What are the 5 monoamines?
- Norepinephrine
- Epinephrine
- Dopamine
- Serotonin
- Histamine
Norepinephrine: Location
- Locus Ceruleus
- Medulla
Norepinephrine: Functions
Wakefulness/Arousal
Norepinephrine: Ionotropic Receptors
NA
Norepinephrine: Metabotropic Receptors
- Alpha-Adrenergic
- Beta-Adrenergic
What is Norepinephrine derieved from?
Tyrosine
Epinephrine: Location
Medulla
Epinephrine: Function
Modulatory
Epinephrine: Ionotropic Receptors
NA
Epinephrine: Metabotropic Receptors
- Alpha-Adrenergic
- Beta-Adrenergic
What is Epinephrine derived from?
Tyrosine
Steps of NE/Epi Synthesis
(1) Tyrosine Hydroxylase converts tyrosine to DOPA (RLS)
(2) DOPA moved into vesicles
(3) Dopamine –> NE
(4) NE leaves vesicles
(5) If the neuron has PNMT, then it converts NE to Epi after NE leaves the vesicles
(6) Epi moved back into vesicles
Proteins that move Epinephrine into vesicles:
Vesicular MonoAmine Transport Proteins – VMAT1 and VMAT2
Reserpine
- Drug
- Inhibits movement of Epi back into vesicle
- Leads to synaptic failure
2 Major Methods that limit the action of Epi and NE:
- Reuptake
- Enzymatic degradation (Monoamine Oxidase, Catechol-O-methyl Transferase)
Monoamine Oxidase
- Located on outer surface of mitochondria
- Metabolites from breakdown of NTs are released into ECF
Catechol-O-Methyl Transferase
Located on Glial cells and post-synaptic membrane – cleans up the NE/Epi that doesn’t get taken back into the presynaptic cell initially
Serpentine Receptors
- Metabotropic receptors
- Work via 2nd messengers
Dopamine: Location
- Substantia Nigra
- VTA (Ventral Tegmental Area; input to basal ganglia)
- Cortex
- Hypothalamus
- Limbic System
Role of Dopamine in Basal Ganglia:
Motor control
Role of Dopamine in Hypothalamus and Limbic System:
Endocrine and emotional control
Dopamine: Functions
- Mood
- Affect
- Hormonal
- General arousal
Dopamine: Ionotropic Receptors
NA
Dopamine: Metabotropic Receptors
- D1
- D2
- D3
- D4
- D5
Dopamine: D1 and D5 Receptors
- Connected to Gs protein
- Increase cAMP (via increased adenylate cyclase activity)
Dopamine: D2 Receptors
- Connected to Gi protein
- Decrease in cAMP (via decreased adenylate cyclase activity) –> increased Potassium Efflux (creates hyperpolarization of the cell)
Dopamine: D3 and D4 Receptors
- Connected to Gi protein
- Leads to decreased cAMP (via decreased adenylate cyclase activity)
Serotonin: Location
- Hypothalamus
- Limbic System
- Cerebellum
- Raphe Nuclei (located in brainstem)
Role of Serotonin in Hypothalamus and Limbic System:
Mood
Role of Serotonin in Raphe Nuclei:
Modification of motor and sensory activity
Role of Serotonin in Cerebellum:
Modification of motor activity
What is Serotonin derived from?
Tryptophan
(via Tryptophan Hydroxylase enzyme)
Serotonin: Functions
- Mood and affect
- Arousal
- Modification of sensory and motor inputs
Serotonin: Ionotropic Receptors
5HT3 (Na+ influx)
Serotonin: Metabotropic Receptors
- 5HT1
- 5HT2
- 5HT4
- 5HT5
- 5HT6
What happens if 5HT3 is activated in the Area Postrema?
Vomiting
What is the effect of Serotonin binding to 5HT6?
Ani-depressant effect
Histamine: Location
Hypothalamus — specifically the Tuberomammillary Nucleus
Histamine: Functions
Arousal
Histamine: Ionotropic Receptors
NA
Histamine: Metabotropic Receptors
- H1
- H2
- H3
Histamine: H1 Receptor
- Binding leads to PLC activation
- Involved in wakefulness
- Largely peripheral
Histamine: H2 Receptor
- Binding leads to increase cAMP
- Associated with gastric acid release
- Largely peripheral
Histamine: H3 Receptor
- Presynaptic receptor
- Binding leads to decreased histamine release – part of feedback system; tells cell ‘you have released enough histamine and can stop now’
Acetylcholine: Location
- Pons and Midbrain
- Striatum (Caudate + Putamen) of Basal Ganglia
Acetylcholine Function in the Striatum
Control of voluntary motion
Acetylcholine Function in the Midbrain and Pons
- Baseline excitation to cortex (brain arousal mechanisms)
- REM sleep
Acetylcholine: Function
- Wakefulness
- Motor Control
Acetylcholine: Ionotropic Receptors
Nicotinic
Acetylcholine: Location of Nicotinic Receptors
- Thalamus
- Cortex (diffusely)
Acetylcholine: Nicotinic Receptors
- 5 subunits coded for by 16 different genes
- Changing the subunits changes the properties of the channel; in some central synapses it creates a nicotinic channel that allows more calcium in
Acetylcholine: Synthesis
- Choline and Acetate
- Moved into vesicles via Vesicular ACh Transporter Protein (VAchT)
- Removed from synaptic space via Acetylcholinesterase bound to post-synaptic cell membrane
Acetylcholine: Metabotropic Receptors
- M1 (neuronal): leads to increase in IP3/DAG (Gq) –> increased Ca++ into cell
- M4: presynaptic autoreceptor, located in striatum of basal ganglia, leads to decreased cAMP (Gi)
- M5: cerebrovasculature (located in large blood vessels), dopaminergic neurons of basal ganglia, leads to increase in IP3/DAG (Gq)
Acetylcholine: Notes
Different from the ACh found in the NMJ and ANS
Two major inhibitory amino acids:
(1) GABA
(2) Glycine
What is the major inhibitory AA NT found in the CNS?
GABA
Location in CNS that contains the lease amount of GABA:
Spinal Cord
GABA: Central Location
Higher CNS
- Cortex
- Cerebellum
- Basal Ganglia
GABA: Critical Functions
- Consciousness
- Motor Control
- Vision (retina)
GABA: Ionotropic Receptors
GABA(A)
GABA: Synthesis
- Glutamate –> GABA via Glutamate Decarboxylase (GAD)
- Transported into vesicels by Vesicular GABA Transporter Protein (VGAT)
- Removed from synapses via GAT (GABA Transporter)
GABA: GAT
- GAT1: located on presynaptic terminal, involved in reuptake
- GAT2: located on glial cells surrounding the synapse, involved in reuptake and further modification
GABA: GAT1
- Takes GABA back up into presynaptic Terminal
- Repackages GABA into vesicles as is
GABA: GAT2
- Astrocytes take GABA in
- Convert GABA to Glutamine and released into ECF
- Once in ECF it is taken up by presynaptic terminal and recycled into GABA
GABA: Ionotropic Receptors - GABA(A)
- When GABA binds, it opens the channel and allows Cl- to enter the cell
- Activation produces IPSP (hyperpolarization) in adult neurons
- Multiple modulatory sites: Benzodiazepine (sedatives), ethanol, Steroids – allow potentiate meaning they allow more Cl- into the cell
There are many ___-____ GABA(A) receptors
Extra-synaptic
(believe these receptors are the site of action for many general anesthetics including Propofol – hyperpolarize the cell until you lose consciousness)
GABA: Metabotropic Receptors
GABA(B)
GABA: Metabotropic Receptors - GABA(B)
- Gi/Go protein coupled – leads to decreased cAMP which results in activation of a K+ channel (GIRK) that allows K+ to exit the cell, hyperpolarization, reduced excitability; also closes down (inhibits) a Ca++ channel
- Located pre- and post-synaptically
- Presynaptic regulates NT release (via negative feedback)
- Postsynaptic leads to inhibition of post-synaptic cell
Glycine: Location
- Spinal Cord
- Lower CNS
Glycine: Function
General inhibition
Glycine: Ionotropic Receptors
GlyR
Glycine: Metabotropic Receptors
None
Glycine: Ionotropic Receptors - GlyR
- Binding opens a Cl- channel which allows Cl- to open the cell and create IPSPs
- Ethanol and general anesthetics bind to this channel and potentiate (increase Cl- influx)
- Strychine binds to it and blocks it – blocking of glycine receptors leads to severe convulsions b/c glycine is critical in keeping excitability in-line
Purines (ATP, ADP, Adenosine): Location
Widespread (cortex, cerebellum, hippocampus, basal ganglia, hypothalamus)
Purines (Adenosine): Function
- Sleep
- Inhibition
Purines (ATP): Functions
Multiple – found in every NT vesicle in presynaptic terminal
Purines (ATP, ADP, Adenosine): Synthesis
- ATP by mitochondria (presyn terminal has many mitochondria)
- Stored in vesicles (VNUT protein)
- Released
- ATP –> ADP –> Adenosine; occurs in synaptic trough
Purines (ATP, ADP, Adenosine): Ionotropic Receptors
P2X
Purines (ATP, ADP, Adenosine): Metabotropic Receptors
- P1(A)
- P2Y
Purines (ATP, ADP, Adenosine): P2 (P2X, P2Y) Receptor Functions
- Learning and memory
(co-release with EAA) - Modification of locomotor pathways
Purines (ATP, ADP, Adenosine): Ionotropic Receptors - P2X
- Ligand: ATP
- Many subtypes
- Binding of ATP leads to influx of Na+ and Ca++ into the neuron –> depolarization
Purines (ATP, ADP, Adenosine): Metabotropic Receptors - P2Y
- Ligands: ATP, ADP, UTP, UDP
- Gs (leads to increase in cAMP) / Gq (leads to production of IP3/DAG –> increase Ca++ release from intracellular stores) coupled
Purines (ATP, ADP, Adenosine): Metabotropic Receptors - P1(A)
- Ligand: Adenosine
- Post-synpatic locations – involved in sleep induction in hypothalamus and general inhibition of neural function
- Pre-synaptic locations – involed in inhibition of NT release via negative feedback loop