Neurotransmitter Systems and Functions

• Neurotransmitter systems are essential for brain function
• They have been broken down into topics based on class/group, precursors, synthesis/storage, location/pathways, receptor types, and termination

Neurotransmitter Function at the Terminal

• Neurotransmitters are synthesized from precursor chemicals
• Neurotransmitters are stored in vesicles
• Neurotransmitters are then released
• Neurotransmitters interact with receptors
• Inactivation occurs after use
• Reuptake can occur after use
• Degradation also occurs

Neurotransmitter Classification

• Amino acid neurotransmitters and modulators include: GLU, GABA, and Glycine
• Other neurotransmitters/modulators include: ACh
• Monoamine neurotransmitters include:
• Catecholamines: DA, NOR, EPI
• Indolamines: 5-HT
• Ethylamine: Histamine
• Peptide modulators include: Endorphins, Oxytocin, Vasopressin, and Enkephalins (endogenous opioids)
• Lipid modulators include: Endocannabinoids (anandamide)

CNS and PNS Functions of Neurotransmitters

• Glutamate is excitatory and interacts with other neurotransmitter systems in the CNS
• GABA is inhibitory and interacts with other neurotransmitter systems in the CNS
• Acetylcholine is involved in learning, memory, and REM sleep in the CNS and muscle contraction in the PNS
• Dopamine is involved in voluntary movement, attention, learning, reinforcement, planning, and problem-solving in the CNS
• Norepinephrine/Epinephrine is involved in vigilance in the CNS and autonomic nervous system regulation in the PNS
• Serotonin is involved in mood regulation, eating, sleep, dreaming, arousal, and impulse control in the CNS, and the enteric nervous system in the PNS
• Histamine regulates wakefulness in the CNS and the immune response in the PNS.
• Opioids are involved in reinforcement and pain modulation in the CNS and pain modulation in the PNS
• Endocannabinoids regulate appetite in the CNS and the immune response in the PNS

Amino Acids: Glutamate and GABA and Glycine

• Glutamate and GABA are amino acids
• Glycine is considered a "non-essential" amino acid.

Synthesis of Glutamate and GABA

• Amino acids are synthesized in the presynaptic terminal.
• Amino acids are packaged into vesicles using transporters.
• Glutamine is converted to Glutamate via glutaminase
• Glutamate is converted to GABA via glutamic acid decarboxylase (GAD). Vitamin B6 is a necessary component
• Glutamate is transported by Vesicular Glutamate Transporter (VGLUT)
• GABA is transported by Vesicular Inhibitory Amino Acid Transporter (VIAAT)

Glutamate and GABA Reuptake and Deactivation

• Amino acids are NOT deactivated in the synapse
• Amino acids are removed from the synapse by transporters in astrocytes or the presynaptic cell

Glutamate Receptors

• Glutamate receptors are either ionotropic or metabotropic.
• Ionotropic glutamate receptors include AMPA (GluR1-4), Kainate (GluR5-7, KA1-KA2), and NMDA (NR1, NR2A-D)
• These receptors control ion currents such as Na+ and Ca++
• Metabotropic glutamate receptors:
• Less prevalent
• In the eye
• Works in the intracellular domain with G-Proteins
• This receptor type includes mGlu1-mGlu8
• Activation of NMDA receptors by glutamate can lead to excitotoxicity.

GABA Receptors

• GABA-A receptors have allosteric sites for barbiturates, benzodiazepines, neurosteroids, muscimol, and ethanol
• GABA-B/C receptors have allosteric binding sites

Glycine

• Glycine receptors are ligand-gated chloride ion channels involved in PNS motor control and pain perception

Acetylcholine

• Acetylcholine is involved in learning, memory, and sleep

Acetylcholine Synthesis and Deactivation

• Acetylcholine (ACh) is synthesized from Acetyl CoA and Choline via Choline acetyltransferase (ChAT).
• Acetylcholine is broken down into choline and acetate by acetylcholinesterase (AChE).
• Choline is transported back into the terminal to make more ACh

Cholinergic Pathways

• Cholinergic pathways, which use Acetylcholine (ACh) has been noted for learning, memory and sleep
• Dorsolateral pons are linked to REM sleep
• Nucleus basalis (basal forebrain) is related to learning
• Medial septum is related to memory
• Also involved in muscle contraction in the PNS

Acetylcholine Receptor Subtypes

• Muscarinic receptors (M1, M3, M5) are excitatory
• Putative allosteric binding sites
• Works with Gq
• Muscarinic receptors (M2, M4) are inhibitory
• Putative allosteric binding sites
• Works with Gi/o
• Nicotinic receptors are either excitatory or inhibitory: α7 and α4β2

Monoamine Neurotransmitters

• Catecholamines: Dopamine (DA), Norepinephrine (NOR), Epinephrine (EPI)
• Indolamine: Serotonin (5-HT)
• Ethylamine: Histamine (HIS)

Synthesis of Catecholamines

• p-Tyrosine is converted to Dopa via Tyrosine hydroxylase (hydroxylation)
• Dopa is converted to Dopamine via Dopa decarboxylase (decarboxylation)
• Dopamine is converted Norepinephrine via Dopamine ẞ-hydroxylase (hydroxylation)
• Norepinephrine is converted to Epinephrine via Phenylethanol-N-methyltransferase (methylation)

Dopamine Functions and Pathways

• Dopamine is linked to reinforcement/reward/addiction, movement, and planning/problem-solving.
• Nigrostriatal pathway is connected to movement
• Mesolimbic pathway is connected to reinforcement/reward
• Mesocortical pathway is connected to STM, planning, and problem-solving

Dopamine Receptors

• D1-like receptors stimulate AC with Gas
• D2-like receptors inhibit AC with Gai/o

Deactivation of Monoamines

• Presynaptic transporters are involved in deactivation
• Enzymatic degradation occurs in astrocytes or the presynaptic terminal with the following enzymes:
• Monoamine Oxidase (MAO)
• Catechol-O-methyltransferase (COMT) (only in CAT)

Norepinephrine

• Norepinephrine (noradrenaline) is linked to vigilance

Norepinephrine and Epinephrine

• Adrenergic Receptor Subtypes: All metabotropic & excitatory
• Alpha 1 / 2 & Beta 1 / 2
• A2/B2 can also serve as autoreceptors.
• Termination:
• Primarily reuptake via transporters.
• Broken down by MAO or COMT.

Serotonin (5-HT)

• Serotonin is distributed from the raphe nuclei through the cortex and into the cerebellum

Serotonin Synthesis

• L-Tryptophan is converted to 5-Hydroxytryptophan via Tryptophan-5-Hydroxylase (TPH).
• 5-Hydroxytryptophan is converted to Serotonin via Aromatic amino acid decarboxylase (AADC).

Serotonin Receptors

• 5-HT1A is linked to regulation of sleep, feeding, and anxiety in the raphe nuclei and hippocampus. Gi,↓ CAMP
• 5-HT1B is linked to neuronal inhibition and behavioral changes in the substantia nigra, globus pallidus, and basal ganglia. Gi, ↓ CAMP
• 5-HT1D is linked to vasoconstriction in the brain. Gi,↓ CAMP
• 5-HT1E is linked to memory in the cortex and hippocampus. Gi,↓ CAMP
• 5-HT IF is linked to anxiety and vasoconstriction in the globus pallidus and putamen. Gi,↓ CAMP
• 5-HT2A is linked to cellular excitation and muscle contraction in platelets and the cerebral cortex. Gq,↑ IP3
• 5-HT2B is linked to appetite in the stomach. Gq, ↑ IP3
• 5-HT 2C is linked to anxiety in the hippocampus and substantia nigra. Gq, ↑ IP3
• 5-HT3 linked to vomiting in the area postrema, enteric nerves. Na+-K+ ion channel
• 5-HT4 linked to gut motility in the cortex, smooth muscle. Gs,↑ CAMP
• 5-HT5A.B linked to locomotion and sleep in the brain. Gi,↓ CAMP
• 5-HT6 linked to cognition and learning in the brain. Gs,↑ CAMP

Serotonin Reuptake and Deactivation

• Serotonin can be degraded by MAO enzyme.
• The primary mechanism to remove effects is REUPTAKE.

Deactivation of Catecholamines and 5-HT

• MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase) are enzymes involved in deactivation
• Transporters like DAT and NAT aid the reuptake process

Deactivation of Catecholamines Pharmacology Insights

• Monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine)
• Reversible inhibitors of MAOA (e.g., moclobemide)
• Selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline)
• Tricyclic antidepressants (e.g., amitriptyline, imipramine)
• Serotonin-noradrenaline reuptake inhibitors (e.g., venlafaxine)

Histamine

• Histamine is related to wakefulness

Histamine Receptors

• All histamine receptors (H1, H2, H3, and H4) are metabotropic:
• H1/2 excitatory
• H3/4 inhibitory

Neuromodulators

Peptides (modulators)

• Neuromodulators peptides that are part of the class of Endogenous opioids include: Endorphins, Oxytocin, Vasopressin, Enkephalins

Features of Peptides

• Peptides are synthesized from mRNA
• Synthesis occurs in the cell body
• Vesicles transport to terminals
• Peptides are released from all parts of the terminal
• There is no reuptake, and they are deactivated by enzymes
• Endogenous opioids like the enkephalins are best known

Endogenous Opioids

• Analgesia/sedation in the brain, brainstem, spinal cord, and primary afferent sensory neurons
• Inhibits defensive responses
• Reinforcement of brain activity

Opioid Enkephalin Receptors

• All the opioid enkephalin receptors are metabotropic and inhibitory.
• Beta-endorphin and Endomorphin can bind to the Mu receptor (MOR)
• Mu receptors lead to antinociception and analgesia.
• Mu receptors may also cause nausea, sedation, constipation, respiratory depression, abuse liability, tolerance to analgesia, and opioid-induced hyperalgesia
• Enkephalins can bind to the Delta receptor (DOR).
• Delta receptors lead to analgesia regarding chronic pain and mood improvement. -Delta receptors could lead to convulsions and hyperlocomotion for a few DOR agonists at a high dose and tolerance to analgesia
• Dynorphins can bind to the Kappa receptor (KOR).
• Kappa receptors, such as KOR, can lead to antinociception, analgesia, sedation, dysphoria, and aversion

Lipids (modulators)

Examples include Endocannabinoids (anandamide)

How Lipids Differ From Classical Neurotransmitters

• Lipids are synthesized on demand unlike classical neurotransmitters
• Lipids are not stored in vesicles
• Lipids primarily deactivated by enzymes
• Communicates within and between cells
• Endocannabinoids are the best-known example

The Endocannabinoid System

• Endocannabinoids have receptors, reuptake and deactivation
  • Receptors are CB1 and CB2
  • Reuptake: Anandamine transporters
• Deactivation: FAAH enzyme

Endocannabinoid Receptors

• Endocannabinoid receptors are metabotropic & inhibitory

Endocannabinoid functions

• The receptors called CB1 and CB2 are located on cell surfaces and impact various biological process
• CB1 is located in the brain, central nervous system, and many other parts of the body -CB1 target motor activity, thinking, Short term memory, Pain perception, and Immune cells
• CB2 is found throughout the body on cells associated with the immune system -CB2 is much broader than CB1 and influences most of the body in such areas as Gut, Kidneys Pancreas, Adipose tissue, Skeletal muscle and Bone to tumors, immune system, skin liver etc
• CBD interacts with both CB1 and CB2 receptors for many effects still being studied

Concentrations of CB1 Receptors

• Basal Ganglia and in the Cerebellum impacts movement
• Cerebral Cortex impacts cognition and psychosis
• Hippocampus impacts learning, memory, stress
• Hypothalamus impacts appetite
• Medulla Nausea/vomiting, chemoreceptor trigger zone (CTZ)
• Spinal Cord impacts Peripheral sensation including pain

Key Neurotransmitters and their functions

• ADRENALINE controls Fight or flight, produced in stressful situations. Increases heart rate and blood flow, leading to physical boost and heightened awareness
• NORADRENALINE affects attention and responding actions in the brain. Contracts blood vessels, increasing blood flow
• GABA calms nerves by calming the central nervous system. High levels improve focus, low levels cause anxiety
• ACETYLCHOLINE is involved in thought, learning and memory, Activates muscle action in the body -GLUTAMATE most common controls learning and memory, regulates development and creation of nerve contacts
• DOPAMINE controls feelings of pleasure, also addiction, movement and motivation
• ENDORPHINS euphoria Released during exercise, excitement and sex, producing well-being and euphoria, reducing pain