
Tyrosine hydroxylase conversion of tyrosine to DOPA is RLS
Then moved into vesicles
NE created
Neurons that have phenoethanolamine-N-methyl transferase (PNMT) covert NE to epi after NE leaves the vesicles
Epinephrine moved back into vesicles
What moves NE and epinephrine into vesicles during synthesis?
VMAT1 and VMAT 2
Inhibited by reserpine (leads to synaptic failure)
What limits the actions of epinephrine and NE?
Reuptake
Enzymatic degradation of monoamine oxidase or catechol-O-methyl transferase
Where is monoamine oxidase found?
Outer surface of mitochondria
Metabolites release into ECF
Where is a catechol-O-methyl transferase (COMT) found?
Glial cells/post synaptic membrane
Have polymorphisms that are associated with increased risk of psychiatric disorders including anxiety and depression
What do epinephrine and NE bind to?
Two general classes of receptors including alpha and beta adrenergic receptors
Both are serpentine receptors
Where can dopamine synthesis be found?
Basal ganglia (motor control) Hypothalamus and limbic system (endocrine and emotional control aka mood) Cortex
How is dopamine made?
Precursor to epinephrine and NE
How are the actions of dopamine limited?
Reuptake
Catabolism by MAO and COMT -> release to ECF
What does dopamine bind to?
5 receptor types with multiple subtypes
Metabotropic (serpentine) receptors
Connected to G proteins including D1 and D5 (increase cAMP), D2 (decrease cAMP and increase K permeability/efflux resulting in inhibition), and D3 and D4 (decrease cAMP)
Where is serotonin (5HT) found?
Cerebellum (modification of motor activity)
Hypothalamus and limbic system (mood)
Brainstem raphe nuclei (modification of motor and sensory activity)*
How is serotonin made?
Derived from tryptophan
Tryptophan hydroxylase
How are the actions of serotonin limited?
Reuptake
Catabolism of MAO and COMT
What are the receptors for serotonin?
7 receptor types
5HT 1, 2, 4, 5 and 6
One ionotropic receptor: 5HT3 (Na influx)
What role does 5HT3 receptor play?
Located in area postrema
Illicit vomiting when activated
What is the role of 5HT6 receptor?
Anti depressant effects
Where is histamine found?
Tuberomammillary nucleus of hypothalamus
Critical for wakefulness
How is histamine made?
Derived from histidine
Histidine decarboxylase
How are the actions of histamine limited?
Reuptake
Catabolism diamine oxidase and COMT
What receptors does histamine bind to?
3 receptor types
Serpentine receptors: H1 (PLC activation), H2 (increases cAMP associated with gastric acid release), H2 (presynaptic R that decreases histamine release)
Which histamine receptors are more abundant in the brain?
More H1 and 3
H1 involved in wakefulness
What are the two major inhibitory amino acids?
GABA (gamma-amino butyric acid) and glycine
Where is GABA found?
Widely distributed throughout higher levels of CNS
Cortex, cerebellum, basal ganglia
Spinal cord has the least GABA of all
What is GABA critical in?
Consciousness, motor control and vision (retina)
How is GABA synthesized?
From glutamate
Important enzyme: glutamate decarboxylase (GAD)
Transported into vesicles by vascular GABA transporter protein (VGAT)
What removes GABA from the synapse after synthesis?
GAT (GABA transporter)
Two forms: GAT1 (on the presynaptic terminal) and GAT2 (on glial cells surrounding the synapse)
What happens when GABA is taken up into the presynaptic membrane by GAT1?
The GABA is repackaged into vesicles as is
If GAT2 (on astrocytes) takes up GABA what happens?
The GABA is converted into glutamine and released into the ECF where it will be taken up by the presynaptic terminal and recycled into GABA
Describe GABA-A receptors
Ionotropic (Cl conductance, allows Cl influx when activated)
Activation produces IPSPs in adult neurons
Multiple biding sites modulate including benzodiazepine site, ethanol, certain steroids (these all potentiate its action causing bigger IPSPs)
Where are a large number of extra synaptic GABA-A receptors found?
On neurons of the cortex
Believed to be the site of action for a number of general anesthetics including propofol
Describe GABA-B receptors
Metabotropic
Gi/Go protein coupled which activate a K channel (GIRK) and close down/inhibit a Ca channel
Where are GABA-B receptors located?
Pre synaptically where they regulate NT release
and post synaptically where they inhibit the post synaptic cell
Where is glycine found?
Spinal cord (major)
Brainstem (medulla)
Much less in higher areas of CNS
What is the function of glycine?
Mediates many spinal inhibitions
How is glycine produced?
The unmodified amino acid
How is glycine removed from the synapse?
GAT proteins (same as GABA) Recycling
Which receptors does glycine bind to?
Ionotropic (allows Cl in)
Influx of Cl leads to IPSPs
Ethanol and general anesthetics bind to it and potentiate
Strychnine binds to it and blocks it
What are the purines?
ATP, ADP and adenosine
Described purine synthesis and vesicular storage
ATP by mitochondria (presynaptic terminal has many mitochondria)
Stored in vesicles (VNUT protein)
Released as ATP
ATP -> ADP -> adenosine (break down occurs in synaptic trough)
Where are purines found?
Virtually everywhere in the CNs
Special mention to cortex, cerebellum, hippocampus and basal ganglia
What are the two major classes for purine receptors?
P1 (aka A receptors)
P2 receptors
Describe P1 receptors
Ligand: adenosine
Postsynaptic locations (sleep induction and general inhibition of neural function - it can stop the heart for a few secs))
Presynaptic locations (inhibition of NT releasE)
Caffein inhibits adenosine receptor
Describe the P2 receptors
P2X receptors are ionotropic and ligand is ATP
P2Y is metabotropic with ATP, ADP, UTP and UDP as ligands + coupled to Gi/Gq
What are the functions of P2 receptors?
Learning and memory (co-release with EAA)
Modification of locomotor pathways
Describe peptide transmitters
Are peptides made in the soma and transported down the axon via fast axonal transport
Includes opioids, tachykinins (substance P), CCK and somatostatin
The opioids are a family of peptides that include what?
The endorphins (endogenous morphines), enkephalins, dynoprhins and nociception
Where are opioids found?
Basal ganglia
Hypothalamus
Multiple pontine and medullary sites
What are the general functions of the opioids?
Modification of nociceptive inputs (cutaneous senses)
Mood/affect (neurophysiology of emotion/drug addiction)
What are the 4 precursor molecules for the opioids?
Proopiomelanocortinin (POMC - the precursor molecule of ACTH) -> beta-endorphins
Pro-enkephalin
Pro-dynorphin
Orphanin FQ -> nociception
What does pre-enkaphalin form?
Tyr-gly-gly-Phe-X
X = methionine = Met-enkephalin
X = leucine = leu-enkephalin
How are the opioids synthesized?
Standard protein synthesis in the cell body
How are the opioids removed from the trough/cleft?
Probably reuptake
Enzymatic destruction via enkephalinase or aminopeptidase
What are the opioid receptors?
Mu receptor (metabotropic) Kappa receptors (serpentine) Delete receptor (serpentine)
What does activation of the Mu receptor (for opioids)?
Analgesia, respiratory depression, euphoria, constipation and sedation
Can decrease dyspnea
What does the kappa (opioid) receptor produce?
Analgesia And Dysphoria
Diuresis (increased water loss via urine) and miosis
What does the delta (opioid) receptor produce when activated?
Analgesia
All opioid receptors are what?
Metabotropic (serpentine) and activate second messenger systems with ligand binding
All connect to Gi/Go proteins
The Mu receptor leads to what?
An increase in K efflux and hyperpolarization
The delta and kappa receptors lead to what?
A decrease in Ca influx
What are the endocannabinoids?
Exogenous effects through THC
Endogenous effects through anandamide and 2AG
Where are endocannabinoids distributed?
Broadly in the CNS
Basal ganglia (mood and motor performance)
Spinal cord (modulation of nociception)
Cortex (neuroprotection)
Hippocampus (memory formation)
Hypothalamus (control of energy/hunger)
How are the endocannabinoids synthesized?
Derived from membrane lipids (arachidonic acid)
Occurs in presynaptic terminal
The synthesis of anandamide and 2AG are separate
What is anandamide derived from?
N-arachydonoyl phosphatidyl ethanol (NAPE
What is 2AG derived from?
Arachidonoyl-containing phosphatidyl inositol bisphoshate (PIP2)
A major source for arachidonic acid in certain tissues especially brain
Consequence: pharmacological manipulation of 2AG production has wide reaching effects beyond those on the endocannabinoid system
What are the cannabinoid receptors?
Cannabinoid receptor 1 and 2 (CB1 and CB2)
Describe cannabinoid receptor 1 (CB1)
Neuronal location
Activation associated with the psychoactive responses to the cannabinoid pes
97-99% homology with the mouse and rat versions of the receptor (must be critical)
Polymorphisms lined to occurrence of obesity, ADHD, schizophrenia, depression in Parkinson’s disease
Can form a heterodimer with other NT receptors including dopamine and orexin
Where is CB1 distributed?
CNS
Uniform distribution in the striatum, thalamus, hypothalamus, cerebellum and lower brain stem
Non uniform distribution (associated with specific neuron types): cortex, amygdala and hippocampus
Where is the synaptic location for the cannabinoid receptors?
Largely presynaptic Some sources will say exclusively Generally away from active zone (where the vesicles are) Greater density at inhibitory synapses Binds AEA and 2AG with high affinity
How is the CB1 relevant for neurophysiology?
Found on presynaptic terminals of EAA and GABA releasing synapses
Reduces EAA and GABA release
Via Gi coupled protein
Anandamide and 2AG are equally effective
Describe the CB2 receptor
Found in the brain and on microglia
Neuronal location (dendrites and within soma) are also reported usually associated with nerve injury
Highly inducible in response to injury or inflammation
Binds 2AG better than AEA
How are the endocannabinoids degraded?
Two different pathways: hydrolysis or oxidation
Describe the hydrolysis pathway of degradation of the endocannabinoids
Prevalent neurons
Anandamide (AEA) and 2AG are degraded via two speratate pathways
AEA: fatty acid aside hydroxylase (FAAH - has polymorphism that decrease its activity and decreased cannabinoid and decreased sensitivity to pain) and two forms now known to exist
2AG: monoacylglycerol lipase (MAGL)
Describe the oxidation pathway of endocannabinoid degradation
Via cycloxoygenase and lipoxygenase pathway (both AEA and 2AG)
Associated with prostaglandins
