Lecture notes with Pharmacological and Biological Approaches to Clinical and Health Psychology at Leiden University

Lecture 1: General introduction genetics

In some patients just medication is not very effective and they still have different symptoms. Different biological factors can play a role in such a case, like genes, endocrine system (like hormones), immune system (depression can have a negative influence on the immune system) and neurobiological factors (changes in the brain network). It is necessary to use a multi-dimensional intervention because of the interaction between all the different factors.

The exposure from the environment (physical and psychosocial) leads to the interaction between these processes. In the end this interaction influences health and disease.

Genetics

Why should we understand genetics?

Phenotype can be described as the observable characteristics of someone. Some examples are appearance, blood type, personality traits and behaviour.

Nature versus nurture

Nature (or heredity): our phenotype is caused by genetics. So our characteristics are congenital and can be seen as a predisposition.

Nurture (or environment): our phenotype is influenced by the environment. The surroundings affect the development of someone.

Nurture and nature are both very important and the combination makes them inseparable. The interaction is shown by the example that certain kind of genes not always lead to a certain type of pathology. These genes can be seen as a risk factor that can lead to pathology if some environmental factors cross a threshold.

Usefulness of the study of genes

The study of genetics leads to knowledge about development and mechanisms of diseases, the possibility to improve treatments and to the individualisation of (risk) prediction, therapy and prognosis (this can be tailored).

Genetics & Psychobiology: Mechanisms

Our DNA is located in the nucleus of our cells, DNA is formed by chromosomes. The entire set of the human DNA is called a genome. In total we have 23 pairs of chromosomes (one from our father and one from our mother). Our DNA is winded by the histones, because otherwise it would be too long. DNA is constituted by bases (four types), namely: A, T, G and C. A gene is a part of the DNA that encodes for one protein. Two processes play a role in de encoding from genes to proteins:

1. DNA is transcribed into mRNA;

2. mRNA is transcribed into a protein.

Variance across humans

Genetic variation

The genotype contains all the genes someone has. It contains the specific genes but also the general genetic constitution. A big part of our genes is fixed, this can be shown by the example that 99% of DNA is the same for every human, only 1% differs. This difference is due to mutations and polymorphisms.

Mutations

Mutations in DNA provoke permanent changes, like duplication of base segments or base change. This mutations can lead to changes in the proteins if the mutations are not repaired.

Polymorphisms

Multiple variants of a gene in the population are called polymorphisms. An example is a copy number variation (CNV), like deletions of stretch of the DNA. A single nucleotide polymorphism (SNP) is the change of one letter of the DNA, these changes are very common.

From genotype to phenotype

The Mendelian inheritance theory makes a distinction between dominant versus recessive alleles and between homozygous versus heterozygous alleles. Someone’s DNA is stable over time, but not encoding of DNA into proteins is not always necessary. This encoding process is constantly influenced by different environmental factors, like interaction of genes and the regulation of gene expression. The encoding process is also dynamic.

Epistasis

This is the interaction of genes: allele for one characteristic interferes or hides an allele for another characteristics. Illustrated image on slide 21.

Epigenetics

The environment influences whether a gene switches off or on. So there is no modification of the DNA sequence. The environmental factors can be either internal or external. External factors or for example diet, smoking and stress. The conclusion is that someone’s phenotype is the result of a gene-environment interaction (G x E).

Application of genetics and psychobiology

Gene-environment interactions can be studied through the comparison of cases and controls, like twin or family (pedigree) studies. Family studies are especially useful in the case of a rare disease that is caused by a mutation in the genes.

Genetic association studies

These kind of studies are possible in two situations:

• Candidate gene association study: knowing the biological mechanisms (beforehand selecting genes that play a role in the disease mechanisms) or in the case of;

• Genome-wide association study: not exactly knowing the genes, but knowing the environmental risk factors (for example smokers, alcohol users etc.) and testing many genetic variants. It is necessary to use a big sample.

Environmental influences

It is important to take both into account:

• Trigger or enhance expression of genetic predisposition (maltreatment, negative live events, early life stress etc.)

• Compensate for or control expression of genetic predisposition (low stress levels, social support, so protecting variables).

What is the influence of genes and environment in the clinical phenotype?

The gene-environment interaction can be shown on a genetic-environment scale. Down syndrome is totally on the genetic side of the scale: these patients have a 3^rd copy of chromosome 21. In most diseases multiple genes play a role in the development.

Allergy

Allergy is an example of a complex gene-environment interaction. It is considered as a Classic psychosomatic disorder, because the G x E interaction is very important. Allergies are very prevalent and increasing. Some examples of common allergies are: eczema, food allergy or asthma. An allergy is an early manifestation of immune dysregulation. 30% of Western people suffer from allergies and the prevalence is still increasing. Allergies are influenced by different psychological factors, like stress. These factors can increase the incidence and severity of the disease.

Indications for a gene-environment interaction are:

• Genes: Within families or twins there is a higher allergy rate (approximately 36-75% is explained by genes).

• Environment: It is impossible to explain the high incidence increase genetically, because it is too fast. The fact that allergies are more prevalent in high developed countries gives evidence for the hygiene hypothesis. This hypothesis states that better hygiene leads to allergies because of the higher immune reaction.

Risk genes: It has been shown that encoding for immune reactions plays a role. Some environmental factors, like having pets, living on a farm or smoking influence the development of allergies. These environmental factors change the DNA transcription and the translation from DNA to mRNA through epistasis processes.

Heterogeneous diseases are diseases that are developed through multiple genes and factors from the environment. The dose (is the exposure chronic or just a single episode?) and the time of the exposure (during childhood or in adulthood?) influences the exposure of risk factors in the environment. Not every environmental factor can be measured, this is also true for the protective environmental factors.

Gene-environment interaction and psychopathology

In research about the G x E in psychopathology there is a heritability gap. Because twins also share their environment there is an overestimation of the genetic component.

Studies concluded that the genetic component of schizophrenia and major depressive disorder is 20-25%. But in schizophrenia 80% of the variance is explained by genetics. There is a much lower heritability component if you approach it via Molecular SNP.

Risk factors for the development of schizophrenia are: season of birth (while pregnant in the winter mothers are more vulnerable for certain types of viruses), cannabis use during adolescence (specifically: cannabis & COMT polymorphisms. This is a gene encoding enzyme that metabolizes dopamine).
The target of treatment for patients suffering from schizophrenia is anti-psychotic drugs, because they supress the dopamine receptors.

Risk factors for the development of major depression are: childhood maltreatment, early stressful life events (in combination with specific SLC6A4 polymorphism). Treatment consists of anti-depressant drugs, because they increase the levels of monoamines.

Environmental risk factors for alcohol dependence are: low parental monitoring, high availability of alcohol and influence of peers. In the genes there are also some risk factors found, like the genes that encode for the GABA-receptor. This because the GABA-receptor binds with alcohol, so treatment focuses on the GABA-receptor antagonist.

Goals of interventions

The human DNA can’t be changed easily, but it biological products can. It is possible to change the environmental factors, like quit smoking and eat more healthy.
 

Lecture 2: Neuro-endocrinology

The brain serves as a source and target of hormones. We will talk about the effects of hormones on the brain, behaviour and especially focus on cortisol.

Glands produce hormones

The brain controls the activity of peripheral glands. The brain itself is also a gland. The hypothalamus decides about hormones (based on information from many brain regions) and is also the outcome of the brain. The hypothalamus emits signals through the blood to the pituitary and to the brain etc. For a visual illustration see slide 3.

Receptors are hormone recognizers. The locations of these receptors depends on the hormones they bind with. To see where the cortisol receptors are, you have to look at the location of the effect of cortisol, this is where the receptors are.

Glands make hormones and hormones coordinate processes

So the hypothalamus is in contact with the pituitary through the blood. There is variation in cortisol ACTH levels in the human body, see slide 3. You can see that there is an increase in ACTH level at 03:20 o’clock and some minutes later a cortisol increase. So you can conclude that first ACTH levels increase and then (somewhat slower) an cortisol increase. So if the pituitary puts out his hormone (ACTH), this travels through the blood to the kidney and 10 minutes later cortisol level is increased. Hormones influence a lot of different processes in the body, for example metabolism, immunity and cardio-vascular function. If you are chronically stressed, this supresses your immune system. Cortisol ensures that immune function goes down, this makes it easier for bacteria to infect us, for example in the case of a stomach ulcer.

Hypothalamus (bottom of the brain)

The production of cortisol (in the adrenal gland) is stimulated by the pituitary (through ACTH) and also by the hypothalamus (through CRH). CRH is an abbreviation for corticotropin-releasing hormone. All these processes influence each other: the production of CRH moves the pituitary to produce ACTH and as a result of this the adrenal gland produces cortisol in response to the ACTH. The hormone CRH is always waiting for stress to occur so that in can initiate the processes. In a stressful situation CRH is released because of the stressor (slide 5). Novelty can be very stressful for a mouse.

CRH production in the hypothalamus

Inflammation, memories and fear influence the working of the hypothalamus. Stress occurs in the brain and you measure the hormonal response to stress.

The limbic-hypothalamus-pituitary-adrenal-axis

How do you know where cortisol acts? Look for the receptors. You find CRH receptors in the pituitary, hippocampus, striatum, cortex and the amygdala (because CRH is used as a neurotransmitter). ACTH receptors are located on the adrenal gland, but also on fat tissue for example. On the website www.brain-map.org you can explore the brain (processes). So in for example the amygdala CRH acts as a neurotransmitter (outside the hypothalamus).

Research about the CRH response in the amygdala

Amygdala CRH response to (non) escapable forelimb shock in sheep. They implanted a chip in the amygdala of sheep’s. CRH increases and decreases over time. In the non-escape group CRH level was higher than in the escape-group. So not being able to escape in a threatening situation is much worse. CRH is a biological indication for how stressed the brain is. Blocking CRH in animals leads them to become less fearful and more curious. Fear or pain is very useful and stress is adaptive. Hormones are a nice way to coordinate organization of different brain parts.

Other releasing hormones

Gonadotropic releasing hormone (GnRH) is made in a region of the hypothalamus. Release of GnRH is responsible for the production of FSH (follicle stimulating hormone) and LH (Luteinizing Hormone). In the case of a high GnRH production this leads particularly to the production of LH. In the case of a low GnRH production this leads to FSH production. LH is produced in the pituitary. In women an increase in LH leads to stimulation of the ovulation. In men LH leads to production of testosterone. The receptors of GnRH are located at the pituitary.

Posterior pituitary hormones direct connection from hypothalamus

The pituitary consists of two parts: posterior pituitary ( or neurohypophysis) and the anterior pituitary ( or adenohypophysis). The posterior pituitary is connected to the hypothalamus and the anterior pituitary is the part of the pituitary that regulates several different physiological processes.

Oxytocin is very important for women in labour: not just for the delivery but also to help bonding the mother and child. Oxytocin is made in the hypothalamus. Oxytocin neuron can also release their product from the dendrites, into the brain, and not only via the axon (as a normal neuron would). It is possible to give birth without having oxytocin released in the brain. But this leads to monogamous pair bonding (release oxytocin into the brain). Bonding in men depends on vasopressin and in women on oxytocin.

Hormone action on the brain: how cortisol affects neurotransmission

Stress is about adaptation to a certain situation. Stress is a good thing because it makes it possible for us to adapt to difficult situations. Novelty and adaptation to novelty is good. But there is a cost, sometimes the stress response may be too much. If you are adapted to one stressor all your adaptive capacity is used. If something else happens you can’t deal with that, this is the moment when stress becomes too much. Chronic stress is stress that is just too much to cope with. In contrast to acute stress (which is a good, adaptable and healthy thing).

Stress response: sheep sees dog

The CRH levels in the amygdala immediately go up and after a while the cortisol levels also go up. There are different time domains: immediate (freeze behaviour: fight/ flight) or lasting. Cortisol is slower activated and stays longer in the blood.

Trier Social Stress Test

The TSST is a social stress test inducing test in which a speaker sees a judgemental audience. This increases stress in humans because of the social exclusion by the audience. An increase in heart rate (the fast stress response, adrenaline) and ACTH and somewhat later cortisol can be found.

The effects of cortisol on the brain

Cortisol determine the initial stress response. It also dampens the stress response or support or specify this response. Cortisol supports adaptation to possible future events or chronic stressor(s). When you are stressed it is possible to experience flashbulb memories (place and time are remembered very well, located in the hippocampus).

Cortisol receptors

Glucocorticoid receptor is located everywhere in the brain, it has a lower affinity because more cortisol is needed to stimulate this stress receptor, it is very insensitive. So a lot of stress is needed to stimulate the glucocorticoid receptor.

Mineralocorticoid receptor is mainly in the limbic (emotional) brain, has a higher affinity. The mineralocorticoid receptor is the sensitive cortisol receptor.

The initial stress response is determined by cortisol level (basal levels). To determine the initial response, the sensitive receptor is used. Less-sensitive cortisol: measure how much cortisol increase has taken place. Processes like recovery, coping and memory depend on the glucocorticoid receptor.

Cortisol is slow and his effects are even slower. Cortisol receptors are located inside the cell. Once cortisol is located on the DNA it effects the activity of the DNA. Another example of an effect of cortisol is that there are more receptors for dopamine, which influence other receptors.

Cortisol can change sensitivity for neurotransmitters

Whether or not there is an effect of serotonin (5-HT) depends on prior exposure to cortisol. If you are exposed to stress levels of cortisol , this responds on the serotonin production. So high levels of cortisol influence other receptors. They change the way brain regions response to other substances. Vulnerability can lead to different psychopathologies. Psychosis depends on dopamine because there is lots of dopamine activity in the brain. Cortisol acts on the active parts in the brain and works as a greaser.

Cortisol, cognition & psychopathology

Cushing’s disease is a result of extreme exposure to cortisol. A tumour leads to too high levels of cortisol (without having stress). This has many effects on the body, like metabolic disturbance, immune suppression, muscle wasting (breaks down muscles to get energy), thrombosis, psychosis and depression.

Acute versus long term changes

Cortisol has long lasting effects on mental health. It leads to less grey matter volume and also to damage of white matter. Cortisol can cause psychopathology and is long lasting.

Synthetic steroids: lowered cortisol after anti-cancer anti-inflammatory pharmacotherapy.
Leukaemia patients get dexamethasone, this inhibits secretion of cortisol. This inhibition in cortisol has extreme psychological effects. But for this patients it is of course very important to continue the treatment, despite the extreme side effects.

In PTSD cortisol has an enhancing effect on memory (these patients engrave to deeply).

The HPA-axis

Cortisol stimulates memory consolidation: object-location-recognition. Cortisol effects memory, because without cortisol a novel task does not produce curiosity and explorative behaviour. Cortisol effects brain regions. Stress and cortisol can change relative dominance of brain circuits.

Lecture 3: Immunology

This lecture is about immunology. We will talk about (un)wanted effects of immunity, the immune response etc.

One important function of the immune system is protection of the body against infectious disease. We are living in a very infectious world, so the immune system keeps our body sterile. Other, but less important functions, are destruction of cancer and the promotion of tissue repair. The tissue repair acts when you get wounded and your skin repairs itself. But the immune system also has harmful effects, like auto-immune diseases. In this case the body reacts strange to a non-harmful target. It starts attacking normal tissue, only the target is chosen wrong. The downside of having an immune system is that it can make you ill. In a lot of cases a disease is caused by the immune system response and not because of the pathogen itself. This leads to discomfort and feeling sick. Virus infections can get very dangerous, because the immune system also attacks the ‘good’ cells and this could lead to damage. The effects of immune activation can sometimes be much worse than the disease itself, which sounds counter-intuitive.

Terminology

The immune system is very complex, a lot of different cells play a role. Immune cells are also called white blood cells or leukocytes. These are made in the bone marrow and produced by stem cells. The immune cells (produced in the bone marrow), are divided into the lymphoid lineage and the myeloid lineage. The lymphoid lineage give rise to the lymphocytes (like B, T and NK cells) and the myeloid lineage give rise to for example granulocytes and monocytes. It is important to remember that the immune system is very diverse. It is so diverse because of the external world is also very diverse, you need the ability to respond in a diverse manner.

Monocyte/ macrophage are the same cells but when they are circling in the blood they are called monocyte and as soon as they enter the tissue their shape changes. At that moment it is called a macrophage. Most of the cells (50%) in the blood are red blood cells. The red blood cells do have DNA. The monocytes are very important, but they are 5% of our leukocytes.

The immune response to infection

Only 2% of all the immune cells are in the blood, 98% are in the tissues. The immune response starts at the outside of the body: the skin and mucosa (soft tissues). The stomach is also the outside world for the immune system. All infections take place in the skin and mucosa (so were it is possible to have contact with the external world, for example in the mouth or stomach). Infections are picked up and brought to the lymph nodes (which swell during infection, like your glands). Than they go back to the place where the infection took place and react. You can consider the skin and mucosa as the front lines and the lymph nodes as the headquarters.
Skin and mucosa: this is where infection takes place. It is called an infection when an infectious cell enters the body and manages to survive. The dangerous cells are brought to the lymph nodes and then the lymphocytes become armed effector cells (instead of doormen cells). These armed effector cells travel through the blood to the place of the infection. To summarize, the important steps are:

1. Infection;

2. Infectious agents intercepted by sentinel cells;

3. Infectious agent is presented to lymphocytes

4. Lymphocytes become armed effector cells.

The frontline defences

An example of a defence mechanisms is the skin. It is a mechanical barrier, has a low pH (between 3 and 5) and has their own endogenous flora that live on the skin.

Mucosa (soft tissues) also have antimicrobial proteins, like in the saliva. Sometimes these defences are breached and the body reacts immediately:

1. Physical barriers: like body temperature;

2. Chemical barriers: antimicrobial proteins;

3. Phagocytic cell responses: (more aggressive) this are cells that ‘eat’ the bad cells and bring them to the lymphocytes, which attack the infection. The three function of this response are that the phagocytose destroy and eat the infectious agent, start the inflammatory response (alert other cells) and then transport an antigen to the lymphoid organs.

Terminology

Activation means anything that happens to start of facilitate an immune response, like cellular or molecular changes.
Antigen has a formal meaning, namely: an antibody generator, anything that generates making of antibodies. Basically it means any molecule that activates the immune system.

Phagocytic cells recognize pathogens because of the PAMPS/ MAMPS (microbe-associated molecular patterns). Viruses make double stranded DNA and the own body makes single stranded DNA, so if the immune system finds double stranded DNA it knows that this is from a virus. The immune cells have receptors on their surface that detect this kind of DNA. The receptors that detect a virus are called pattern-recognition receptors (PRRs). In the case of detecting a virus, cytokines are secreted. Cytokines are very important because they are the signal molecules of the immune system. Cytokines are hormones or neurotransmitters that are made by the immune system. Cytokines regulate activity and movement, they convey information. They can work autocrine, paracrine and endocrine (get released and for example go to the brain). Cytokines are involved with inflammation, response regulation, chemotaxis and growth and differentiation. Sometimes this functions do overlap.

The inflammatory response

So the first action of the immune system is that phagocytic cells eat the pathogen when they detect one and try to destroy it. It also initiate the inflammatory response and transporting it to the lymph nodes. The inflammatory response causes vasodilation (skin looks red etc.), capillary permeability and influx of leukocytes. You recognize these processes because of the symptoms: redness, swelling, heat, pain and loss of function. But the processes can also influence other organs, like when your metabolism is going up.

In the next phase the pathogen is brought to the lymph nodes and the lymphocytes become armed effector cells. The antigen cells are produced in the primary (bone marrow) lymph nodes and then move to the secondary. They move via the draining lymphatics. So you can pick up antigens everywhere in the body, but they are collected in specialised locations like glands. The antigens and lymphocytes become clustered together in the lymphoid tissues. This clustering maximises the change that an unique antigen will meet its own unique receptor. An example: going to a pub to meet someone. Not everyone will suit you, preferences are not limitless, you only like a few people. The chance to encounter ‘the one’ on the streets is small, but the change is higher to find a match in a pub because you can find out if there is a click. In the case of the immune system: only one kind of lymphocyte can recognise one kind of bacteria or virus. So the lymphocytes wait until they found a good match and generate an immune response. So the immune system is not very efficient, because of the one-on-one relationship. This is why the immune response most of the time takes days, the body has to found the match between the right lymphocyte and the bacteria or virus. This time can be a cause for getting sick from the pathogens. When the lymphocytes get activated they start cloning themselves (clonal selection). Helper T-cells: regulate immune system via release of cytokines. they make the macrophages a ‘license to kill’, makes them more aggressive. B cells make antibodies (that neutralize infections agents).

The immune response exists of two parts: innate response (immediate response) and an adaptive response (lymphocytes, which only recognize one pathogens). The adaptive immune can learn, it develops memory. The price we pay is that it is very slow, but when it is detected once you have the right antibodies for the rest of your live and never get ill from that pathogen. The innate immune response is fast but does not learn. After eliminating the pathogens most of the effector cells die because of neglect, but the memory cells stay alive. When we get infected another time the immune response is much faster because of these memory cells.

There is an interaction between the brain, immune system and stress. In the 80s a lot was discovered about the immune system. The immune system and nervous system communicate with each other via cytokines and hormones & transmitters.

An old conditioning experiment showed that the communication does matter. See slides for an image. First phase is shaping, drinking for a specific time. Then training, animal get injected. After that is the testing, an animal can make a choice between novel flavour and water. The conditioning response means that they become ill because of the conditioning. When you give an animal an antigen the immune response get suppressed. Learning has an effect on how the immune system works. In the late 80s/ beginning of the 90s research is done about depression and immune system. They found that depressed people have lower life expectancies, so stress is bad for the immune system. Bosch et al. (2007) found that the wounds in the mouth of depressed people healed slower. The effects of stress on wound healing are very robust. S-IgA is a protein in saliva, first layer of defence against infections. Difference in researches focused on prolonged and acute stress. The studies who focused on the prolonged stress found decrease in S-IgA protein and the studies on acute stress found increase in this protein.

Stress in the laboratory

To induce stress in the laboratory, you give participants a task that is cognitively challenging. For example giving a presentation and combining this with social evaluation. This because people become very nervous when they know they are being judged. Anxiety, heartrate and adrenaline levels go up. You also see effects in immune system lymphocytes and Natural Killer cells go up. This al happens within a minute. If you get stressed the body releases a lot of adrenaline. The adrenal receptors give a cascade that causes them to get released and move into the circulation. The cells travel through the blood to the ‘front lines’ (for example the skin). The release of cytokines is also enhanced during stress, this influences mood. The brain and stress effects how the immune system works. Stress effects the activity of the immune system, wound healing is poor for example. The immune system also influences the brain. People who have an inflammatory disease (attacking tissues of own body) have a much higher chance of having a psychopathology. For example people with Rheumatoid Arthritis have a two times higher change of having a psychopathology (McWilliams et al. (2003)). Keep in mind that a lot of psychopathology patients have also an chronic disease. 28-35% of the CVD, Arthritis, Asthma or Irritable Bowel Syndrome patients have an anxiety disorder, like GAD of PTSD.
Sickness behaviour is for example having a negative mood, fatigue, irritability, social withdrawal etc. There are a lot of ways in which cytokines can enter the brain. Many studies find that cytokines are elevated in major depression. Giving anti-inflammatories (celecoxib, aspirin) has an anti-depressive working (like Ketamine). But the range for ketamine is very narrow, so be aware of this. Important to remember is that several studies replicated this effect. You can induce a mild inflammation (vaccination) to study the affective information processing. If you give people an inflammatory stimulus they perform worse on ‘reading the mind in the eyes test’, so they are less good in interpreting social cues.

Lecture 4: Neuroscience

This lecture is about the processing of emotions in the brain, anti-depressants and effects on neural networks.

Emotion and the brain

Different areas in the brain play a role in processing different emotions. For processing the emotions anxiety and fear the amygdala is involved. The emotions anger and sadness are studied by using neuroimaging, to see which areas become active when processing these emotions. The general idea is that the orbitofrontal cortex and anterior cingulate cortex are the most important areas for processing anger. Sadness is processed in the right temporal pole in the amygdala. About disgust was a lot of controversy. A lot of brain imaging research is done using the same techniques as in anger and sadness research. The general idea is that the anterior insula (this area is relatively clear) and the anterior cingulate cortex are involved in processing disgust. But there are still different views on this topic.

Depression and the brain

The same brain structures for processing emotions are affected if someone has a depression. The brain structures are affected by three monoamine neurotransmitters, namely: serotonin, noradrenaline and dopamine. These MOA neurotransmitters are produced in the main stem or in the mid brain and are released in areas that are important for emotions. Neurotransmitters modulate the activity and influence functioning of the brain areas. This leads to the hypotheses that in depressed patients something is wrong with the monoamine neurotransmitters, this is called the monoamine hypothesis of depression. This hypothesis states that there are deficiencies in the MOA neurotransmitters.

Decreasing monoamine neurotransmitter availability can induce symptoms of depression, but this is easily reversed by stopping the medication. Increasing monoamine neurotransmitter availability diminishes depression. But the Monoamine hypothesis of depression has a problem, namely the lag time (therapeutic delay). The increase in availability occurs very fast (when you give the medication), this increases within minutes. So you would expect similar timing of the effects of medication, but this is not the case, it takes weeks before changes in symptoms occur. This is also a problem for depressed patients because it could lead to problems with motivation.
There are many different brands of medication that cause an increase in monoamine neurotransmitters. It is a trial and error process to define which brand will decrease depression for a patient, because you never know beforehand because of the lag time.

The Revised monoamine hypothesis states that depressed patients have higher levels of presynaptic auto receptors (activates negative feedback, inhibitory loop), this leads to a stronger feedback loop. Downregulating presynaptic auto receptors takes time. The reinstatement of normal cell functioning takes place after a few weeks. So it takes a long time to experience the positive effects of medication.

Antidepressant medication:

• Selective serotonin reuptake inhibitors (SSRIs)

SSRIs work because they increase the availability of serotonin. Proteins ensure that serotonin reuptakes, this is a selective process. The reuptake of serotonin causes serotonin to be transported back into the presynaptic terminal, this leads to an overload of serotonin. So the duration of the reuptake is determined by the protein. SSRIs block the reuptake port, no more reuptake of serotonin if this port is blocked. This leads to more serotonin in the space between and increases the activation of serotonin receptors. Prozac is an example of a SSRI, it is selective for serotonin reuptake. But also serotonin-norepinephrine reuptake inhibitors (SNRIs) exist and in some cases reuptake inhibitors for dopamine.

SNRIs exists of a similar substance, but is selective for both serotonin and norepinephrine. There are differences between brands in affinity for serotonin or norepinephrine.

• Tricyclic antidepressants

These medicines are called tricyclic antidepressants because of the molecular structure. They have a similar working mechanisms as the SNRIs, they increase both serotonin and norepinephrine. But the tricyclic antidepressants have side effects, they block acetylcholine receptors. But, besides the side effects, for some people they work very well.

• Monoamine oxidase inhibitors (MAOIs)

In the presynaptic terminal, MAO is an enzyme (same as in d, s, n ). An intact neurotransmitter can be used again because of the MAO inhibitors. MAO inhibitors are not selective. These medication is not used very much, because of the bad side effects.

Depression as a network disorder

In the past researchers studied depression in the targeted brain regions, for example in the amygdala. But they came to the conclusion that brain structures work together, in networks and not isolated. This is why depression is considered as a network disorder.

Studying networks

• MRI

You can use different scanning sequences and discriminate between structure (grey, white matter) and function (measure oxygen use). The more active, the more oxygen it uses. Colour, does not directly roll out of the scanner, you have to calculate that. MRI is safe, but do not bring irons in the vicinity of the MRI (because of the strong magnet!).

A transversal (or horizontal section) is often used to label the brain. It is important to check what the left or right side of the brain is.

• Resting state fMRI

This is a neuroimaging technique which we can study networks in the brain. Measure the functioning of the brain in a rest state (so without giving a participant a task, but not really resting). In resting state fMRI spontaneous variation and oxygen use is studied. After a participant lay under the scanner you ask what they thought about, because you don’t want to measure working memory for example.

Discovery of resting state fMRI

Biswall et al. (1995) completed a study with a block design. They used blocks of rest and blocks of finger tapping. They found that the variation in oxygen level within rest state was very big. They studied the rest blocks and found motor networks. The neurons in these networks were still talking to each other in resting state, there were spontaneous fluctuations. The ‘noise’ was larger than expected during resting state. So even if the network is not in use, it is still there.

Functional connectivity

Resting state fMRI measures spontaneous brain activity. A resting state network shows similarities in brain activity during rest. Certain brain areas show functional connectivity. Groups of areas in which is spontaneous oxygen level correlation is called a network. Correlate spontaneous fluctuations with each other, so discover networks. Increase in connectivity does not mean significant activation, but significant amount of connectivity.

Pros and cons of RS fMRI

Resting state fMRI is very easy to measure. But you have to be careful with giving information you really want to measure resting state and not working memory for example. But you don’t have to give your participants a task, just tell them not to fall asleep. Skip someone’s data if he or she falls asleep or if there was too much movement. A disadvantage is that RS fMRI cannot detect subtle effects on psychological functions, you have to use task-related fMRI for that.

For examples of resting state networks who are associated with psychological functions look at slide 9.
Network 4 is involved in introspection, self-referential thought, it isn’t correlated with a task. This network is very often implicated in psychopathology. In depressed patients introspection can turn into rumination. Networks 8, 9 and 10 are involved in emotions. For example the insula, prefrontal cortex and the anterior cingulate cortex form a network (also in rest state). Network 8 is involved in other processes, like inhibition.

NESDA: functional connectivity

The Netherlands study of depression and anxiety found that the amygdala and parts of the frontal cortex form a decreased functional network. The default mode network frontal hyper-connectivity has been linked to rumination in depression. It is also related to chronic pain.

Ketamine

All anti-depressants are based on the monoamine hypothesis, only ketamine is different. It is a fast acting antidepressant and not monoamine based. Ketamine works very fast (faster than monoamine antidepressants). In different doses it can induce psychosis in patients. Ketamine has side effects.

Ketamine and brain activation: research

In general were the effects in line with analgesic effects, but there was no effect on the default mode network found. In healthy participants ketamine didn’t lower DMN.

The default mode network

The DMN that Niesters et al. (2012) used did not contain much of the frontal cortex. With using a larger part of the frontal cortex we found a DMN (rather than using a small template). So it was necessary to contain more of the frontal cortex in to find the DMN. We can conclude that ketamine modulates the DMN.

Conclusions

We can conclude that several different brain areas are important in the processing of emotions. These areas are affected by depression. Most of the currently used antidepressants are based on the monoamine hypothesis of depression. Depression may be a network disorder, because of the fact that brain regions work together and not isolated. Resting state fMRI is a technique to study the networks in the brain. In depression the Default Mode Network is overactive. Ketamine can be used to normalize this over activation.

Lecture 5: Innovative non-pharmacological interventions

Innovation: from theory to practice or treatment

A theoretical framework makes it easier to improve treatment and control factors. Translational research works from theory to practice or treatment, from mechanisms to the application. It also works from fundamental research, to efficacy studies and then to effectiveness studies. With fundamental research we measure how something works. With efficacy studies we measure if it can work and in effectiveness studies we measure if it works in practice. Randomized controlled trial is a golden standard in research.

We need innovation, because not everyone is helped by just Cognitive (behavioural) therapy. In America the mental health system has stages of giving medication, namely: 1. Common SSRI; 2. Less common SSRI; 3. TCA; 4. MAOI. But MAOI, the last option, can be dangerous for patients. Not everyone improves from this four options, after four treatments 30% of the patients do not improve.

Electroconvulsive therapy (ECT or electroshock therapy)

Researchers in the 20^th century concluded that giving symptoms of epilepsy (administration of shock) lowers symptoms of schizophrenia. They tried out every mental illness and concluded that is worked well for depression. They thought that it was because electroshocks creates energizing substances in the brain.

In ECT people get anaesthesia and muscle relaxants (because they move) and the shock is send through one part of the brain (uni-lateral). 70% of the patients who tried ECT report much less depressive symptoms, but it is short-lived. There are also a lot of severe side-effects, like loss of memory (amnesia) and confusion, which is very unpleasant. You only give it to people who don’t respond to normal therapy or are suffering from a life-threatening depression (when for example self-harm occurs). ECT is sometimes used for mania, but only for the severe cases. It is rarely given to schizophrenia patients because of the side effects.

The theory is that patients who suffer from a depression have a lot of stress, so very high cortisol levels. This is very bad for their brain. Functioning of neurons in the brain is repaired by Brain Derived Neurotropic Factor (BDNF). BDNF promotes the synaptic plasticity, so the dendritic growth and receptor transcription for example. People with a depression have reduced BDNF synthesis, so their ability to repair and restore neurons is impaired because of the down-regulated MOA. The neurotropic hypothesis of ECT states that ECT increases the neural cell and vascular growth in various structures because of the increased BDNF. This theory explains the ‘semi’ long-term effects (after a few weeks), but not the immediate effects the therapy has. ECT is used a lot in movies so it may have a bad reputation, and has a lot of side-effects.

Transcranial magnetic stimulation (TMS)

TMS may be an alternative for ECT. The Faraday law of induction is a law of electromagnetism, it predicts the interaction between a magnetic field and an electric circuit to produce an electromotive force. In the case of faster or stronger change this leads to higher voltage. It creates a strong magnetic field, this can generate neural circuitry. When using two electric coils you get a much stronger magnetic field and some neurons will be stimulated. To decide about the size of the dosage you have to stimulate the motor cortex, namely the contralateral muscle twitch. You can use the thumb response as a measure of cortical excitability. Search for the intensity of stimulation that creates thumb movement, you need an individual measure. Navigate around the brain by navigating the outside of the brain. Define were the thumb motor cortex is, this allows for precise stimulation.

Stroke patients with acute hand palsy

Started TMS with stimulating motor cortex, measuring the response. Acute after hand palsy there was a low response. After a while was more response. One day after palsy the response is predictive of how good someone will revalidate.

Clinical interventions

Repetitive TMS (Multiple pulses)

• Low frequency stimulation: inhibit local neurons.
• High frequency stimulation: excite neurons.

If you want to treat: give multiple sessions of repetitive stimulation. It could be used for depression, but you can’t hit the deep areas of the brain (like limbic system). The prefrontal asymmetry hypothesis of affect states that the cortex has an inhibitory activity, the left and right side both influence each other. This is seen in the fact that if the right frontal cortex is removed in rats this induces extreme aggression.

Motivation can be divided into approach and avoidance. The approach part is dominated by the left side, in de dorsolateral prefrontal cortex. Avoidance is dominated by the right DLPFC of the brain and includes anxiety and depression.

rTMS: antidepressant

High stimulation of left DLPFC or low stimulation of right DLPFC was found to be equally effective. It was not as effective as ECT, but can be used as an alternative treatment in people with a not very severe depression. For depression it is the most clearly that TMS seems to be effective. Even for schizophrenia it is effective.

Clinical trials use a placebo condition to compare the treatment group with a control condition. If a treatment is shown to be effective, it is applied in treatment. A treatment can get commercially available.

Bright Light therapy (BLT)

This is the first line treatment for seasonal affective disorder. BLT seems also to be effective for major depression (without a seasonal component), the results are inconsistent but promising.

Background chronobiology

Chronobiology is basically the 24-hour circadian rhythm (or internal clock) that people have of the physiological processes in the body. This circadian rhythm controls body temperature, metabolism and heart rate. Melatonin is a sleeping hormone, with the highest quantity during the night. It is related to the core body temperature (which is lower during night) and cortisol. When you get older your internal clock gets later. Around the age of 20 people have the latest peek in internal clock. After the age of 20 it goes down. This shift in chronobiology increases the risk or vulnerability of illness. During morning the cortisol level peaks, this is the cortisol awakening response. Chronobiology differs per individual, namely if you are a morning larks vs. late chronotypes (night owls) and differs per day of the week. A lot of people suffer from a social jetlag on Monday, when they have to get up early for work or school and didn’t get much sleep in the past days. This way the chronotype is delayed in the weekend.
Chronobiology is related to performance. Early chronotypes perform best during the morning. Later chronotypes perform best in the afternoon. The most mistakes are made if the later type has to perform in the morning.

Chronobiology is mainly depended by light. The suprachiasmatic nucleus (SCN) is located in the hypothalamus. When light is going through the eyes, they send a signal to the SNC. In this case melatonin is decreased. Light is the main influence, but there are also other factors that influence chronobiology, like exercise, body temperature and food. SCN influences cortisol secretion and sensitivity adrenal cortex through ANS. Light influences the expression of clock genes. Genes are translated into proteins. All cells are aligned to the SCN.

Chronobiology in major depression

80-90% of MDD patients have problems with sleeping. Chronic insomnia leads to an increased risk for recurrent depression and suicidality. If the sleep pattern of a patient normalizes, this is an early predictor of positive response to treatment.

Biological picture of the dysregulated chronobiology in MDD

Patients have a high body temperature during the night and high cortisol levels during the day (because of HPA-axis over activation). The morning peek is often phase-advanced and the melatonin level variance is higher during the night. The peak of melatonin is later, so it is much harder to fall asleep. Most often patients are phase delayed or internal desynchronization (all the processes, like cortisol and melatonin, are not aligned).

Use of bright light to reset the internal clock?

The right time to undergo BLT depends on chronobiology dysregulation. Morning BLT is effective in the case of phase advance and evening BLT is effective in phase delay.

Lieverse et al. (2011) studied the BLT effects in MDD. They found that it led to reduced depressive symptoms after three weeks of intervention. See slide 12 for an image. In this image the higher the score, the more the depressed symptoms were reduced. In general there are less side effects, but the side effects that can occur are headache, feeling wired, blurred vision and sometimes an interaction with medication that is sensitive to light.

Biological effects induced by placebo

Mostly in the experimental research phase (just about placebo) and in clinical research phase (clinical trials, like control condition). Placebo and expectations from the patient form the placebo effect. The active ingredients are verbal suggestion, place cues, social cues, treatment cues and internal context. Expectations can be learned, for example by verbal suggestion (decrease in pain: essential to subjective responses) and conditioning (saliva secretion: physiological).

External context in placebo effects

Research about post-operative pain made a distinction between two groups: morphine injection or interruption. The blue group got informed about morphine injection, it decreased pain. The red group just got morphine and was not informed. See slide 17 for the images about open vs. hidden injection.

Placebo effects are to be found in neurobiological, immune and endocrine systems. Placebo effects lead to reduced activity in areas in the brain that are involved in the processing of pain. They release endogenous opioids, which are made by the own body and are natural painkillers. But you can also block the placebo-effect by giving opioid antagonist (naloxone).

Allergic responses can be blocked with anti-histamine, they block the histamine receptors, this leads to less allergic response.

Research by Goebel et al. (2008) showed that the placebo-effect is related to the verbal suggestion and environmental factors. See slide 22 for illustration. The immune responses that was found was probably the result of the conditioning procedure. Insulin is made by the body in response to the placebo.

The ethical aspects

Even if you know a medicine is a placebo it can work. We can inform patients that they receive a placebo treatment that has shown effective. We should give patients a placebo because placebo’s have less side effects and are cheaper. But it is a hard decision because it is not ethical correct to give keep important information from the patients.

Lecture 6: Psychopharmacology I

Neurotransmission

Neurotransmission is information exchange between neurons. This takes place in the pre- and post-synaptic neuron, it is a chemical exchange. This has electrical consequences. There are two kind of potentials:

• Graded potentials (takes place in the dendrites);
• All-or-none potentials (takes place in axon of the pre synaptic cell).

The inside of the neuron is in rest negative. See slide 5 for an image about the presynaptic all-or-none action potential. Sodium travels in the cell.

The post-synaptic terminal has receptors. When a receptor receive neurotransmitters this leads to post-synaptic potentials. Exhibitory receptors increase the chance that postsynaptic will fire. Inhibitory receptors lower the chance that this will happen.

The neurotransmitter can provide chemical signalling across the synapse. There are characteristics that all neurotransmitters have in common, for an overview see slide 6.

Different types of receptors and synapses

The first way to distinguish receptors is looking at metabotropic versus Ionotropic receptors. A receptor is always specific for one neurotransmitter. If a neurotransmitter binds to a metabotropic receptor there is a series of effects that start inside the neuron which lead to production of a second messenger.
The second way to distinguish receptors is to look if it is a excitatory or inhibitory receptor. GABA is an inhibitory receptor, glutamate is an excitatory receptor.
The third way to make a distinction between receptors is to look at the place where they can be found. Post- versus pre-synaptic cell (can be auto-receptors, for the same neurotransmitter; or hetero-receptors, receptor for another neurotransmitter).

A receptor is activated by a specific neurotransmitter, but neurotransmitters can bind to series of receptors. The number of different receptor can be very large. There are for example 50 serotonin receptors.

Some neurotransmitters do have individual functions, for example GABA is important for anxiety & alcohol dependence and dopamine is important for substance dependence.

Drugs like SSRI, Ritalin and MAO-I often inhibit finish receptor activation. Neurotransmission is a way of chemical signalling. There are multiple neurotransmitters which can interact with each other.

Basics of Pharmacology

Psychopharmacology is the study of drugs that effect the Central Nerves System, behaviour, cognition and affect.
A drug is a chemical substance that has biological effects on animals. It can be used in treatment or in diagnosis of a disease.
The same chemical is known by different names, for example the chemical name, brand and generic name.

Pharmacokinetics and dynamics

Kinetics means the way the body affects the drug, the body tries to inactivate and excrete the drugs. Kinetics is important because it determines how long the substance stays in the body. Dynamics means how the drug effects the body. This has to do with binding of the receptor and neurotransmission.

Pharmacokinetics

There are several ways to take a drug, the most commonly used is orally. Absorption is when a substance is in the blood. Distribution can be done through the blood. The metabolism of drugs takes several steps, this takes place in the liver. Excretion happens in the kidney, it is used in urine drug screening.

Pharmacodynamics

This means what a drug does in the body. A drug can have several effects on the neurotransmission process. In general an effect can work agonistic or antagonistic (it can block or produce opposite effect of the neurotransmitter itself). In the case of for example nicotine drugs stimulate post-synaptic receptors, this has an agonistic effect. A drug can also bind to a receptor but does not produce an effect, so it blocks the receptor (antagonistic effect).

Mood disorders

The monoamine hypothesis states that depression is caused by monoamine deficits. These deficits can be found in the limbic system (the amygdala) and in the ventromedial frontal cortex. But this hypothesis does not account for the ‘lag time’, the finding that the antidepressants do not work immediately. This lead to the revised form of the hypothesis, namely that some changes in the body take more time to happen. An important change is that there needs to be more BDNF, to repair the neurons. It takes about two weeks to increase the BDNF.

Biologically depression is described as being chronically stressed. Chronic stress leads to an increase in glucocorticoids, the regulation of the feedback loop doesn’t work like it should, this leads to cellular changes in the hippocampus. The process is circular, it gets worse and worse. So increasing BDNF can interrupt this negative circle and make a change. BDNF decreases as a depression is worse , so the more severe the depression the less high BDNF levels are.

Guidelines for pharmacological treatment of depression

In the case of an out-patient (a patient that can be treated at home), you start with SSRI. The reason for choosing SSRI is that it has less side-effects compared to other categories of treatment for depression.

In the case of an in-patient (in the clinic) TCA or SNRI is mostly used. TCA is less selective as SSRI, so it has more side-effects.
Blocking serotonin receptors has several effects, the acute effect is that there is an increase in neurotransmitters in the synaptic left. But it also has chronic effects.

Problems with antidepressants:

• Most of the medicines have side-effects. Examples of side-effects of SSRI’s are decrease libido and sexual functioning, decreased appetite, gastrointestinal problems, insomnia and agitation. Examples of side-effects of TCA are fatigue and drowsiness (because of the histamine blockade) and other effects that are the result of ACH blockade, like dry mouth, blurred vision, memory etc. It is important to choose an antidepressant that is effective but tolerable in an individual patient.

• Another problem is the efficacy. Krisch et al. (2008) published an article that states that only in severely depressive patients treatment with pharmacotherapy was effective.

• Suicidality rate increased when drug treatment increased. Especially in the start of the treatment in a young patient suicidality is a high risk. So it is important to be aware of this negative effects.

Treating bipolar disorder with antidepressant is not always a good idea because it is possible that a depression can turn into a mania. It is possible to treat bipolar disorder with Lithium, because it increased BDNF and has an anti-manic and antidepressant working. The problem with lithium is that is has a narrow therapeutic range, it can have side-effects like intoxication. Another possibility to treat bipolar disorder is anticonvulsants, which increases inhibition and BNDF.

Treatment for anxiety disorders

There is only one approved barbiturate, namely methoexital. Methoexital is used as an aesthetic.

Benzodiazepines are more safe than barbiturates and used a lot in the Netherlands. For example 130.000 patients use oxazepam and 70.000 patients use diazepam. Long term use of benzodiazepines is discouraged. When GABA binds to the receptor, chloride will go into the cell. The same will happen in barbiturate. But in the case of benzodiazepines it does not directly open the ion channel, but it changes the structure of the receptor, this makes it easier for GABA to bind to the receptor (it boosts the GABA activity). This makes barbiturates less safe than benzodiazepines.

But there is a dependence risk, health politics discourage long-term use of benzodiazepines because of tolerance. Also a physical dependence is possible, when stop taking the medicines you will feel agitated. Also secondary psychological dependence acts, people are afraid of the physical dependence and they think they cannot function normally without meds.

Self-administration is a strong model for dependence, next week we will talk about this.

Lecture 7: Psychopharmacology II

Chapter 8: Drug abuse and dependence

In dependence we have physical symptoms like tolerance. If you can’t function without the substance and are constantly looking for it you are dependent of the substance. DSM-5 substances of abuse are for example alcohol, opioids, sedatives and stimulants. A schedule I drug has the highest potential for abuse and dependence and schedule V has the lowest risk. Marijuana is in the Netherlands on list two instead of on list I in the international version.

DSM-5 Criteria for substance use disorder

The most important criteria is the impaired control factor. For example needing larger amounts, it is time consuming, having cravings and unsuccessful attempts to control it. Also social impairments like giving up on social activities (for example work). Risky use is seen in hazardous situations (like on the road) or continue using it in risky situations. The DSM-5 also distinguishes pharmacological criteria, like tolerance and withdrawal.

Ettinger states that dependence is more like the physical dependence, for example withdrawal. Impaired control is important for addiction, this is due to structural changes in the brain.

Ettinger’s definition differs from the DSM definition, it states that dependence is defined as behaviourally.

It is possible to specify the substance, for example alcohol. You have a substance disorder when you have at least two symptoms during the last 12 months. You can specify the severity of the substance disorder:

• Mild (2-3 symptoms)

• Moderate (4-5 symptoms)

• Severe (> 6 symptoms)

Tolerance can be defined in two ways:

• The same dose leads to a smaller effect;

• The same effects requires a larger dose.

Tolerance is seen in the dose-response curve, where dose is on the horizontal axis and the response on the vertical axis. Tolerance is seen as a shift to the right part of the graphic.

Processes underlying tolerance

An example of a underlying process is that there is a problem with the liver, it becomes more active and enlarged. This way metabolic processes are influenced. Then there is cellular tolerance, this takes place at the neuronal level. The neurons become less sensitive to a certain drug, because of the downregulation of the receptors. This way there are less receptors for the substance to bind to. Also behavioural forms of tolerance, like associative tolerance. Cues from the environment can start of compensatory mechanisms. Associative tolerance is also a model for relapse. Higher chance of relapse in environment where you used to use drugs. Behavioural tolerance to prevents effects of drugs, like drinking water to prevent you from heating by XTC. Associative and behavioural tolerance are involved in associative learning. The fact that you learned an association under influence of drug, will lead you to associate the use of drugs with the learned association. For example if you learn to cycle when you are drunk you learn to compensate for the instability and will perform better on a cycling test if you are sober.

Cross-tolerance

Cross-tolerance is the case if tolerance has developed to one substance and this will also make you tolerant for another substance. This is seen in for example receptors for GABA and benzodiazepine, so if you use benzodiazepines there are less receptors to bind to GABA. This is tolerance at an cellular level. So tolerance can generalise to multiple substances, but can also specify.

Toxicity and over-dose

Once you become tolerant of analgesia, respiratory depression pops in and it can become life-threatening. This was probably the case for Michael Jackson.

DSM criteria 1-4: impaired control

Are described as long-term effects on psychology and on the brain. Brain effects where on the ‘liking’ system (it induces euphoria, caused by the endorphins) and on the ‘wanting’ system (related to the reinforcement system of the brain). Brain systems that produce liking and wanting are different from natural reinforcers and produce larger effects. When you stop taking the drug withdrawal pops in. You can experience dysphoria (caused by the endorphins), craving and physical pharmacological effects.

Self-administration and dependence

Development of the self-administration test shows that every substance that a rat wants to work for triggers the wanting or liking systems. We can use this system to study substances which are intended as medication to test whether they have dependence liability. If this is the case they will not be put on the market. If someone becomes dependent, fast activation of dopamine reinforcement system, the incentive sensitization leads to more craving. Dopamine system is no longer stimulated, large motivational effect to look for the drug.

Dopamine reinforcement systems (wanting or craving)

In the midbrain are several dopamine pathways, like the striatal pathway. The pathway that is part of the mesocortical system, goes to the nucleus accumbens, is the reinforcement system connected to wanting or craving. The nucleus accumbens is close to the striatum. Glutamate cells are sensitive to cues from the environment that the drug might be present. They are upregulated and this leads to incentive sensitization, craving and seeking for drugs.

Long-term metabotropic effect on DNA expression

When metabotropic activates a cascade of secondary messages is the result. This leads to activation of the glutamate receptor and chances in the nucleus of the cell. Messages goes from cell to nucleus of the cell. C-FOS protein gets synthesized and the production of DNA is stimulated.

Dependence on video games, gambling and sex

If the long-term maladaptation is the most important part of the definition, than you can become dependent in the psychological and behavioural part (DSM 4/5). But little is known about the brain chances in video games, gambling and sex.

Psychostimulants (‘wanting’ & craving drugs)

• Cocaine: can be processed to different kinds of drugs of abuse. The most powerful is crack, because it can be injected and inhaled. Both have very fast onset of plasma concentration, very fast entry of the substance to the brain. Cocaine leads to the presence of more dopamine in the synaptic left and more activity in the post synaptic cell. Indirect way can also be motivated by cocaine.

• Amphetamines: are synthetic drugs, have a structural resemblance of dopamine. Come in tablets. Amphetamines block the dopamine and norepinephrine reuptake transporter. They have one extra effect (except from the effects of cocaine) secretion of dopamine from the pre synaptic cells. They directly stimulate the mesolimbic dopamine system and cause long-term changes and increase reinforcement and dependence. Also changes in nigrostriatal dopamine system and stereotyped behaviour is the results of this. Indirectly they stimulate the endorphin system, this produces feelings of euphoria. In treatment abstinence and relapse prevention are important. It is important to replace the time that was spend on obtaining the drugs with meaningful activities. This is a difficult task, this is why dependence and addiction are a very long-lasting problem.

Opiates (stimulate the liking)

• Opium: come from the opiates plants. Can be transformed into heroine.

• Opioids: this are synthetic analgesics and not from the natural opium product.

All opiates and opioids bind to several categories of endorphins. There are three kinds of receptors: Analgesia (medical use of drugs), euphoria (feeling of well-being, is produced by receptors in the nucleus accumbens, is related to the liking of drug. The nice feeling of a drug in the beginning of using it. After a while the liking gets less) and dysphoria (feeling of being miserable, receptors are found in the amygdala because they have to do with anxiety).

Natural ligands are the endorphins. All of this receptors are metabotropic and inhibitory (lead to hyperpolarization and happen to be heterosynapses).

All opiates and opioids have the same effects. But synthetic analgesics have mixed agonist-antagonist effects (so they have smaller effect). Also partial agonistic (only focus on one part). But the most effective analgesic is still morphine.

Opiates are liable for dependence. The effect on the dopamine system is indirect. Pre synaptic cells which is dopaminic (part of reinforcement system) is controlled by GABA . GABA is the most important inhibitory neurotransmitter.

Treatment of opiate dependence

Methadone is an opiate itself, but prevents the severe withdrawal effects. Has a long half-life, so the opiate levels are stable during the day, which prevents craving. It is a liquid, so the intake is oral and does not produce a large peek in the blood level of this opiate. This will only work if you have a relapse prevention, so having meaningful activities is very important. Opiates are also used as analgesia. Pain signal is send to the dorsal horn (this is the receptive part of the spinal colon) and goes up to the thalamus (spinothalamic pathway). The information goes to two locations: somatosensory areas (where is the pain) and anterior cingulate (affective evaluation, how bad was it?). The pathway is controlled by the descending pathway. Intersection of pathways in the dorsal horn, neurons form the spinothalamic ascending pathway.

Alcohol

Alcohol has important pharmacokinetics aspects. Alcohol can be absorbed in the blood and can cross cells, it can be transported to the brain and specific parts of the brain. Alcohol is absorbed from the small intestine (80%) and has a first-pass-metabolism (25-30%: will be metabolised before it has any effect). Finally it gets metabolised and excreted. Enzyme is rate-limiting, it takes one hour to rate the maximum (c-max at t-max). The body can only metabolise a certain level of alcohol at a time.

Pharmacodynamics

The GABA receptor is an inhibitory neurotransmitter, alcohol has a direct effect on GABA (agonism), which leads to inhibition. Alcohol has an antagonism effect on glutamate NMDA. Alcohol has indirect agonistic effects on opioids (feelings of euphoria) and is an substance of abuse (dopamine agnostic, leads to reinforcement). The effect of dopamine is biphasic, first an increase and then a decrease (hangover).

All symptoms of dependence can be found in alcohol dependence, like impaired control, social impairment, risky use etc.

Treatment for alcohol dependence

The alcohol anonymous approach has 12 steps, relapse % is dependent on the criteria that are used. A lot of attempts to treat on a pharmacological way, for example targeting the dopamine system. But the effectiveness is limited.

Lecture 8: Psychopharmacology III

Innovation and validation

Several kinds of research are important, for example efficacy studies (asking yourself: can something work?). Today we go through the evolution of studies. Today’s mechanisms and how we try to apply it are emotional memory, exposure therapy for anxiety disorders and potential adjunctive drugs.

Nowadays GABA-agonist sedatives are the available anxiolytic drugs. For example alcohol works well in reducing anxiety, it will sedate you and makes you less anxious. Alcohol works in the short term to deal with anxiety on for example a party. Barbiturates have many side effects, like death. You can easily overdose on barbiturates. Benzodiazepines (Valium, anything ending on ‘am’) are better because they can’t open the chloride channels themselves. This way it is much more difficult to overdose. But tolerance is a major problem for benzodiazepines, it only works well on the short term. Ettinger states that benzodiazepines are not addictive, but this is only true if you use a very strict definition of what is addictive. The dependence impact of benzodiazepines is nowadays increasingly recognized. At this moment dependence is a very big health problem.

SNRI’s or SSRI’s are also a anxiolytic drug. But they have a limited effect and are better for anxiety or neuroticism instead of fear.
The problem with most drugs, it does not matter which one it is, is that it leads to psychological dependence. This is the idea that patients have of themselves that they cannot deal with situations without a pill (for example benzodiazepines). Psychotherapy also needs to be improved, because about 40% of the people with an anxiety disorder don’t do well after psychotherapy. We need to boost therapy.

Exposure therapy for PTSD exist of different phases:

1. Exposure to the feared object, situation, person or thought (in vivo is in real life, in vitro is just imaging it). During treatment you want to induce fear;

2. Creating fear;

3. Fear will decrease, you will habituate during the sessions. Every session will start off with a lot of fear and it will slowly decrease;

4. Repeating will lead to less fear (between session habituation).

Two theories that partly overlap:

• Pavlovian extinction model: exposure to only the stressor without actual negative results weakens the fear. Exposure leads to less fear.

• Emotional processing theory: there is more than just the Pavlovian association. The emotional response is part of a multi-modal mnemonic ‘fear structure’. Full activation of memory structure, you have to engage the entire brain association to limit fear. Higher order (cognitive) learning takes place and facilitates Pavlovian extinction. Pharmacological methods can be helpful.

In classical (Pavlovian) conditioning you ring a bell and this is followed by food, this leads to salivation in a dog. After classical conditioning just ringing a bell leads to salivation. In this case the bell is the conditioned stimulus (or CS+). Use a strong unconditioned stimulus or repeating to accomplish this. Classical conditioning is applicable in many situations, like in the case of a women who had a very bad car accident and got very injured. Just traffic can make her very anxious. In this case traffic is the conditioned stimulus and being anxious is the conditioned response. Some stimuli have a priori an certain emotional load (like if you are born to be afraid of spiders). This influences the conditioning, but this is influenced by culture and environment.

If the conditioned stimulus no longer leads to the conditioned response this is called extinction. This is the case if the subject is repeatedly exposed to the conditioned stimulus without the unconditioned stimulus. But avoidance prevents exposure to the conditioned stimulus, so in anxiety disorder extinction is not happening because the conditioned stimulus is avoided. This explains why exposure to the conditioned stimulus can be very effective. In the case of extinction (disappearance of an emotional response) a new rule is learned and can overrule the old ‘rule’. But the old rule is still locked in the brain. We see reinstatement of fear, this is the case if the old fears come back again. So return of fear is a big problem, we have to do something about that.

Stages of mnemonic processing:

1. Encoding: the process of encoding information into the brain. Perception, attention and working memory play a role in this process.

2. Consolidation: transition from working memory to the permanent memory. So it travels from the hippocampus to the association cortex.

3. Retrieval: re-representation of consolidated information into the working memory. Memory is not fixed, during retrieval the memory traces become unstable. It is possible to slightly change memory and encode it again.

4. Re-consolidation: in this phase re-consolidation of ‘old’ information takes place. The information might change a little bit and get stored again.

Long term potentiation

Hebb said: ‘Cells that fire together, wire together.’ He meant that memory gets represented at a relatively permanent functional coupling of neurons. If one does something, another neuron responses is meant by coupling of neurons. Neurons who respond together can be the basis of memory traces.

This requires plasticity of the post-synaptic cell and plasticity of the pre-synaptic cells. NMDA glutamate receptor is an important receptor in this process. It responses to glutamate. You have to have glutamate on the glutamate receptor and that might open up a calcium channel. Than the process of firing and hyperpolarisation happens. Magnesium prevents this from happening. You need glycine for removing the magnesium from the cell. The ionotropic response relies on glutamate and glycine. The metabotropic response: after this receptors are activated and different steps take place which leads to DNA transcription in the cell. Once the cell is activated, structural changes at the post-synaptic cell take place. In the case of the sheets you get more receptors.

Changes in the secondary cell will increase the chance that the pre-synaptic cell will fire glutamate. Protein synthesis is needed to make all this extra receptors and induce the chances at the pre-synaptic cells. If you block protein synthesis this cannot longer happen. If an animal learned an association and then you block protein synthesis the next time the animal should response to an association he does not do that. Blocking of the protein blocks the reconsolidation process that occurs after retrieval.

The hippocampus is very important for memory. Information first gets stored in the hippocampus. Hypothalamus produces CRA, which travels to the pituitary (and produces ACTH). ACTH travels to the adrenal gland, which produces cortisol. This effects also immunity etc. The negative feedback system means that cortisol in the blood signals to the hypothalamus to produce less CRH. So release of cortisol lowers the release of CRH, this is called a negative feedback loop (in the case of non-pathological circumstances). If cortisol levels remain high during longer time this can be damaging. Adrenaline (epinephrine) is also produced in the medulla of adrenal glands. Adrenaline can’t cross the Blood brain barrier, it only activates through adrenergic receptors. But adrenaline can stimulate the vagus nervus and this way information is translated into the brain. Stimulation of the vagus nervus will tell the locus coeruleus (LC) to produce nor-adrenaline to be released in the brain. The effects of adrenaline in the brain are indirect. The other mechanism of the influence of adrenaline is via direct release of noradrenaline in the brain. If we have stress the locus coeruleus will directly output noradrenaline (this is the fast route).

Neurobiology of memory

Stress leads to:

Glucocorticoid (cortisol in a high enough level) will activate the basolateral amygdala and the hippocampus. The same thing will happen if the locus coeruleus decides to produce noradrenaline, it projects to the basolateral amygdala. The BLA and facilitating projections to the hippocampus are good for memory consolidation, based on animal studies. So BLA is important in memory consolidation and this will somehow influence the hippocampus. Since glucocorticoid and noradrenaline influence the BLA it seems that they influence memory consolidation. Research showed that cortisol administration impaired retrieval of long-term memory. You need both glucocorticoids and noradrenaline to activate the BLA and it will influence memory consolidation.

Research of Abercrombie et al. (2006) showed that cortisol increase predicted the free recall of (negative) words in people who already had a high stress level. We can conclude that both glucocorticoids and arousal (noradrenaline) are needed to enhance memory consolidation (it did so mostly for negative words). You need chronic stress for your cortisol levels to be high, also arousal for your (nor)adrenal levels to be high and only at the moment that you see a negative word this tells your memory system to pay attention and this will improve your memory. So glucocorticoids and noradrenaline will increase memory consolidation via the BLA system and the hippocampus.

The hippocampus is also crucial for memory retrieval. Should retrieval also be influenced by GC and NA? We have evidence for the effect in animals. In humans there was almost no effect on retrieval of neutral words. An increase in retrieval was seen for negative words.

An aversive cue leads to retrieval of an aversive memory. People with PTSD will re-experience the trauma. Retrieval makes memory unstable. High cortisol levels (beforehand) will interrupt the retrieval process, so retrieval of emotional information can be damaged. Researchers thought that glucocorticoids will influence the retrieval process and thus will lower the re-experiencing or phobic fear. But cortisol can also increase reconsolidation. Cortisol reduced the vividness of the emotion that was retrieved. Cortisol (in combination with (nor)adrenaline) lowered fear of spiders in phobic people. Cortisol might be useful in exposure therapies. Cortisol only works in combination with (nor)adrenaline.

Extinction is the case if a conditioned stimulus (who has acquired a conditioned response) no longer produces this response. There are two ways to measure fear, namely a subjective expectancy rating and a physiological measurement of fear (for example the Galvanic Skin Response). If your hands are sweaty (more salt) there is increased electrical conductivity between the two electrodes on the skin. But the downside is that it is about arousal, so it tells you nothing about the valence of the response. Automatic eye-blink (startle response) can be used to measure how scared someone is. The startle response increases with fear and is more useful than the Galvanic Skin Response.

In extinction you see a gradual decline of the conditioned response. Repeating will lower the response.

Giving propranolol (instead of placebo) enhances extinction, it really changed the original memory chain. It looks like the original memory is gone.

Cortisol can mess with the retrieval process. It can reduce retrieval of aversive memory. A less-fearful experience can overwrite the aversive memory and re-write it into a normal or even strengthened re-consolidation. The memory becomes less fearful in the next retrieval.

A beta-blocker disrupts memory consolidation or normally retrieved memory. This way there is no fear to be retrieved in the next retrieval.

D-cycloserine (antibiotic) acts as a glycine receptor agonist (facilitator of glutamate effects), it enhances glycine activity. Anything that increases glycine could improve long-term potentiation (and increase conditioning). It is difficult to do a largescale study about the effect of D-cycloserine. The combined effects of multiple studies found a clearly significant effect of D-cycloserine (Rodrigues et al., 2014). But there is still room for improvement. Doses are important because it can be too much. Only use D-cycloserine when it matters the most.

Memory is an important factor in anxiety disorders. Memory is not stable, it is plastic. BLA is of major importance in the process of emotional learning (including conditioning).