Other neurotransmitters

Posted on June 3, 2019  in Pain

For a long time, four of the above neurotransmitters were considered the only main substances acting in the process of transmitting nerve impulses. But with the development of more sophisticated research technologies, it became clear that we are still waiting for the discovery of many more neurotransmitters.
In the late seventies, substances similar in chemical properties to opiates were found in the mammalian brain tissue. Because of this similarity, they were called endorphins (short for “endogenous morphine”). Their functions in the body are varied and are not yet completely clear, but no doubt that these substances contribute to the relief of pain. For a detailed description of endorphins, see Chapter 9.
Another important neurotransmitter is gamma-aminobutyric acid (GABA). Its brain tissue contains much more than other known neurotransmitters, and it acts a little differently. The analogy of the key and the lock still works, but GABA, entering the receptor, does not open, but closes the lock, that is, it does not excite a neuron, but on the contrary, prevents it. Therefore, it is usually called the suppressive neurotransmitter (although other neurotransmitters can act in certain synapses in this capacity). If the GABAergic receptor of the neuron is activated, then in order for the neuron to be excited, a very large number of appropriate neurotransmitters are needed. A lot of drugs are now known to act like GABA. These are classic depressants: barbiturates, diazepam (Valium) and chlordiazepoxide (Librium) tranquilizers, and alcohol.

Nervous system

After considering the smallest parts of the nervous system and the effects of drugs at the neuron level, consider the entire nervous system as a whole. Its structure is depicted in Figure 3-3. It has two fundamentally different departments: the central nervous system and the peripheral nervous system. The central nervous system includes the brain and spinal cord. All nerve tissues outside of them belong to the peripheral nervous system. It consists of nerves (axonal ligaments) that transmit information from the sense organs to the brain (sensory nerves) and from the brain to muscles (motor nerves).

Vegetative nervous system 

In addition to the nerve endings, the peripheral nervous system has an important regulatory system, called the autonomic nervous system. It regulates automatic reactions, and in turn is divided into two parts. The sympathetic branch of the autonomic nervous system is activated during the period of emotional recovery by the release of adrenaline and norepinephrine from the special glands. She is responsible for various physiological changes that accompany instantaneous subconscious reactions: an increase in pressure, increased heart rate and respiration, dilated pupils, perspiration, dry mouth, changes in blood flow in the body (it pours from the internal organs and rushes to the brain and large muscles). Many psychoactive substances cause the same changes in the body. Such substances are called sympathomimetics, and they include cocaine,amphetamines and some LSD-type hallucinogens. Other substances block a certain type of sympathetic norepinephrine receptors, the so-called beta receptors. They regulate blood pressure. Substances called beta-blockers (which include propranolol) are widely used in the treatment of hypertension.
The second, parasympathetic branch of the autonomic nervous system is associated with actions opposite to those of the sympathetic. It reduces pulse, blood pressure, etc. Unlike sympathetic neurons, the synapses of the neurons of this system are mostly cholinergic. Substances that act directly on the parasympathetic nervous system are usually very toxic. For example, the nervous paralytic gases zorin and soman bind acetylcholinesterase, which leads to excessive activity of this branch of the nervous system. The result is death from suffocation or cardiac arrest.

Monoamines

Three important neurotransmitters belonging to the same amino group are called monoamines, norepinephrine (norepinephrine), dopamine and serotonin. Like acetylcholine, norepinephrine was discovered long ago, because it is also located outside the brain. This is the main chemical that regulates the physical changes that accompany emotional recovery. It is also found in the brain and plays the role of a neurotransmitter responsible for the feeling of hunger, wakefulness and waking up from sleep. Serotonin is found in all parts of the brain and plays an important role in regulating sleep. Dopamine is the main neurotransmitter in areas of the brain that provide consistent movements of body parts. This discovery gave rise to the hypothesis that dopamine deficiency can be the main cause of Parkinson’s disease, which affects mainly older people and is characterized by progressive movement inconsistency, hardening of muscles and trembling in the body. In accordance with this hypothesis, new approaches to the treatment of

Parkinson’s disease began to be applied, including the use of the drug L-DOPA, the “initial substance” of dopamine. L-DOPA was prescribed to patients to restore the level of dopamine in the tissues, and gave amazing results. Acceptance of dopamine itself is ineffective, since it cannot get into the brain along with blood. The brain is protected from toxic substances by the blood filtration system or the blood barrier of the brain (encephalogen barrier), which also detains dopamine. But L-Dofa overcomes this barrier and, getting into the brain, turns into dopamine. The use of L-Dov in the treatment of Parkinson’s disease is a vivid example of the value of scientific studies of neurotransmitters. Although L-Dova does not eliminate the disease at all (the loss of dopaminergic neurons continues, and even this drug cannot completely fill it), it prolongs the life of people with Parkinson’s disease, who would have died many years earlier without it.

In addition to these functions, monoamines are closely related to mood and emotional disorders. The discovery of substances affecting monoamines has revolutionized psychiatry. There is strong evidence that severe clinical cases of depression are associated with biological disorders. According to the latest theories, clinical depression occurs due to changes in the level of monoamines, especially norepinephrine and serotonin. This is also confirmed by the fact that drugs destroying monoamines cause depression. As we have said, reserpine causes leakage in the vesicles of nerve endings and the subsequent destruction of neurotransmitters, as a result of which there is a shortage of monoamines in the body. Drugs used in the treatment of depression significantly increase the production of norepinephrine and serotonin.

Monoamines, and especially dopamine, also constitute the biochemical basis for the occurrence of another serious mental illness, schizophrenia. When it happens, there is an almost complete loss of connection with reality, manifested in deceptions of feelings, hallucinations, disturbed emotional reactions and falling out of public relations. It is proved that these symptoms are caused by increased activity of monoamines. First, all drugs used to treat schizophrenia block monoamines. There is a very close relationship between the strength of the therapeutic effect of the drug and its ability to block dopamine receptors. In addition, compounds incapable of this, as a rule, do not relieve the symptoms of schizophrenia, even if they possess all the other properties inherent in effective drugs. Another interesting piece of evidence: stimulant drugs such as cocaine and amphetamines increase dopaminergic brain activity. Although small or moderate doses of these stimulants improve mood, overdosing often leads to paranoid disorders and loss of connection with reality, which almost exactly repeats the symptoms of schizophrenia. When the effect of the drug diminishes and dopaminergic activity returns to normal, these symptoms disappear. This again indicates a connection between increased dopaminergic activity and schizophrenia.

Acetylcholine

Of all the neurotransmitters, acetylcholine was one of the first to be discovered, possibly because it is located in the most convenient neurons for studying, located outside the brain. It is contained in the endings of the neurons that control the muscles of the skeleton. At the junctions of the nerves with the muscles, there is a space similar to a synapse, which is called a neuromuscular junction. When neurons connected to muscle fibers are excited, they release acetylcholine to the neuromuscular junction area, and the muscles contract. Acetylcholine also plays an important role in the brain, but like most other neurotransmitters, its function is not fully understood. Nevertheless, it is known that he is an important regulator of thirst. In the formation of adjectives from a neurotransmitter, the root of the word is simply taken (in this case, choline) and the suffix “ergic” is added to it. So, we call thirst cholinergic function, acetylcholine-containing neurons — cholinergic neurons, and drugs that block acetylcholine — anticholinergic drugs. Presumably, acetylcholine is also an important element of the memory system.

There is evidence that Alzheimer’s disease – progressive memory loss in old age – is associated with impaired functioning of neurons in one of the cholinergic sites. The most recent studies of Alzheimer’s disease are aimed at determining the nature of damage to these areas and developing methods for treating or preventing these injuries. In 1993, the Park-Davis Commission announced that it had received and officially approved the first drug for the treatment of Alzheimer’s disease, takrin (Sodpech), which increases the level of acetylcholine in the brain tissue. Studies of Alzheimer’s disease have provided new evidence that the cause of mental illness is a disruption in the normal functioning of neurotransmitters.

Drugs and nerve impulses transmission

There are many ways in which drugs can interfere with impulse transmission. Suppose that the chemical structure of a drug is very similar to the structure of a neurotransmitter in the body. If the degree of similarity is great, then the drug molecules will bind to the receptors and “deceive” the neuron, causing it to react in the same way as a real mediator. This is how many drugs work (this is called mimicry). For example, morphine and heroin exert their effects due to their similarity with the recently discovered endorphin.

The narcotic effect is produced by changing the following neurochemical systems:

  1. Synthesis of neurotransmitter. Drug increases or decreases the amount of neurotransmitters produced.
  2. Neurotransmitter transport. The drug interferes with the delivery of neurotransmitter molecules to the nerve endings.
  3. The accumulation of neurotransmitter. The drug interferes with the accumulation of neurotransmitter in the vesicles of nerve endings
  4. Isolation of the neurotransmitter. The drug causes premature release of neurotransmitter molecules into the synapse.
  5. Disintegration of the neurotransmitter. The drug affects the breakdown of the neurotransmitter through enzymes.
  6. Reverse neurotransmitter uptake. The drug blocks the reverse absorption of the neurotransmitter into the nerve endings.
  7. Activation of the receptor. The drug activates the receptor through mimicry.
  8. Lock receptor The drug makes the receptor inert, blocking it.

In addition to mimicry, drugs can affect the transmission of nerve impulses in many other ways. Models of the mechanisms of this influence are shown in Table 3-1. Neurotransmitters are produced from less complex compounds, the so-called “source molecules.” The production of mediators usually occurs in the cellular body or nerve endings, and if this process goes on in the cellular body, then before the mediator can work, it must also be transported to the nerve ending. Some drugs interfere with the production or delivery of a mediator. Neurotransmitter molecules accumulate in small containers (bubbles) along the edges of nerve endings. Some drugs affect the ability of bubbles to accumulate the necessary substances. For example, under the influence of a drug, reserpine, which was once used to treat high pressure, leaks appear in the bubbles, and the neurotransmitters contained in them cannot reach the synapse in the right amount in time. Other drugs have the opposite effect, increasing the flow of mediators into the synapse.

This is how stimulants act, such as amphetamines. 

Another important feature of the transmission of nerve impulses is that the neurotransmitters should be deactivated after exposure. A neuron can be compared with a rechargeable electric battery: after excitation, it needs recharging. But it begins after the keys are taken out of the locks. Deactivation of the neurotransmitter can be done in two ways: by fermentation (destruction by enzymes) and reverse absorption. Enzymes are special compounds responsible both for the production of neurotransmitters and for their destruction to the state of inert substances. These are very complex processes. There are many chemicals in the brain tissue, and they are constantly changing their structure. Consider the production and destruction of acetylcholine, one of the most important neurotransmitters. To obtain it, the enzyme acetyltransferase reacts with the “original” choline molecule. As a result of the destruction of acetylcholine, for which another enzyme, acetylcholinesterase, is needed, two metabolites, choline and acetate, are formed. (The names of enzymes necessarily contain the roots of the names of the substances with which the enzyme reacts, as well as the ending – ase.) The drug can interfere with the process of impulse transmission, affecting the enzyme. For example, some antidepressants interfere with the deactivation of the neurotransmitters norepinephrine, dopamine and serotonin, weakening the effect of monoamine oxidase, an enzyme that destroys these compounds.

The second way to remove neurotransmitters from the synapse is reverse absorption. Neurotransmitters return back to the nerve ending from which they were isolated. Such a decontamination process is more economical, since the neurotransmitter molecule remains intact and can be used again without spending energy on the development of new ones. Some drugs (especially cocaine and amphetamines) have one of their actions, blocking the process.

The last group of drug actions is directly on the receptor. Some drugs affect the receptor, posing as a real neurotransmitter (a kind of duplicate key that fits the lock). Other drugs wedge the lock and prevent the neuron from exciting. They are called blockers. In general, any substances, endogenous or not, that approach the receptor lock and activate the neuron, are called the protagonists of this receptor. Any compound that does not activate the neuron itself and prevents other substances from doing this is called an antagonist. For example, naloxone is an antagonist of receptors that are affected by opiates like heroin. If you give naloxone to a person who has just taken a lethal dose of heroin, he will not only not die, but will even come to such a state as if he had not taken the drug.

In general, naloxone completely blocks and repeals all effects of heroin and other opiates. Therefore, naloxone is called an opiate antagonist. It should be remembered that although drugs interact with brain tissue very differently, the mechanism of this interaction always contains processes characteristic of the normal functioning of the body. The drug activates or slows down the functioning of certain parts of the brain with certain natural functions. Differences in the action of different drugs can be explained by examining which neurotransmitters they influence and how. Therefore, it is necessary to consider the neurotransmitter systems of the human brain and some of their known functions.

Transmission of nerve impulses

At the ends of the axon are small thickenings – nerve endings. In them lies the answer to the question of how electrical impulses are transmitted from one neuron to another. When the microscopes were created, which made it possible to clearly see the neurons, an amazing thing came to light: most of the endings of one neuron do not come into close contact with the dendrites of the next, as it has been assumed so far.

The space that separates them is called a synapse (shown in Figure 3-2). Of course, the question arises, how is the electric current conducted from one neuron to another, if they do not touch? It is now known that when the current reaches the nerve ending, the chemicals (neurotransmitters) in it are released into the synapse, and it is they who activate the adjacent neuron.

Thus, the transmission of nerve impulses is an electrochemical process: electric, as long as current flows along an axon, and chemical at the synapse. This is important, since it can be assumed that drugs act on the nervous system through the synapse, because here there are chemical processes of information transfer. Indeed, most psychoactive substances produce their main effect through the synapse. Therefore, it is appropriate to consider in detail the chemical processes occurring in the synapse.

To describe the process of transmission of nerve impulses, we use the analogy with the key and lock. Special endings are scattered across the entire surface of the dendrites and the cell body – receptors. They can be compared with locks that protect the neuron from excitation. For excitation, you need to open the locks, and this is done by neurotransmitters released into the synapse. Molecules of neurotransmitters – the keys. The mechanism for opening the lock is shown in Figure 3-2. Receptors are depicted as circular depressions on the surface of the dendrite, neurotransmitters – balls released from the nerve ending. The idea is simple – in order to trigger the nerve impulse transmission mechanism, the key must go to the lock.
In fact, neurotransmitter molecules and receptors have a much more complex chemical structure than can be seen from the figure, and the analogy with the key and lock does not fully explain the process. The mediators and their receptors are electrically charged, and therefore attract each other, and when the mediator key enters the receptor lock, they bind. When a mediator molecule enters the receptor in a neuron, a reaction occurs causing its excitation. It is important to note that there are many types of neurotransmitters and their corresponding receptors. In brain tissue, there are chemically encoded paths along which various neurotransmitters move.

Neuron

The simplest components of the nervous system are cells called neurons. They are in many ways similar to other cells of the human body, such as blood cells or muscle cells, but they have a unique feature – they can communicate with each other. To understand the nature of the process of transmission of nerve impulses need to consider the unique structural properties of neurons. From Figure 3-1 it can be seen that there are cellular bodies in a neuron that are similar to the bodies of any other cells. Among them is the nucleus containing the genetic information for a given neuron and controlling the metabolic processes in the cell. Several related formations, called dendrites, and one long cylindrical formation, the axon, depart from the neuron cell body. Such formations have only a neuron, and their specific functions are associated with them.

Axons are of different lengths, but in any case they are longer than shown in the figure, sometimes several thousand times longer than the diameter of the cell body. The axon is covered with a white fat coat called myelin. (Not all axons are covered with such a shell, and the “open” ones are gray). Myelin can be compared to electrical wire insulation. This is a suitable comparison, since the main function of the axon is to transmit electrical current. Axon transmits information by transferring electrical charge from one end of the neuron to the other. The current is always transmitted from the cell body, which sends an electrical impulse to small branches at the end of the axon. The difference in potential is small (about 110 millivolts). When an axon conducts a current, it is called excited, when not – in a state of rest.

Drugs and Nervous System 

Any of our feelings or emotions – in essence, any psychological sensation – is based on brain activity. The fact that the brain, this physical entity, is the basis of mental activity, gives us the key to understanding the mechanism of action of chemically active substances (drugs) on mental processes.
All psychoactive substances produce their effect by acting in different ways on the tissues of the nervous system, and this chapter is devoted to such physiological effects of drugs. Most of these effects occur at the level of the brain.Recently, many significant discoveries have been made in the sciences that study the brain, shedding light on the mechanisms of the functioning of the brain. In parallel with these successes, our ability to study the effects of drugs on the body is increasing. There were fundamentally new approaches to solving problems such as addiction to drugs. However, before discussing the effect of drugs on the brain, one should consider the basic principles of the brain.

Chemical abuse

Abuse of a chemical leading to a worsening condition or disease requiring clinical treatment, as evidenced by one or more of the following symptoms:
Periodic use of a chemical that makes it impossible to fulfill important social obligations, such as: study, work or manage a household (for example, systematic absences of work related to substance use, absenteeism, prolonged non-attendance children or household).
Periodic use of a chemical in situations where it is life threatening (for example, driving a car or working on a machine while intoxicated).
Periodic legal problems associated with substance use (for example, arrests for unlawful acts committed under the influence of a chemical).
Prolonged use of a chemical, despite constant or regular social or interpersonal problems caused or aggravated by this substance, for example, disputes with the spouse (s) about the consequences of intoxication, fights).

These criteria should not overlap with the criteria for determining dependence on a given chemical substance.
“Unlike others, he (a heroin addict) cannot find a job, make a career, engage in meaningful activities around which he could build his life. Instead, he relies on his habit in everything.”
Psychologist Isodor Chain

Drug tolerance and withdrawal

Among the criteria for dependency in the DSM-4 is tolerance. Another new term is abstinence syndrome. Abstinence is a disease caused by the discontinuation of drug use or its reduction after the body is so accustomed to the presence of the drug in it that can no longer function without it. Clearly defined withdrawal syndrome does not cause all drugs. Abstinence symptoms may be stronger or weaker depending on the individual characteristics and the duration of the drug. Psychological symptoms, such as irritability, depression, and persistent desire for a drug, are usually part of an abstinence syndrome. It depends on their presence or absence whether a person can stop using drugs for a while.

Impact of drug use, tolerance and withdrawal on behavior

In this introductory chapter, attention was drawn to tolerance and withdrawal because these are central problems in psychopharmacology. Without them, the study of the drug and the evaluation of its action are impossible. Detailed consideration of these issues can be found in the following chapters. Now it is important to note that tolerance and abstinence affect the nature of drug use. For example, if tolerance increases, then a person needs to consume an increasing amount of the drug to get the desired effect. This in turn leads to the fact that a person spends more time on the acquisition and use of drugs. In the end, an increase in the number and frequency of drug use leads to the emergence of new physical, social and other problems.
Similarly, withdrawal leads to continued drug use, and most often in high doses. Studies have shown that the desire to get rid of withdrawal symptoms is a powerful incentive for further use of the drug. Abstinence begins when the level of the drug in the blood falls. If a drug is taken at this point, the withdrawal symptoms will disappear. But they will reappear and cause a vicious circle: the use of a drug – withdrawal – again the use of a drug.

The study of the mechanisms of action of tolerance and abstinence is the basis of psychopharmacology, which is looking for incentives for human consumption (or other living beings) of drugs. In Chapter 5, devoted to the principles and methods of psychopharmacology, this issue will be considered in detail.
We have shown that prolonged drug use changes the very nature of this use. The DSM-4 criteria specifically stipulate this duration. Tolerance and abstinence not only lead to changes in the production and consumption of drugs, usually their result is a jumble of one effect on another – the effect of a snowball. In the end, they are added phenomena that fall under other criteria for the diagnosis of diseases caused by drug use.

Determination of harmful drug use

Focusing on what exactly can be called harmful use of drugs or use associated with harmful effects for a person taking drugs, or for other people. The research on the cost of health care uses the terms “drug abuse” and “alcohol abuse.” However, as already noted, different people put different meanings in the concept of “abuse”. This problem greatly complicates cooperation in the study of drug use. The lack of standard definitions slows down the growth of scientific knowledge. If we cannot figure out what it is that we want to study, it is hardly possible to move forward.

In the United States and other countries, people responsible for health care have solved the problem of definitions by developing diagnostic systems. The diagnosis is based on a group of symptoms, indicated in one word. This gives us an advantage. For example, if two doctors talk about pneumonia, while using a single diagnostic system, each of them clearly understands what the other means by the word “pneumonia”. He means above all a certain group of symptoms. A similar diagnostic system can be created for mental illness. In the US, the organization responsible for creating such a system is the American Psychiatric Association (ARA). Since the beginning of the 50s. The association publishes official diagnostic systems for various mental illnesses or disorders: Diagnostic and Statistical Manual (DSM). In the light of new research, these systems are reviewed from time to time. The latest version of the official diagnostic system was released in May 1994 and is called the DSM-IV. It has a section on chemical use disorders (that is, alcohol and other drugs), which contains definitions of chemical dependency and chemical abuse.
Table 1-1 gives the criteria for making a diagnosis of chemical dependence and abuse according to DSM-4. It is necessary to comment on these criteria. Basically, each criterion is applicable to the definition of dependence and abuse of any drugs and non-medical drug groups. Another important observation is that dependence and abuse are different diagnoses. It is impossible to make one person diagnoses of dependence on a chemical substance and its abuse at the same time, although it is possible to combine diagnoses for different substances.

In terms of dependence, criteria 3–6 define what is called a drug habit. Its essence is that the main thing in human life is the consumption and purchase of drugs, while all other aspects of life are ignored, or much less attention is paid to them. A man uses drugs, despite the risk. He cannot stop using drugs or shorten it for any significant amount of time, even if he wants to. This phenomenon is called loss of control.
The first 2 criteria of dependence introduce two terms: tolerance and abstinence. Next, we analyze them in more detail. In the DSM-4 diagnostic system, a dependency diagnosis can be made based on one of these criteria, or without them. For a more accurate diagnosis, at least 3 of the 7 criteria are needed.
When discussing the definition of addiction given in DSM, you need to consider a widely used term: psychological addiction. Like many other terms related to drugs, a different meaning can be put into the concept of psychological dependence. Most often, psychological dependence is an emotional state characterized by a sense of urgency towards the drug, either to gain an effect associated with its use or to relieve negative feelings associated with its abuse. As you can see, this is a narrower, but less detailed definition than that given in the DSM-4, and it focuses on the desire to use a drug in order to change its psychological state or avoid unpleasant sensations.

In the criteria for the abuse of chemicals, negative events in various spheres of life (family, social, professional) related to the use of chemicals are of prime importance. In relation to abuse, 4 criteria are given, and to make a diagnosis, it suffices to reveal one of them.
These criteria, which are based on the latest developments in the field of disorders associated with the use of chemicals, remove part of the problem of the scientific study of this topic. These are clear descriptive criteria. Of course, they are not perfect and will be refined as scientific knowledge grows.

Drug sensations

Since, as a rule, people do not use drugs for medical purposes, it will be absolutely right to say that they like the sensations given by drugs. A very important question arises: what forms such sensations? Part of the answer lies in the chemical action of drugs, but this is not the only reason. Not so long ago, chemical action was called the main factor influencing the character of sensations. But studies of the past 30 years in the field of pharmacology, psychology and sociology have shown that these sensations are not the product of the pharmacological action of chemicals.

In order to better understand the nature of the sensations caused by drugs, we have divided all factors, pharmacological and non-pharmacological, into three groups. The first group consists of pharmacological factors. The first factor is the chemical properties and effects on the body of the drug. The next is his dose, that is, the amount of the substance consumed. The third pharmacological factor is the way of taking the drug, the way in which it enters the body. This is important because it depends on the method of administration which part of the dose reaches the organ affected by the drug and how quickly it will occur.
In Chapter 4, we will look at how to take drugs in detail and how sensations arise from this.
The second group of factors – non-pharmacological.

It consists of the characteristics of the person taking the drug, such as the genetic structure of the organism (inherited biological properties of the organism, which determine the response to the use of various drugs), gender, age, drug abuse tolerance and individuality. An important part of individuality is a psychological series, which includes knowledge, attitudes towards drugs, expectations and thoughts about them. For example, sometimes a firm belief that drugs must produce a certain effect is enough for an effect to take place, although a person has taken some inactive chemical (in pharmacology this is called a harmless medicine prescribed to calm the patient).

The third and last group, which also includes non-pharmacological factors, are circumstances in which the drug is taken. They come in different planes and include the environment, the laws of a given society, prohibiting the use of drugs and the presence or absence of other people at the time of taking the drugs.
All these three groups of factors influence the nature of sensations experienced while taking drugs. Tracing this influence is often very difficult. Still, many people try to do this. The knowledge gained by their efforts forms the basis of this blog.