NROSCI 0080: Neurotransmitters

Classes of Neurotransmitters

Small-molecule transmitters: synthesized from dietary nutrients and packaged ready for use in axon terminals

• Amino Acids: Glutamate (Glu), Gamma-aminobutyric acid (GABA), Glycine (Gly), Acetylcholine (ACh)

• Amines: Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT)

Peptide transmitters (= neuropeptides)

• Small proteins

• Synthesized in the soma based on the genetic information from the nucleus

• E.g. Endogenous opioids

Lipid transmitters

• E.g. Endocannabinoids

Nucleotide-related transmitters

• E.g. Adenosine

Glutamate

Main excitatory neurotransmitter in the brain and spinal cord (CNS). Amino Acid. Is a component of many proteins that we consumed as food.
Receptors: Ionotropic, metabotropic.

• Ionotropic glutamate receptors depolarize the postsynaptic cell membrane, which leads to excitatory response

• 3 types of ionotropic glutamate receptors

  • AMPA, NMDA, Kainate

How Does Glutamatergic Synapse Work?

1. Action potential depolarizes presynaptic

membrane

2. Depolarization opens voltage-gated Ca2+

channels and Ca2+ ions go inside the

presynaptic terminal along their

electrochemical gradient.

3. Ca2+ ions stimulate glutamate

(transmitter) release from synaptic vesicles

into the synaptic cleft.

4. Glutamate binds to the glutamate

receptors and opens transmitter-gated ion

channels on postsynaptic membrane.

5. Na+ and Ca2+ ions go inside the dendritic

spine (postsynaptic cell) along their

electrochemical gradient and generate

depolarizing response on the postsynaptic

membrane, EPSP, that propagates along

dendritic membrane towards axon hillock.

6. Excessive glutamate is re-uptaken onto

presynaptic terminal and transported into

astrocytes

Glutamate: Excitotoxicity

High levels of glutamate can be toxic to nerve cells.

Excitotoxicity hypothesis: prolonged depolarization of receptive neurons leads to their eventual damage or death

• may occur with brain ischemia (interruption of blood flow) like from stroke

• massive release of glutamate occurs in the affected area

GABA (gamma-aminobutiric acid)

Main inhibitory neurotransmitter in the brain.
If either GABA or glycine is blocked, convulsions and death can result.

Amino acid.
GABA is made from glutamate.

GABA binds to GABA receptors.

Has two receptors: ionotropic, metabotropic

GABA receptor channels allow Cl- to move from outside to inside the cell.

• Causes hyperpolarization and inhibition of the postsynaptic cell

How does GABAergic Synapse Work?

1. Action potential depolarizes presynaptic

membrane

2. Depolarization opens voltage-gated Ca2+

channels and Ca2+ ions go inside the

presynaptic terminal along their

electrochemical gradient.

3. Ca2+ ions stimulate GABA (transmitter)

release from synaptic vesicles into the

synaptic cleft.

4. GABA binds to the GABA receptors and

opens transmitter-gated Cl- ion channels

on postsynaptic membrane.

5. Cl- ions go inside the postsynaptic cell

along their concentration gradient and

generate hyperpolarizing response on the

postsynaptic membrane, IPSP, that

propagates along dendritic membrane

towards axon hillock.

6. Excessive GAB is taken up into the presynaptic terminal and transported to the

astrocytes → this is the deactivation process for GABA

GABA: Benzodiazepines, Barbiturates, Alcohol

GABAA receptors are sensitive to some CNS-depressent frugs with antianxiety, sedative, and anticonvulsant profiles.
Benzodiazepines and barbiturates activate GABAA receptor.
Alcohol has similar properties (is a GABA agonist)

GABA and Epilepsy

Since GABA is involved in neuronal inhibition, it might play a role in epilepsy.

Some forms of epilepsy are linked to mutations in GABA receptor subunits.

Many epileptic drugs enhance GABA response.

Glycine

Acts as inhibitory neurotransmitter in the spinal cord, brain stem.

Amino acid synthesized from serine.

Bonds to Ionotropic receptors. These receptors produce IPSPs by opening Cl- ion channels and allowing Cl- into the cell. Can be blocked by strychnine.

Deactvation: Can be re-uptaken onto presynaptic terminal and transported into astrocytes.

Mechanisms of action of glycine at the synapse

Bonds to Ionotropic receptors. These receptors produce IPSPs by opening Cl- ion channels and allowing Cl- into the cell. Can be blocked by strychnine.

Mechanisms of action of acetylcholine at the synapse

ACh is formed from choline and acetyl CoA, and there are 2 types of receptors:

• Nicotinic ACh receptors are ionotropic and respond to nicotine (agonist), which is an alkaloid found in the tobacco plant → these mediate fats excitatory responses in the NMJ, brain, and autonomic nervous system

  • When ACh binds, the channel opens and Na+ and Ca2+ enter, depolarizing the membrane

• Muscarinic ACh receptors are metabotropic and respond to muscarine (agonist), which is an alkaloid first found in fly agaric mushrooms

What drugs potentiate (make something more powerful) GABA receptors?

GABA-A receptors are sensitive to some CNS depressant drugs used for antianxiety, sedatives, and anticonvulsants

• things like benzodiazepines and barbiturates. These are GABA agonists (a substance or muscle that triggers or enhances a specific action or biological response), and alcohol has similar properties

What is strychnine?

A glycine receptors blocker. It causes muscular convulsions and eventually death through asphyxia or sheer

exhaustion. Was used as a pesticide.

What are the mechanisms of deactivation of glutamate, GABA?

GABA: Excessive GAB is taken up into the presynaptic terminal and transported to the astrocytes

Glutamate: Excessive glutamate is re-uptaken onto presynaptic terminal and transported into astrocytes

How is acetylcholine deactivated? What is acetylcholinesterase?

ACh is broken down by acetylcholinesterase (AChE, an enzyme) into acetic acid and choline in the synaptic cleft

Mechanisms of botulinum toxin

Potentially deadly illness caused by a toxin produced by the Clostridium botulinum bacteria, and this toxin blocks the release of ACh leading to skeletal muscles not being able to activate

• This toxin is used (called botox) to treat facial wrinkles and chronic migraines → injection of the toxin causes localized paralysis, reducing wrinkles for several months

Mechanisms of curare

Has been used historically as a paralyzing poison by South American indigenous people.

• blocks acetylcholine receptors at the neuromuscular junction

Mechanisms of sarin

Irreversible inhibition of AChE, leading to ACh accumulation and overstimulation of cholinergic synapses in the CNS and PNS. Very toxic varieties are “nerve gas”. ACh accumulation and overstimulation of cholinergic synapses throughout both the CNS and PNS lead to muscle paralysis and death by asphyxiation.

Dopamine

Produced from amino acids in foods like phenylalanine and tyrosine. It is a precursor to both norepinephrine

and epinephrine (adrenaline, mostly acts as a hormone).

• There are 3 Dopamine (DA) pathways:

  • Nigrostriatal: axons from neurons in the substantia nigra project to the basal ganglia (SN→ striatum) for motor control

  • Mesolimbic: axons from neurons in the VTA projects to the nucleus accumbens (VTA→ NAc) mainly for reward processing and action

  • Mesocortical: axons from the VTA project to the prefrontal cortex (VTA→PFC) for selective attention, working memory, memory consolidation

There are 5 metabotropic DA receptor subtypes (D1 to D5)

that all interact with G proteins and function via second

messengers

Drugs that increase DA response stimulate behavior: cocaine, amphetamine

Drugs that decrease DA response (DA receptor antagonists) like antipsychotics such as haloperidol and clozapine suppress exploratory and locomotor behavior

Norepinephrine

Receptors are metabotropic, and the noradrenergic system is involved in many behavioral functions like arousal, cognition, and consolidation of memories and emotional experiences

• NE neurons in the brain are in the pons and medulla in the brainstem → they project to most areas of the forebrain, the cerebellum, and the spinal cord

• NE is used in the periphery in the sympathetic nervous system, where their projections target organs throughout the body causing increased heart rate, blood pressure, and breathing (stimulatory)

Serotonin

Synthesized from the amino acid tryptophan and is associated with eating behavior, anxiety, pain sensitivity, and learning and memory. It activates behaviors

• Almost all serotonergic neurons in the CNS are found along the midline of the brainstem in the raphe nuclei

• The 5-HT receptors are the receptors for serotonin, and they are mostly metabotropic (5-HT3 forms a transmitter gated channel→ionotropic)

Dopamine, Norepinephrine, Seratonin

Dopamine + Norepinephrine: DA and NE move

from the synaptic cleft into

the nerve terminal via specific

membrane transporter

proteins. #6

The molecules are then

repackaged into vesicles or

broken down.

2. Breakdown of catecholamines

by catechol-O-

methyltransferase

(COMT) and monoamine

oxidase (MAO). ##7,8,9

Serotonin is deactivated through reuptake and degradation by MAO

What are COMT and MAO?

MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase) are two major enzymes in the human body that break down and clear out key neurotransmitters—such as dopamine, norepinephrine, and serotonin—to keep our nervous system balanced

What chemicals are used as neurotransmitters in the autonomic nervous system?

The main neurotransmitters of the autonomic nervous system (ANS) are acetylcholine (ACh) and norepinephrine (NE), which regulate involuntary body functions through the sympathetic and parasympathetic divisions.