2.3 Chemical messengers

2.3 Chemical messengers

What is a chemical messenger

is a substance that can transmit information within an organ or between organs. It requires specialized cells to release them and specific molecules to stop them.

Which types of chemical messengers do we have?

• Neurotransmitters

• Neuromodulators

• Hormones

• Pheromones

Neurotransmitters

• They are manufactured by neurons and their function is to transmit information through the synaptic cleft and nerve impulses.

• Chemical substances, created by the body, that transmit information signals from a neuron across synapses.

• Some drugs can be very similar to neurotransmitters in part of their chemical structure, allowing them to act through the receptors for these neurotransmitters.

Neuromodulators

• Chemical substances released by neurons that can modify the effects of neurotransmitters.

• Neuromodulators do not produce postsynaptic potentials; instead they modulate the activity of a large number of neurons.

  • E.g. Endorphin

Hormones

• Chemical messengers of the body and are part of the endocrine system.

• They are produced by the endocrine glands, transported through the bloodstream to tissues and organs, and control most of our body's major systems.

Pheromones

Chemical substances produced by other animals that affect reproductive physiology and behavior.

Criteria which define a substance as a neurotransmitter

• It is synthesized and present inside the presynaptic neuron.

• The substance must be released in response to presynaptic depolarization (Ca+ dependent).

• It is released in sufficient quantity to exert a defined action on the postsynaptic neuron.

• Specific receptors for the substance must be present on the cell.

• When administered from the outside (as a drug) it exactly mimics the action of the endogenous release transmitter.

• There is a specific mechanism to remove it from its site of action (the synaptic cleft).

Types of neurotransmitters:

• There are a number of neurotransmitters but acetylcoline (ACh) and noradrenaline (epinephrine) are the main types.

The synapses releasing the acetylcholine

known as the cholinergic synapses

Synapses releasing the noradrenaline

Known as the adrenergic synapses

Sequence of event typical cholinergic synapses

• an arriving action potential depolarizes the presynaptic membrane.

• the calcium (Ca2+) ion channels open and the calcium ions enter the cytoplasm of synaptic knob.

• the calcium ions cause synaptic vesicles to fuse with the presynaptic membrane and release their content (ACh) into synaptic cleft through exocytosis.

Neurotransmitter groups

Neurotransmitter: ACETYLCHOLINE

• Excitatory effect

• Receptor: Cholinergic (muscarinic and nicotinic)

• Functions: Parasympathetic response, skeletal muscle, memory

Synthesis of ACETYLCHOLINE

• Choline and Acetyl coenzyme A: Acetylcholine

• First neurotransmitter discovered.

• Main neurotransmitter secreted by efferent axons from the central nervous system to the peripheral nervous system.

• Important role in learning and memory.

• ALL MUSCLE MOVEMENT IS CARRIED OUT BY THE RELEASE OF ACETYLCHOLINE

Storage of ACETYLCHOLINE

• In presynaptic terminals

Vesamicol: causes a depletion of acetylcholine in vesicles.

Reuptake of ACETYLCHOLINE

• Choline transporter, key in the reuptake function.

• Hemicholine: Inhibits the choline transporter.

Role of acetylcholinesterase

ACh is degraded by the enzyme acetylcholinesterase (AChE), present in the postsynaptic membrane.

Receptors of ACETYLCHOLINE

• Muscarinic Receptors (metabotropic)

• Nicotinic Receptors (ionotropic)

Effects of ACETYLCHOLINE

• located in the dorsolateral pons has a role in REM sleep

• located in the basal forebrain are involved in activating the cerebral cortex, facilitating perceptual learning.

• located in the medial septum control the electrical rhythms of the hippocampus and modulate its functions of formation of memories.

Parasympathetic Nervous System release the neurotransmitter:

Both pre- and post-axons release ACETYLCHOLINE.

Sympathetic Nervous System release the neurotransmitters:

• Preganglionic axons → Ach

• Postganglionic axons → NA

Neurotransmitter: EPIEPHRINE

• Receptor: Alfa & Beta adrenergic

• Functions: Sympathetic response

Neurotransmitter: NOREPINEPHRINE

Excitatory effect

Receptor: Alfa & Beta adrenergic

Functions: Sympathetic response, arousal, attention, mood

Adrenergic receptors

• Sensitive to adrenaline as well as noradrenaline.

Receptors B1 + B2 =

• They increase the neuron's response to its excitatory synapses.

Receptor A1 =

• Postsynaptic slow depolarisation - Excites the neuron, making it more likely to fire.

Receptor A2 =

• Slow hyperpolarisation - Inhibits the neuron, making it less likely to fire.

• Pre- (autoreceptors) and postsynaptic - regulate the release of noradrenaline and act as a feedback mechanism.

Medications and Drugs Affecting Noradrenaline:

• Reserpine

• Clonidine

• Propranolol

• MDMA (Ecstasy) and Cocaine

• Selective NA Reuptake Inhibitors (SNRIs)

Reserpine

storage inhibitor that prevents the vesicles from storing noradrenaline.

Clonidine

• autoreceptor agonist that inhibits noradrenaline synthesis and release.

• often used to treat opioid withdrawal

Propranolol

• A beta-receptor antagonist, which blocks the action of noradrenaline (and adrenaline).

• Used in treatment for anxiety disorders.

MDMA (Ecstasy) and Cocaine

• These drugs inhibit the reuptake of noradrenaline, along with serotonin and dopamine.

• Cause a rush of euphoria by increasing the levels of noradrenaline

Selective NA Reuptake Inhibitors (SNRIs)

• Reboxetine, a medication that inhibits the reuptake of noradrenaline, increasing its levels in the brain.

• used for depression, especially in cases where fatigue, apathy, and cognitive impairment are present due to low noradrenaline.

NOREPINEPHRINE/ Noradrenaline pathways

From locus coeruleus to different parts of the encephalon.

The signals are sent to amygadala, thalamus, hypothalamus, hippocampus and cortex.

Noradrenaline and Mood Disorders

• Both noradrenaline (NA) and serotonin (5HT) are involved in mood disorders like depression, anxiety, and bipolar disorder.

• Low levels of NA are associated with fatigue, apathy, and cognitive disorders, contributing to conditions like depression.

Adrenaline/Epinephrine

• Molecule that carries information or message between the organs and the body (body periphery).

• Prepares the body as a fight or flight system.

• Works more like a hormone rather than neurotransmitter

Noradrenaline/Norepinephrine

• It acts with similar functions to Adrenaline but rather as a neurotransmitter

• Its identification was carried out by Von Euler in 1946.

• Increases the state of vigilance (alertness, arousal, activation).

• It prepares us to face events

• Food and hunger control

• Sexual behavior

• Learning, memory and attention

Neurotransmitter: DOPAMINE

Inhibitory effect

Receptors: DA1, DA2, DA3, DA4, DA5 (five types of receptors)

Functions: reward & reinforcement, motivation, extra-pyramidal motor control

DOPAMINE produce

It can produce EPSP or IPSP depending on the postsynaptic receptor.

DOPAMINE involved in

• Movement

• Attention

• Learning

• Reinforcing effects of drugs - triggers dopamine release in the nucleus accumbens

Disorder related to DOPAMINE alteration

Parkinson´s Disease

Symptoms:

• Tremors

• Stiffness of the limbs

• Alterations in balance

• Difficulty in initiating movements.

Causes of Parkinson´s Disease:

• Degeneration of the Nigrostriatal System = degeneration of dopaminergic neurons in the substantia nigra which connects to caudate nucleus (brain region involved in controlling movement)

• Dopamine Loss = loss of these neurons leads to the characteristic motor symptoms of Parkinson's disease.

Treatment for Parkinson´s Disease:

• L-DOPA = precursor to dopamine

• Deep Brain Stimulation (DBS) = implanting a device that sends electrical impulses to specific areas of the brain

Receptors of DOPAMINE

• Indirect transduction (G Protein)

• D1 and D5 (act through G protein)

• D2, D3 and D4 (acting through G-proteins)

• D2 and D3 (autoreceptors)

Degradation enzymes of DOPAMINE

• MAO and COMT(catechol-O-methyltransferase)

• Inhibitors

  • MAO: clorgiline, selegiline, tranylcypromine and phenelzine)

  • COMT: tropolone, tolcapone and entacapone)

Metabolite after inactivation related to DOPAMINE

Homovallinic acid (HVA)

Dopamine and social media

• Social media and new technologies can activate the dopamine system by giving instant rewards (likes, notifications, etc.).

• This can make these platforms addictive, as they provide constant stimulation and feedback, leading to frequent dopamine surges.

• Some people might develop dopamine-driven addictive behaviors as they seek the rewarding sensations from using social media, often at the cost of other important activities.

DOPAMINERGIC NEURONS

• The brain contains several systems of dopaminergic neurons.

• The most important originate in the midbrain: in the substantia nigra and in the ventral tegmental area

Dopaminergic neuronic pathways

• Mesocortical pathway

• Mesolimbic pathway

• Nigrostriatal pathway

• Tuberoinfundibular pathway

Mesocortical pathway

Essential cognitive pathway, connecting the ventral tegmental area (VTA) with the cerebral cortex, particularly at the frontal level.

Mesolimbic pathway

Connects the VTA with the limbic system.

Associated with reward mechanisms and sustained attention.

Nigrostriatal pathway

• Pathway from substantia nigra to basal ganglia.

• Influences movement control.

Tuberoinfundibular pathway

Pathway from the arcuate nucleus of the mediobasal hypothalamus to the median eminence.

Regulates prolactin secretion.

Hypothalamus-Pituitary Axis.

Dopamine functions

• Movement, attention, learning, and the reinforcing effects of drugs that people tend to abuse.

Dopamine and catecholamine

Dopamine constitutes about 80% of the catecholamine content in the brain.

Functions of Dopamine inside the PNS

• In blood vessels it inhibits norepinephrine release and acts as a vasodilator.

• in the kidneys it increases sodium excretion and urine output.

• in the pancreas, it reduces insulin production.

• in the digestive system, it reduces gastrointestinal motility and protects intestinal mucosa

• in the immune system, it reduces the activity of lymphocytes

Stimulus Perception of dopamine

When a rewarding stimulus (e.g., food, a social connection, or a pleasurable activity) is encountered, sensory information is processed by the brain.

Dopamine Release

The VentralTegmentalArea releases dopamine, a neurotransmitter associated with pleasure and reward, into the nucleus accumbens and other connected regions.

Feedback Loop in dopamine

• The nucleus accumbens signals the prefrontal cortex, leading to conscious awareness of the reward and motivation to repeat the behavior.

• The hippocampus and amygdala encode contextual and emotional aspects of the rewarding experience

Behavior Reinforcement

Dopamine surges reinforce behaviours, making individuals more likely to repeat actions that lead to similar pleasurable outcomes.

Neurotransmitter: SEROTONIN

Inhibitory effect

Receptors: 5HT1, 5HT2 — 5HT7 (seven types of receptors).

Functions: Digestion, sleep, anxiety, mood, appetite, social behvaiour

Where is SEROTONIN Produced?

• Serotonin is produced by neurons in the Raphe nuclei (a group of cells in the brainstem)

Tryptophan

• Tryptophan is an amino acid found in food that is a precursor to serotonin.

• Serotonin (5-HT) is a neurotransmitter that helps regulate many behaviors and emotions.

Functions of SEROTONIN

• Ingestion: Helps control appetite and eating behavior.

• Dreaming: Involved in regulating sleep, especially during dreams (REM sleep).

• Mood: Affects mood, and low levels are linked to depression.

• Pain Regulation: Helps reduce pain perception in the body.

• Termination of the Stress Response: Helps stop the body's reaction to stress once it's no longer needed.

• Key role in mental disorders

Degradation of SEROTONIN

• Serotonin is broken down in the body by an enzyme called monoamine oxidase (MAO).

• MAO works both inside the cell (intracellular) and outside the cell (extracellular) to break down serotonin, reducing its levels in the synapse.

First Antidepressants Discovered

Monoamine Oxidase Inhibitors (MAOIs)

• They work by inhibiting MAO, preventing the breakdown of neurotransmitters like serotonin

Reuptake of SEROTONIN

After serotonin is released into the synapse, it is typically reabsorbed (reuptake) by the presynaptic neuron via active transport pumps, specifically the serotonin transporter (SERT).

Antidepressants and 5HT

• Reuptake inhibitors (like SSRIs) block the reabsorption of serotonin, making more serotonin available in the synapse. This action increases serotonin levels and helps improve mood and alleviate depression symptoms.

 antidepressants interact

• Interact with one or more receptors related to monoaminergic receptors.

  1. Block the reuptake of monoamines

  2. Block alpha-2 receptors

  3. Block monoamine oxidase (MAO) enzyme

Which cortex is affected during depression?

Ventromedial prefrontal cortex

Receptors SEROTONIN

Receptors (at least 9 types identified)

- 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E

- 5-HT2A, 5-HT2B, 5-HT2C

- 5-HT3

- 5-HT4

- 5-HT5A, 5-HT5B

- 5-HT6

- 5-HT7

SEROTONIN Mood Regulation

Serotonin is commonly associated with mood stabilization. It helps regulate mood, happiness, and well-being. Low levels of serotonin are linked to depression and anxiety.

SEROTONIN

SEROTONIN

SEROTONIN Appetite and Digestion

In the gastrointestinal tract, serotonin influences appetite, satiety, and digestion.

About 90% of the body's serotonin is found here.

It helps control gut motility, aiding in processes like peristalsis and the secretion of digestive enzymes.

SEROTONIN Sleep Regulation

Serotonin plays a crucial role in the sleep-wake cycle.

It is converted into melatonin in the pineal gland, which helps regulate sleep patterns.

Serotonin levels also influence the quality of sleep.

SEROTONIN Cognitive Functions

Serotonin impacts learning, memory, and cognition.

It affects how we process information, make decisions, and learn from experiences.

SEROTONIN Nausea and Vomiting

Serotonin receptors in the gut and the brainstem's chemoreceptor trigger zone can trigger nausea and vomiting, especially in response to toxins or chemotherapy drugs.

SEROTONIN Blood Clotting

Serotonin can promote vasoconstriction and platelet aggregation, aiding in blood clotting.

It's released by platelets to facilitate wound healing.

SEROTONIN Pain Perception

Serotonin can modulate pain perception.

It's involved in the descending pain pathways that inhibit pain signals, contributing to pain relief.

SEROTONIN Sexual Function

Serotonin affects sexual behavior and libido. High levels of serotonin can decrease sexual desire and can cause sexual dysfunction, which is one reason why some antidepressants that increase serotonin might lead to side effects like reduced libido.

SEROTONIN Bone Health

Recent research suggests serotonin might have roles in bone metabolism, influencing bone density and structure, although the exact mechanisms can be complex and involve both central and peripheral serotonin pathways.

SEROTONIN Stress Response

It plays a role in how the body responds to stress, interacting with the hypothalamic-pituitary-adrenal (HPA) axis to modulate stress hormone release.

SEROTONIN Social Behavior

Serotonin is implicated in social behavior, aggression, and even decision-making in social contexts.

It can modulate prosocial behaviours like cooperation and empathy.

SEROTONIN Temperature Regulation

Serotonin helps regulate body temperature, influencing thermoregulatory responses.

Neurotransmitter: GLUTAMATE

Receptors: NMDA, AMPA, Kainate

Functions: Main excitatory transmitter (CNS)

GLUTAMATE

Most important or principal excitatory neurotransmitter in the brain and spinal cord.

Responsible for 75% of neurotransmissions.

Synthesis of GLUTAMATE

by the transmission of α-ketoglutaric acid.

Receptors of GLUTAMATE

• Kainate receptor

• NMDA Receptor

• AMPA Receiver

Roles of GLUTAMATE

• Vital role in learning and memory

• Learning and Long-Term Potentiation (LTP)

• Excitotoxicity

  Chinese Food Syndrome

  • Monosodium glutamate (MSG), often found in Chinese food, can cause neurological symptoms in sensitive individuals.

Why can Chinese Food Syndrome occur?

When we eat a lot of food with GLUTAMATE

because GLUTAMATE is the most excitatory mechanism

Excitotoxicity

Occurs when there is an excess of glutamate in the brain, which can lead to neuronal death.

This happens due to high calcium levels inside the neuron, leading to the formation of free radicals that can damage and kill neurons

Learning and Long-Term Potentiation (LTP)

Glutamate is involved in learning through the mechanism LPT

NMDA receptors (a type of glutamate receptor) are critical for synaptic changes that underlie learning = biological basis of learning

Chinese Food Syndrome sympotoms:

• Vertigo

• Tachycardia (rapid heart rate)

• Nausea and vomiting

• Temporary paralysis

GLUTAMATE action through receptors

Acts through several types of receptors, including ionotropic receptors which directly affect ion channels, and metabotropic glutamate receptors (mGluRs) which influence intracellular signaling pathways.

Why is the balance between glutamate and inhibitory neurotransmitters like GABA vital?

Glutamate is excibitory, while GABA is inhibitory.

The balance between them is vital for maintaining normal brain function.

Dysregulation in glutamate

Can lead to various neurological and psychiatric conditions, which is why glutamate modulators are explored for therapeutic purposes in disorders ranging from schizophrenia to depression.

Neurotransmitter: GABA

Receptors: GABAA & GABAB

Functions: Main inhibitory transmitter (brain)

Functions of GLUTAMATE

• Neuronal Excitation

• Learning and Memory

• Brain Development

• Sensory Information Processing

• Motor Control

• Neurotransmitter Release

• Pain Sensation

• Cognitive Functions

• Mood Regulation

• Neurotoxicity

• Synaptic Plasticity

• Addiction and Reward

Motor Control of GLUTAMATE

Involved in motor control in the spinal cord

Neurotransmitter Release of GLUTAMATE

• Glutamate can influence the release of other neurotransmitters, both excitatory and inhibitory, by acting on presynaptic receptors to either enhance or inhibit neurotransmitter release.

Pain Sensation of GLUTAMATE

• Glutamate is a key player in the transmission of nociceptive (pain) signals.

• It's involved in both acute pain signaling and in the central sensitization that contributes to chronic pain conditions.

Cognitive Functions of GLUTAMATE

• Beyond learning and memory, glutamate influences other cognitive functions such as attention, decision-making, and executive functions through its actions in various cortical areas.

Mood Regulation of GLUTAMATE

• Although primarily known for its excitatory role, imbalances in glutamate signaling can contribute to mood disorders.

• For instance, excessive glutamate activity has been implicated in conditions like depression and anxiety.