How does the human nervous system function? - Chapter 1

The different neurons in our brains, and in particular the interaction between them, are responsible for human behaviour. They do this by sending and receiving neurotransmitters. Knowledge of associated processes is very important to have a good understanding of the effect of psycho pharmaceuticals.

This chapter describes the functioning and interaction of neurons to get a better picture of how the brain responds to the environment and adapts to it.

What does the structure of neurons look like?

The different neurons in our brains do not all look the same. The function and location of the neuron affects the size, shape and other properties of the neuron. The three most important neuronal groups are sensory neurons, motor neurons and interneurons. The sensory neurons pick up signals, the brain interprets these signals and the motor neurons then respond to this. In the central nervous system you find the interneurons which enables the transition between the other two groups of neurons.

The cell body

The cell body is also called soma and is the largest part of the neuron. Here the metabolism of the cell takes place and you can find the nucleus with DNA.

Dendrites

Dendrites receive signals from surrounding neurons. The more dendrites a neuron has, the more information this neuron can receive. The location of the neuron affects the number of dendrites, for example, interneurons have more dendrites than neurons in the spinal cord.

Axons

The signal from the neuron is passed through the axon, which is an extension of the cell body and can have a length of a few millimetres to tens of centimetres. The axon hillock is the place where both the axon and the electrical signal start. Some axons have a myelin layer, especially the peripheral axons. The myelin is a glial cell that isolates the axon and enables an accelerated transportation.

Terminal button

The end of the axon is called the terminal button. Here, neurotransmitters are stored, released and in some cases reuptake takes place. A particular protein is very important for this reuptake, which will  get more attention later in this chapter, as many psychotropic drugs work on this protein.

Neural transfer

The neural transfer is the process by which the signal from the terminal button is transported to the dendrite of the next neuron (in the central nervous system). Signals are transmitted through nerves in the peripheral nervous system.

Electrical activity in the neuron

The lipid bilayer is a double layer of lipids that form the membrane of the neuron. This membrane enables that the neuron can have its own internal environment. In the membrane there are proteins which enable that glucose and ions can enter the cell and carry waste products out of the cell. By transporting the ions, the electric potential of the neuron changes. The important ions are An - , Cl - , Na + and K + . The sodium and chloride ions only enter the cell when they are permitted, through the ion channels (proteins). They become active due to changes in the membrane.

Resting potential

The charged ions have to deal with two forces: diffusion and electro stasis. When there is an equilibrium between these forces, a state of rest takes place. The electrical potential of the neuron during rest is determined by the distribution of the positive and negative ions. Due to the cellular properties, cells are negatively charged during the resting potential, while a positive charge exists outside the cell. There is often a load of -70 mV in the cell. This resting potential helps the cell store energy. This energy can be used when the cell is activated.

Graded potentials

As soon as a neuron receives a signal from another neuron, the resting potential (-70mV) is disturbed. This disturbance is called a graded potential . In case of rapidly successive or simultaneous graded potentials , the threshold value is reached and the neuron depolarizes, creating an action potential.

Action potentials

The threshold value for depolarization and thus the creation of an action potential is approximately  -55mV. During a depolarization a load shift occurs from -70 to +30mV. This is because the sodium ions (Na+) are left through the cell membrane. In addition, some negative ions leave the cell. After this, the resting potential restores, resulting in a short hyper polarization in the membrane. The action potential alone lasts only 1 millisecond.

Once the action potential reaches the terminal button, neurotransmitters will be released allowing the receiving neurons to transmit the process.

The degree of intensity of the action potential is always the same: there is an all-or-none principle. A neuron therefore always has the same intensity when transmitting the signal. There are other factors that can contribute to the strength of the signal: the amount of neurons that are active and the amount of the action potentials.

The properties of the axon determine the speed at which an action potential reaches the next neuron. Both the resistance (smaller in the case of larger axons) and the myelin sheathing result in greater speed. The myelin in the central nervous system consists of oligodendrocytes. In the peripheral nervous system Schwann cells produce the myelin. Between each glial cell the axon has a small opening called nodes of Ranvier. Here sodium can facilitate depolarisation.

The action potential does not slide along the axon, but goes from node to node in jumps. This is called saltatory conduction and this makes the process run faster.

The above knowledge tells us why diseases where myelin disappears (such as MS) have such far-reaching consequences: the nerve impulses move much more slowly.

Other glial cells than previously mentioned, the astrocytes, also play an important role in the nervous system. They help with the migration of developing neurons and with the formation of connections between different neurons.

The communication between neurons mainly consists of the release of neurotransmitters. Less common is the electrical synapse, where an electrical signal from neuron to neuron is transmitted. The process of the electrical synapse will not be discussed further.

How does synaptic transfer proceed?

Release of neurotransmitter

When an action potential reaches the terminal button, calcium can penetrate here too. This allows that the neurotransmitters in the presynaptic membrane can be released. The amount of calcium determines the amount of neurotransmitters that will be released. This is controlled by proteins, which can affect certain drugs.

Receptors

The postsynaptic membrane of the receiving neuron captures the neurotransmitter in receptors. The molecular design of the receptor determines which neurotransmitters can and cannot bind. Drugs work on this fact: they can mimic the action of neurotransmitters and thereby bind to a receptor, or they can block receptors instead.

An ionotropic receptor directly controls the ion channel. A metabotropic receptor is bound to ion channels that it does not control itself. This enables that ionotropic receptors are much faster. However, the metabotropic receptors need more time.

Re-uptake of neurotransmitter

Some neurotransmitters are broken down by enzymes once the signal has been passed to the next neuron. These enzymes are made by the same neuron that makes the neurotransmitters. The broken down substances are then taken up again by the terminal button where they will be recycled. Sometimes neurotransmitters are recycled as a whole. The process of reuptake is controlled by transporter proteins. More of these proteins gives a quicker reuptake process. Different drugs can influence this, these drugs can facilitate that the breakdown process or reuptake will be blocked.

Excitatory and inhibiting synapses

The permeability of the postsynaptic membrane can be adjusted by allowing some cells to enter the cell. The ion channels allow both positive and negative ions to enter the cell. Positive ions facilitate that the membrane becomes depolarized (becomes more positive). This is what happens with exciting neurotransmitters. They send excitatory postsynaptic potentials (EPSPs). When negative ions are allowed to enter the cell, the action potential is inhibited (the cell becomes more negative). This happens with inhibitory neurotransmitters, which send inhibitory postsynaptic potentials (IPSPs). Both EPSP and IPSP can take place simultaneously. To achieve an action potential, there must be more EPSPs than IPSPs, otherwise the threshold value will not be reached.

There are neurons that are specifically excitatory or inhibitory. Other neurotransmitters are sometimes excitatory and sometimes inhibitory. In the last case, the effect will be determined by proteins in the postsynaptic receptor.

Autoreceptors

Autoreceptors are receptors located on the presynaptic neuron. They regulate the activity of this neuron. The amount of neurotransmitters that is released can thus be controlled. The autoreceptor does this by regulating the internal cell process via secondary messenger systems.

Heteroreceptors

Heteroreceptors receive neurotransmitters from other neurons. Like autoreceptors, these receptors are metabotropic, so the effects are obtained by a secondary messenger system. These receptors can both enhance or inhibit the process within the cell.

What is the function of neurotransmitters?

About fifty different neurotransmitters are known. Other substances in the nervous system are called neuromodulators. They modulate the effects of neurotransmitters. A substance is called a neurotransmitter when:

• the substance is synthesized and stored in the presynaptic neuron;
• the substance is released into the synapse after activation of the neuron;
• the substance a postsynaptic effect causes after interaction with the receptor;
• there is a breakdown or reuptake mechanism.

Acetylcholine

Acetylcholine was the first neurotransmitter that was discovered (1921). A disease in which acetylcholine plays an important role is Alzheimer's disease. The amount of acetylcholine in the basal forebrain decreases. To treat Alzheimer's symptoms, medication with acetylcholine can be administered.

There are two types of acetylcholine receptors: muscarinic (metabotropic) and nicotinic (ionotropic) receptors. The first type of receptor is important in cognitive and motor functions and for reward. The second type of receptor can be found on all muscle cells. When they bind with acetylcholine, they control the calcium channels which leads to muscle contractions.

Norepinephrine

Norepinephrine is spread by both the central and the peripheral nervous system. The neurotransmitter play a role in the maintenance of cortical excitation by using the reticular activating system (RAS) . This system affects attention, emotion and food. Organ regulation is also an important part. There are different types of receptors to which norepinephrine can bind and these receptors all have different functions. All receptors for norepinephrine are metabotropic, so they activate secondary messenger systems. There are two subtypes, α and β which in turn consist of two types. The α 1 , β 1 and β 2 receptors are excitatory and the α 2 receptor is inhibitory.

Dopamine

Dopamine can be found in the nigrostratial pathway (substantia nigra, which is important for voluntary movement and the initiation of movement), the pathway in the ventral tegmental areas of the punch (mesolimbic system) and the pathway that projects on the frontal cortex (mesocortical system or the reward system). When dopamine in the nigrostratial pathway decreases, Parkinson's disease may develop. Drugs mainly affect the reward system. The three pathways mentioned also seem to play a role in schizophrenia.
The two main receptors in dopamine (D 1 and D 2) activate the secondary messenger system, but have opposite effects. D 1 activates the second messenger AMP and D 2 inhibits it.

Serotonin

Serotonin belongs to the monoamines and diffuses in the brain and spinal cord. Serotonin affects the sleep-wake pattern, mood, aggressive behaviour and appetite. This neurotransmitter, like the previously mentioned neurotransmitters, develops in the brainstem. There are many different subtypes of serotonin, some of them possess autoreceptors and some have metabotropic receptors. The many different receptors have their own functions and can be found in different areas in the brain.

Glutamate

Glutamate is an amino acid that is obtained from glutamine. The substance plays an important role in long-term potentiation , this is the process of changing the neuronal functioning to benefit learning and memory. Glutamate does not appear in the brainstem. The brain areas with projections on the cerebral cortex, hippocampus and the cerebellum contain the most glutamate. The receptors for glutamate can be both ionotropic and metabotropic. You have the receptors AMPA, kainate and NMDA, but the main receptor is NMDA. This receptor can be both ionotropic and metabotropic and plays an important role in long-term potentiation. It turns out that long-term potentation is one of the long-term synaptic changes that plays a role in learning. Drugs that disrupt NMDA can therefore hinder learning.

GABA

The largest inhibitory neurotransmitter is GABA (Gamma-Amino-Butyric Acid). This neurotransmitter is located in both the brain and the spinal cord. Neural inhibition is important for regulating and controlling all physiological and behavioural functions. Different drugs have an effect on the functioning of GABA, resulting in changes in behaviour and mood. The neurons secreting GABA are located in different brain areas such as the basal ganglia and the cerebellum. Most of the GABA neurons are interneurons. The receptors can be ionotropic (GABA A) or metabotropic (GABA B). Most drugs have an effect on the GABA A that functions both as a postsynaptic and as an autoreceptor (regulation of the synthesis and release of GABA).

Endorphins

Endorphins consist of peptide neurotransmitters that chemically resemble opiates. These neurotransmitters are located in the brain and spinal cord. Different behavioural and psychological processes are influenced by this neurotransmitter group including the feeling of being surprised, a feeling of euphoria, discouraging the influence of stress and the regulation of the intake of food and drink (metabolic processes). Three types of receptors for endorphins are known and all are metabotropic. These three are μ (mu), κ (kappa) and δ (delta).   

Substance P

Substance P belongs to the peptide neurotransmitters. This substance mainly receives messages from the nociceptors and plays a role in pain.

What is important in the organization and structure of the nervous system and the brain?

The nervous system consists of the central (brain and spinal cord) and peripheral (muscles, glands, organs and skin) nervous system. These two nervous systems have to work together. Drugs used for psychological disorders often have an effect on both systems. During treatment, the focus is on effects on the central nervous system, while there are often many peripheral side effects.

The central nervous system

The cerebral cortex is the outer part of the brain, including many other structures. The left and right half of the cortex are separated by the longitudinal sulcus. The two sides are also called hemispheres.

Cerebral cortex

As mentioned above, the thin outer layer of the brain is the cerebral cortex and is also called the neocortex. There are many deep grooves in the cortex these are called fissures or a sulci. A protrusion (brainwinding) is called a gyrus. The cortex can be divided into four lobes: the frontal lobe, temporal lobe, parietal lobe and the occipital lobe. These lobes are subdivided into several functional areas.

Spinal cord

Messages to and from the brain are spread through the spinal cord. In addition, the spinal cord regulates reflexes in which the brain is not involved since reflexes can be seen as simple, automatic responses.

Medulla

The medulla is the lowest part of the brain and is located just above the spinal cord. The medulla is important in the control of the vital functions (for example breathing, heartbeat, blood pressure, consciousness, reflexes), awareness and regulation of reflexive functions (such as sneezing and coughing).

Punch

The punch is located (dorsally) above the medulla. This structure is important in refining the motor signals and processing sensory (especially visual) information.

Cerebellum

The main function of the cerebellum is to coordinate and regulate motor movement. The cerebellum refines movements (for example the timing of movement). In timed movements, the process of learning is very important. When this structure gets damaged, movements become awkward and uncoordinated. In addition, speech can deteriorate.

Reticulate formation

The reticular formation consists of neural structures from the medulla to the thalamus. These structures are important for awareness and controlling excitement and alertness. This series of structures is called the reticular activating system (RAS). It seems that this system produces too little excitement in people with ADHD.

The reticular formation also appears to be important in the sleep pattern. Little is known about this, however. We do know that people with damage to these structures are extremely drowsy and they can even get into a coma for a long time.

What is the function of the limbic system?

The limbic system is very important for emotion and motivation. In addition, the associated structures also play a role in learning and memory. The limbic system includes the amygdala, the hippocampus, the nucleus accumbens and the hypothalamus (partly). Damage or stimulation of areas in this system can give raise to extreme reactions to a situation or a reduced emotional response.

Amygdala

The amygdala is located in the inferior temporal lobe. The structure is important in the expression of anger, aggression, learning and fear of motivated behaviour. The amygdala is also important in social cognition and decision making. Damage in this area ensures that a memory no longer evokes an emotional state.

Nucleus accumbens

The nucleus accumbens is part of the mesolimbic-cortical system, which is an important pathway for dopamine.

Hippocampus

The hippocampus is particularly important in forming new memories. This structure seems to be sensitive to stress. People who experience a lot of stress often have a smaller hippocampus. People with schizophrenia or post-traumatic stress disorder also have a reduced hippocampus. The stress hormone cortisol can cause both atrophy (tissue decline due to cell death) and the growth of new cells. Both can lead to a decreased memory.

Hypothalamus

'The hypothalamus is located beneath the thalamus and above the optic chiasm. This structure plays a role in physiological functions and the motivation of behaviour. In addition, the hypothalamus is important for the neuro-endocrine system. This structure facilitates the production of hormones that activate the pineal gland. The pineal gland produces different hormones (growth hormone, male hormones, female hormones, etc.).

Thalamus

The thalamus consists of two oval-like lobes that lie next to each other, each in a different brain. All sensory information (except smell) is passed through the thalamus.

What is the function of the basal ganglia?

The basal ganglia includes the caudate nucleus, putamen and the substantia nigra. These brain structures receive information from both the cortex and the thalamus. This information is used by the basal ganglia for the coordination of motor movement. People with Parkinson's disease suffer from a reduced amount of dopamine in the substantia nigra. This reduces the activity in the entire basal ganglia. Another movement disorder, tardive dyskinesia seems to arise when people use antipsychotics for a longer period of time. These medications block dopamine receptors, by which they make them hypersensitive. This, in turn, causes excessive movement.

What is being studied in psychopharmacology? - Chapter 2

Pharmacokinetics is the science that studies how chemical agents are absorbed and distributed in the body and how they leave the body. The effects of these agents depend on the amount of drugs, how quickly the drug diffuses through the body, the way of intake and the environment of ingestion. The same medicament often has several names. You have the chemical name which tells us what kind of substances are in the product and the amount of them. There is also the brand name, which is the name that can only be possessed by one company (the company of that brand), because that company has patent on this name. You can see it in the pharmacy. If a certain medicament is older than five to seven years, the patent expires. This means that other companies may copy the drug (with the same content). This content is called a generic drug and it has one generic name.

In what ways can medication be administered?

Absorption of medication is how the medicine is taken in, how it enters the bloodstream and how it spreads through the body. The focus of this book is mainly on how a drug reaches the brain. How quickly and how many drugs the brain reaches depends on various factors including how the drug has to be administered:

Oral: this is the most common way. A medicament must be able to pass through the stomach acids and not be broken down by these acids. It must be fat-soluble to some extent so that it can pass through the stomach wall by diffusion. Oral intake may take longer before the drug comes into effect.

Inhalation: some drugs are inhaled, such as nicotine and asthma inhalers. Thus the agents are quickly absorbed into the blood, because the lungs have a large area with many blood vessels in it. For this to work, someone must have a stable blood level.

Intravenous (IV): administering a medicament via an infusion. The drug gets directly into the blood vessel, and that’s why this way is very fast. However, this way is dangerous, because of the rapid absorption. In this kind of situations, an overdose can occur quickly.

Intraperitoneal: the drugs are inserted into the abdominal cavity. This method is not used in humans because of the risk of inflammation or damage to the organs. This is the reason why this method is only used in lab animals when the drugs have to be taken up quickly. Intravenous is too difficult to use with lab animals because they are often very small.

Intramuscular: medicaments are absorbed through the muscles more slowly but more stable. Hormones are often injected in this way.

Transdermal: this is the absorption through the skin which is usually done with a plaster or gel. This makes the process often very slow. This, in turn, makes this manner ideal for resources that need to be absorbed evenly over a longer period of time. Examples are nicotine patches and hormonal contraception in women. The drug has to be able to pass through fatty substances, otherwise it will not pass through the skin.

Subcutaneous: this is the insertion of a substance under the skin by means of an injection or an implant that regularly releases a dose of medication.

Once the drug is absorbed in the body, there is more to be done. A substance cannot just leave, but has to pass through different membranes. A membrane consists of two layers of fat molecules. These are phosphide molecules consisting of a head and a tail. The heads are directed towards the outside and are hydrophilic (water-attracting), the tails are directed inwards and are hydrophobic (water-repellent). As a result, aqueous substances cannot simply pass through the membrane. The substances must be transported by transport cells or they have to consist of fat molecules to pass through the membrane. Transport cells take the substance with them and then travel through the membrane.

In addition to membranes, the drug must also pass through small blood vessels called capillaries to get in and out of the blood stream. The capillaries have miniscule holes through which some substances can get through. If a substance is too large, it has to be removed by a diffusion process. There are two types of capillaries, those of the body and those of the brain.

The brain needs a very stable and protected environment in order to function properly. This is why the capillaries exist. Without them, it would be more difficult to get through; they are surrounded by glial cells, called astrocytes. Together they form the blood-brain barrier (BBB). Due to this barrier only essential substances such as glucose and some amino acids can pass without problems. Other substances can only come through via special transport. In this way the brain is protected against the dangerous effects of all kinds of toxic substances.

There is another special barrier in the body in women, namely the placental barrier when she is pregnant. This protects the foetus and ensures that the blood of the mother can pass through the placenta. In addition, this barrier ensures that the harmful substances can be removed from the foetus. Unfortunately, this barrier also allows medications to facilitate developmental problems in the foetus.

What is meant by drug metabolism?

Drug metabolism is the processing and secretion of the drug from the body. If a number of agents bind to inactive sites (inactive proteins or dissolvings in fats) you speak of depot binding. As soon as the concentration of the drug in the blood drops, the substances that have bound on depot sites can dissolve and re-enter the bloodstream. In this way, the drug can be hold active for a longer time.

After treatment, a medicine can leave the body in several ways: via exhalation, sweating, or excretion of the kidneys. The liver cells produce cytochrome P450 / CYP450. This enzyme breaks down the agents into water-soluble metabolites that are then filtered out by the kidneys. This ends up in urine, as a result of which drug tests are often done with urine. 

How long an agent remains active in the body is indicated with the medicine half-life . This indicates how long it takes for a substance, in terms of amount, to halve in the body. This process is important to prescribe the correct dose and frequency of medication. It also helps with how much of the drug is needed per ml of blood. If there is too little medicine, the drug has no use. If you take too much, it can be life-threatening. The ratio in which this is indicated is the dose response curve .

What types of tolerance exist?

Tolerance may occur after repeated use of medication. With tolerance, the effect of the medications is reduced. Tolerance varies per resource per time. If tolerance has occurred for a particular substance, tolerance may have occurred for other agents with a similar composition. The name of this phenomenon is cross-tolerance . There are different types of tolerance:     

Metabolic tolerance: here your liver makes more enzymes that break down the drug due to repeated exposure to the drug. As a result, the substance will be broken down faster, making the drug less effective.   

Cellular tolerance: cellular adaptation to some medications leads to a reduced effect on the targeted cells. This is also called downregulation. 

Associative tolerance: if medication is always taken in the same environment, this environment acts as a kind of stimulus for tolerance. When the same amount of medicine is taken at another location, it can suddenly be fatal because you are not tolerant anymore. This is also the reason why addicts often return to their home after treatment in a clinic. After all, they are back in an environment where they first always used narcotic drugs, so that the associated actions automatically reappear. This is similar to the principle of classic conditioning of Pavlov, where an automatic response to a stimulus also arose.     

Behavior tolerance: if you use a lot of medication while you learn a certain task or action, you can improve at this task or action better later when you use the medicine again, than when you don’t use it. This is similar to the principle of operant conditioning and is also called state dependent learning.   

Psychoactive drugs often have a lot of unpleasant effects besides their intended effects: the side effects. In addition to the side effects of some drugs, you can also suffer from non-pharmacological reactions such as an allergic reaction or damage to the liver, kidneys and/or to the foetus. All these harmful reactions are due to drug intoxication. If such a severe reaction takes place after too much drug has been taken in, this is called an overdose. Some studies also look at what the lethal dose is LD (fatal dose). This is the dose at which the user dies. If 50% of users die at a certain dose, you speak of an LD 50 dose. When everyone dies you call it an LD 100 dose. At the moment when a dose is effective, this is indicated with the effective dose of ED. The range between the ED and the LD is called the therapeutic index. If, for example, the effect decreases due to tolerance, the therapeutic index decreases.   

Sometimes there is improvement in someone by thinking that he or she is taking medication, this is called the placebo effect. Drug research is therefore often tested with a double-blind study so that both the patient and the doctor do not know who is receiving the medication and who receives the placebo. The placebo effect may even cause pain to diminish, probably the same systems will be activated as the real drugs would do. 

How do medications work?

Once a few substances enter the brain, they will influence the neuronal functioning. Medications in particular affect their target cells. Pharmacodynamics study how this works. In fact, two groups of medicaments can be distinguished:

Agonists

These are drugs that cause the neural communication promoted. Agonists can work in a few manners. They provide more neurotransmitters in the presynaptic terminal or block the breakdown or reuptake of the neurotransmitter. As a result, there are more neurotransmitters available or they remain longer in the synaptic gap. You also have a direct agonist, these drugs can bind to a specific receptor due to their chemical composition. Because there is no degradation or reuptake of such drugs, they can have a long operating time.       

Antagonists

These are drugs that block or reduce the effect of neurotransmitters. Antagonists enter by binding with the receptor themselves so that the other substances can no longer bind. It does not activate the receptor, but only blocks him. Agonists and antagonists can both occur in all steps of the neurotransmitter process. Both groups of drugs can still be subdivided into subgroups. There are drugs that have a direct effect on the brain. These drugs bind directly to the correct receptor. There are also drugs that have an indirect effect, these work often via a second messenger. They bind to a substance that, in turn, releases a substance which causes the effect.