PS231: Neuropharmacology II

Neurotransmitters

chemicals involved in synaptic communication, binds to receptors to initiate a response

Effects of neurotransmitters

defined by the receptor

• Depolarization (EPSP): excitatory, glutamate

• Hyperpolarization (IPSP): inhibitory, GABA

Different neurotransmitter types

• classical

• neuromodulators

EPSPs summate to produce action potentials in the axon hillock

Receptors

proteins on cell surfaces or within cells, have binding sites for their ligands

Ligand

• molecule that binds to a receptor with some selectivity

• can either activate the receptor or block the receptor

• general term for drugs and other molecules that bind to a receptor

Binding affinity

strength of the binding interaction between receptors and ligands

Agonist-receptor interaction

initiates or enhances receptor activity, leads to drug action/effect

Antagonist-receptor interaction

blocks or reduces receptor activity, no drug action/effect

Agonist

A molecule (e.g. a drug) that binds to receptors to initiate or enhance a response

Antagonist

A molecule (e.g. a drug) that binds to receptors and blocks or reduces the action of a neurotransmitter

Competitive agonist

Binds to receptors at the same location as the neurotransmitter, activating it

Competitive antagonist

Binds to receptors at the same location as the neurotransmitter to block its action

Non-competitive agonist

Binds to receptors at a different location as the neurotransmitter, enhancing its activity

Noncompetitive antagonist

Binds to receptors at a different location as the neurotransmitter, reducing its activity

Acetylcholine

• An amine neurotransmitter that is synthesized at the base of the frontal cortex (“basal forebrain”) and brainstem, and cholinergic projections are widespread throughout the CNS and PNS

• The first neurotransmitter discovered (in the NMJ by Otto Loewi)

Cholinergic

Neurons that use ACh as a neurotransmitter are referred to as this

ACh signaling

important for muscle contractions, learning, memory, arousal

Nicotinic AchRs

• competitive agonist from the tobacco plant

• causes skeletal muscle to contract

• no effect on the heart

• mostly found in skeletal muscle

• ionotropic

Muscarinic AchRs

• competitive agonist from some mushroom species

• has little effect on skeletal muscle

• but slows heart rate considerably (dangerous!)

• mostly found in heart muscle

• metabotropic

Competitive antagonists and agonists

both bind to the neurotransmitter’s binding site on the receptor

Only agonists

produce a biological response in the cell

Muscarine

mimics the effects of acetylcholine on muscarinic Ach receptors (“competitive agonist”)

Heart ventricles

• contain mAchRs that mediate a decrease in contraction force (inhibitory), leading to reduced blood pressure

• can become dangerously low if muscarine is ingested even at relatively low concentrations

• can lead to shock—cold skin, rapid/shallow breathing, weak pulse and reduced awareness/ confusion

Acetylcholinesterase

an enzyme that breaks down excess acetylcholine in the synaptic cleft

Blocking AChE

Organophosphorus “nerve agents” like sarin gas used in chemical warfare irreversibly inhibit AchE function resulting in too much Ach buildup in the neuromuscular junction (NMJ)

Glutamate

• a small amino acid neurotransmitter, and the primary excitatory neurotransmitter of the brain

• glutamatergic projections are widespread and found throughout the CNS (green)

• excessive activity is associated with excitotoxicity, a phenomenon in which a stroke or physical trauma (e.g. TBI) provokes excessive release of glutamate that overexcites neurons, eventually killing them (induced apoptosis)

Three types of ionotopic glutamate receptors

• AMPA, NMDA and Kainate receptors and many mGluRs (metabotropic)

• all competitive agonists of their respective receptors, all mimic effects of glutamate

Neuropharmacology of glutamate receptors

• An AP causes glutamate (GLU) release, and GLU binds to AMPARs and NMDARs

• The influx of Na+ though AMPARs and Na+/Ca2+ though NMDARs causes an EPSP in the postsynaptic neuron (depolarization)

• NMDARs only allow ion flux when the membrane is already depolarized 

Signaling termination

• Excess Glutamate Is Taken Up By Astrocytes And Recycled

• Glutamate in the synapse is taken up by transporter proteins on nearby astrocytes, converted to glutamine, and transported back into the presynaptic neuron where it is turned back into glutamate and recycled

• This presynaptic process terminates the excitatory action of glutamate in the synapse

What is the difference between an agonist and antagonist?

• Agonist: A molecule that binds to a receptor and activates it, mimicking the natural neurotransmitter.

• Antagonist: A molecule that binds to a receptor but does not activate it; it blocks the receptor, preventing the natural neurotransmitter from binding.

What are the differences between competitive and non-competitive agonists and antagonists?

• Competitive Agonist/Antagonist: Binds to the same site as the endogenous neurotransmitter (the active site). Their effects can be overcome by increasing the concentration of the natural neurotransmitter.

• Non-competitive Agonist/Antagonist: Binds to a different site on the receptor (an allosteric site), which changes the receptor's shape. Their effects cannot be overcome by increasing the natural neurotransmitter concentration.

How do agonists and antagonists affect receptor activity?

• Agonist: Increases receptor activity.

• Antagonist: Decreases or blocks receptor activity.

Which acts like the endogenous neurotransmitter and which blocks receptor activity?

• Agonist acts like the endogenous neurotransmitter.

• Antagonist blocks receptor activity.

What are the two main types of acetylcholine receptors?

Nicotinic receptors (nAChRs) and Muscarinic receptors (mAChRs).

Which agonists activate each acetylcholine receptor subtype?

• Nicotinic Receptors: Activated by nicotine.

• Muscarinic Receptors: Activated by muscarine.

Are nicotinic and muscarinic receptors ionotropic or metabotropic?

• Nicotinic Receptors: Ionotropic (they form ligand-gated ion channels).

• Muscarinic Receptors: Metabotropic (they are G-protein-coupled receptors, or GPCRs).

Does activity at these receptors usually result in EPSPs or IPSPs? Are there any exceptions?

• Nicotinic Receptors: Almost always result in EPSPs (depolarization) due to Na+ and K+ flux.

• Muscarinic Receptors: Can result in either EPSPs or IPSPs, depending on the subtype and location. For example, in the heart (M2 receptors), they cause hyperpolarization (IPSPs), while in the CNS, they can be excitatory.

How is synaptic acetylcholine signaling terminated?

Primarily by enzymatic degradation. The enzyme acetylcholinesterase (AChE) in the synaptic cleft breaks down acetylcholine into choline and acetate.

What are the three main types of ionotropic glutamate receptors?

NMDA receptors, AMPA receptors, and Kainate receptors.

Which agonists activate each receptor subtype?

• NMDA Receptors: Activated by N-Methyl-D-Aspartate (NMDA).

• AMPA Receptors: Activated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA).

• Kainate Receptors: Activated by kainic acid (kainate).

Which ions pass through each of these receptors?

• AMPA & Kainate Receptors: Primarily permeable to Na+ and K+ (and sometimes Ca2+, depending on subunit composition).

• NMDA Receptors: Highly permeable to Na+, K+, and Ca2+. Their channel is blocked by Mg2+ at resting membrane potential.

Does activity at these receptors result in EPSPs or IPSPs?

Activation of all three ionotropic glutamate receptors results in EPSPs (excitatory postsynaptic potentials).

How is synaptic glutamate signaling terminated in the synapse?

Primarily by rapid reuptake via excitatory amino acid transporters (EAATs) located on astrocytes and neurons. It is not significantly degraded in the cleft like acetylcholine.