INTRODUCTION TO CNS PHARMACOLOGY

Action Potential’s Significance

Action potential is a crucial concept in neuroscience that plays a fundamental role in neuronal signaling. It refers to the brief electrical event that occurs in the membrane of a nerve cell (neuron) when it is stimulated, allowing it to transmit information over long distances.

Neurons are specialized cells responsible for transmitting electrical signals within the nervous system. These signals, known as action potentials, allow communication between neurons and facilitate the transmission of information throughout the body. Here’s how the process works:

1. Resting State: In the resting state, a neuron maintains a stable negative charge inside its membrane compared to the outside. This difference in charge is called the resting membrane potential and is typically around -70 millivolts (mV). It is primarily maintained by the concentration gradients of ions across the membrane and the selective permeability of ion channels.
2. Threshold: When a neuron receives a strong enough stimulus, such as an excitatory input from other neurons, sensory input, or a change in the local environment, it can reach the threshold potential. The threshold potential is the minimum depolarization required to trigger an action potential, usually around -55 mV.
3. Depolarization: If the threshold is reached, depolarization occurs. Depolarization is the rapid influx of positively charged ions, such as sodium (Na+) ions, through ion channels in the neuron’s membrane. This sudden influx of positive charge causes the inside of the neuron to become less negative and approach a more positive value. As a result, the membrane potential rapidly rises.
4. Rising Phase: Once depolarization reaches a critical point, typically around -40 mV, voltage-gated sodium channels open fully, causing a massive influx of sodium ions into the neuron. This influx leads to a rapid and dramatic increase in membrane potential, known as the action potential or the rising phase. The membrane potential quickly rises from the resting potential to around +40 mV.
5. Falling Phase: Following the rising phase, voltage-gated sodium channels become inactivated, and voltage-gated potassium (K+) channels open. The efflux of potassium ions out of the neuron repolarizes the membrane, restoring its negative charge. The membrane potential rapidly falls back towards the resting potential.
6. Undershoot: Sometimes, after repolarization, the membrane potential briefly becomes more negative than the resting potential. This temporary hyperpolarization is known as the undershoot or the afterhyperpolarization. It occurs because potassium channels remain open for a short period, causing an excessive efflux of potassium ions.
7. Resting State: Eventually, the ion channels return to their resting states, and the neuron’s membrane potential stabilizes back to its resting potential of -70 mV. The neuron is now ready to transmit another action potential if it receives a strong enough stimulus.

The importance of action potentials lies in their ability to propagate rapidly along the axon (a long, slender projection of a neuron) from the initial site of depolarization to the axon terminals. This rapid transmission allows for efficient and precise communication between neurons, enabling information processing and coordination of various physiological functions.

Additionally, the all-or-nothing nature of action potentials ensures the fidelity of information transfer. Once the threshold is reached, the action potential occurs with a consistent magnitude and duration, regardless of the strength of the initial stimulus. This property ensures that the information encoded in action potentials is reliable and robust.

In summary, action potentials are crucial for neuronal signaling. They serve as the electrical impulses that enable rapid communication between neurons and facilitate the transmission of information throughout the nervous system, allowing for coordinated responses and complex cognitive processes.

 

Neurotransmitters and Brain Functions

 

Two major Neurotransmitter Life Cycles

Acetylcholine and norepinephrine are two major neurotransmitters involved in the communication between nerve cells in the central nervous system (CNS) and the peripheral nervous system (PNS). Let’s explore the life cycle of each neurotransmitter:

1. Acetylcholine (ACh): Synthesis: Acetylcholine is synthesized in the nerve terminal by combining choline, obtained from the diet, with acetyl coenzyme A (acetyl CoA), derived from cellular metabolism. The enzyme choline acetyltransferase facilitates this synthesis process.

Storage: Once synthesized, acetylcholine is packaged into vesicles within the presynaptic nerve terminal. These vesicles act as storage units for the neurotransmitter until it is released.

Release: When an action potential reaches the nerve terminal, it triggers a series of events that cause the vesicles containing acetylcholine to fuse with the presynaptic membrane, leading to the release of acetylcholine into the synapse.

Binding and Receptor Activation: Upon release, acetylcholine diffuses across the synaptic cleft and binds to acetylcholine receptors on the postsynaptic membrane. This binding activates the receptors, initiating a response in the postsynaptic cell.

Termination of Signaling: The signaling of acetylcholine is terminated by the enzyme acetylcholinesterase, which is present in the synaptic cleft. Acetylcholinesterase breaks down acetylcholine into choline and acetate. Choline is then transported back into the presynaptic nerve terminal for recycling.

2. Norepinephrine (NE): Synthesis: Norepinephrine, also known as noradrenaline, is synthesized from the amino acid tyrosine. Tyrosine is converted into levodopa (L-dopa) by the enzyme tyrosine hydroxylase. L-dopa is further converted into dopamine, and then dopamine is converted into norepinephrine by the enzyme dopamine beta-hydroxylase.

Storage: Similar to acetylcholine, norepinephrine is stored in vesicles within the presynaptic nerve terminal until it is released.

Release: Upon the arrival of an action potential, the vesicles containing norepinephrine fuse with the presynaptic membrane, leading to the release of norepinephrine into the synapse.

Binding and Receptor Activation: Norepinephrine diffuses across the synaptic cleft and binds to adrenergic receptors on the postsynaptic membrane. There are several types of adrenergic receptors, such as alpha-1, alpha-2, beta-1, and beta-2, each with different effects when activated.

Reuptake: Norepinephrine reuptake transporters on the presynaptic membrane actively transport norepinephrine back into the presynaptic nerve terminal. This process is known as reuptake and serves to terminate the signaling of norepinephrine.

Metabolism: Once taken back into the presynaptic terminal, norepinephrine can be metabolized by the enzyme monoamine oxidase (MAO). MAO breaks down norepinephrine into inactive metabolites, such as dihydroxyphenylglycol (DHPG), which can be further metabolized and excreted.

The life cycle of neurotransmitters like acetylcholine and norepinephrine is a dynamic process involving synthesis, storage, release, receptor binding, termination, and recycling. These neurotransmitters play crucial roles in various physiological and cognitive processes, contributing to the functioning of the nervous system.

 

Drug mechanisms and classes

 

Agonists, Antagonists, and Biased

Let’s differentiate between agonists, antagonists, biased agonists, inverse agonists, and biased agonists:

1. Agonists: Agonists are molecules or drugs that bind to a specific receptor and activate it, leading to a biological response. They mimic the action of endogenous ligands (substances naturally present in the body) and stimulate the receptor to produce a response. Agonists can have varying degrees of efficacy, meaning they can activate the receptor to different extents, ranging from partial to full activation.
2. Antagonists: Antagonists, also known as inhibitors or blockers, are molecules or drugs that bind to a receptor without activating it. By binding to the receptor, antagonists prevent other molecules, including agonists, from binding and activating the receptor. Consequently, antagonists block or inhibit the biological response that would have occurred if the receptor had been activated. Antagonists can be reversible or irreversible, depending on their ability to dissociate from the receptor.
3. Inverse agonists: Inverse agonists are a special type of ligand that binds to the same receptor as an agonist but produces the opposite effect. Unlike antagonists, which simply block the receptor, inverse agonists actively stabilize the receptor in an inactive conformation, leading to a decrease in basal (constitutive) activity of the receptor. In some cases, receptors may have inherent activity in the absence of any ligand, and inverse agonists reduce this basal activity to below the baseline level.
4. Biased agonists: Biased agonists, also known as functional selective agonists, are ligands that preferentially activate specific signaling pathways or downstream cellular responses mediated by a receptor, while having reduced or no effect on other pathways. They exhibit selectivity in activating certain intracellular signaling cascades while sparing others. Biased agonism arises due to ligands stabilizing distinct receptor conformations, resulting in preferential coupling to specific signaling pathways.
5. Biased antagonists: This term is not commonly used, as the concept of biased action usually refers to ligands that activate a receptor in a selective manner. However, in theory, a biased antagonist could refer to a ligand that blocks specific downstream signaling pathways while sparing others. The term is not widely used because antagonists typically block all downstream signaling without displaying pathway selectivity.

In summary, agonists activate receptors and stimulate a biological response, antagonists block the receptor and prevent activation, inverse agonists stabilize an inactive receptor conformation, biased agonists selectively activate certain signaling pathways, and biased antagonists theoretically block specific downstream pathways.