Depression Author Paul Kenyon Overview & Learning Objectives Signs of clinical depression The Catecholamine Theory of Mood Catecholamines: Dopamine & noradrenalin DA distribution within the brain NA distribution within the brain Synthesis of DA & NA Effects of drugs on catecholamines Rationale for animal models of human behaviour

Predictions of CA theory of Mood Drugs used to test the CA theory Skinner box cumulative recorder Sidman avoidance behaviour Tetrabenazine: An animal model of depression? Tetrabenazine and imipramine Summary of TBZ antagonism studies Common drug names Prozac Supplementary material Further reading Visit the SALMON Bookshop for recommended books on this topic

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Signs of clinical depression
Warning! The information provided below is to be used for educational purposes only. It should NOT be used as a substitute for seeking professional care for the diagnosis and treatment of any medical/psychiatric disorder. The diagnosis and treatment of depression and other psychiatric disorders requires trained medical professionals.
I have included this information in the lecture because a significant number of depressed people contemplate suicide, some attempt suicide, and some of these attempts succeed. Therefore depression is a serious disorder and should be considered life-threatening. If you think you or a friend is depressed - Seek Help - the majority of depressed people can be helped by modern psychiatric treatments.

How do you know when what you are experiencing is just a bad day or something more serious? We all have our ups and downs depending on how our day or week is going. The transition from bad day to rut to clinical depression can be gradual and leave even the strongest person thinking, "What is wrong with me? I just have to try harder! Why am I so lazy? Why can't I get out of bed?"

If someone experiences most of the following symptoms for more than two weeks, there is a good chance they are suffering from a clinical depression.

Ludwig van Beethoven wrote "...my misfortune pains me doubly, in as much as it leads to my being misjudged. For me there can be no relaxation in human society; no refined conversations, no mutual confidences. I must live quite alone and may creep into society only as often as sheer necessity demands; I must live like an outcast. If I appear in company I am overcome by a burning anxiety, a fear that I am running the risk of letting people notice my condition...such experiences almost made me despair, and I was on the point of putting an end to my life - the only thing that held me back was my art. For indeed it seemed to me impossible to leave this world before I had produced all the works that I felt the urge to compose, and thus I have dragged on this miserable existence..." - from Emily Anderson, The Letters of Beethoven, Vol. 3   Vincent van Gogh (1853-1890) is generally considered the greatest Dutch painter after Rembrandt; he powerfully influenced the current of Expressionism in modern art. His work, all of it produced during a period of only 10 years, hauntingly conveys through its striking colour, coarse brushwork, and contoured forms the anguish of a mental illness that eventually resulted in suicide. To me, these self portraits capture the decline of his mental condition. Autumn, 1886 January, 1889 September, 1889 These portraits of other people may also reflect his mental condition. Winter, 1886/87 October, 1889 June, 1890 David Brooks wrote: "Vincent van Gogh's final works are a paradox and this is probably no better demonstrated than in his work Wheat Field with Crows, shown here. Vincent's mental state during the last six months of his life fluctuated wildly. At times, Vincent was in good health and in seeming perfect control of his faculties; at others he was deep in the throes of complete mental breakdown. Some of his best, and most moving works come from these months. There's a peace and near contentment in many of the paintings of parks and fields he undertook while in Auvers-sur-Oise. Given that, how then can one interpret Wheat Field with Crows? This is one of Van Gogh's final works and is among the most controversial. Many feel that the dramatic and stormy skies, as well as the churning wheat field with the ominous crows rising above it, are a clear reflection of Vincent's own mental state in his last days. Others find some glimmer of hope in the vibrant colours and the path which may finally lead to peace at last. Whatever the case, it's clearly one of Vincent's greatest works and, given the ultimate tragedy of his too-short life, one of the most moving. " Commentary from David Brooks' Vincent Van Gogh Information Gallery - a rich resource on the artist's life and work. Scots writer and poet Robert Louis Stevenson (1850-1894), best known for works such as 'Treasure Island', 'Kidnapped', and 'The Strange Case of Dr. Jekyll and Mr. Hyde', showed symptoms of manic-depressive illness early in life; once, reminiscing how as a child he would lie for hours in bed in a "miserable exaltation," . On a winter day, he wrote "Let me get down on the hearthrug, full of laudanum grog, or as easy as may be, into the nice wormy grave." Shakespeare's fictional character Hamlet is the manic-depressive that everyone can relate to in some sense. Hamlet shows a full range of emotions, beginning with confusion and depression, to melancholy and eventually murderous rage. The British wartime prime minister, Winston Churchill, suffered from what he called "Black Dog", Churchill's name for depression The recent Russian president, Boris Yeltsin, may have experienced periods of depression. The Supplementary material section at the end of this page contains links to pages which discuss the impact of depression on the lives of these and other famous people.

The Catecholamine Theory of Mood

The catecholamine theory of mood was suggested by Schildraut and Kety. They suggest that:

• Depression is associated with a catecholamine deficiency in the brain
• Mania is associated with a catecholamine excess in the brain

This proved to be a very fruitful theory because it was put forward at a time when there was an explosion in our knowlegde about where neurotransmitters were located in the brain, and the discovery of chemicals that interfered with the manufacture and actions of various neurotransmitters in the brain.

Catecholamines: Dopamine & noradrenalin
Dopamine and noradrenalin are both members of a family of chemical molecules called catecholamines.
Noradrenalin is also known as norepinephrine
The following abbreviations are commonly used:

• CA catecholamine
• DA dopamine
• NA noradrenalin (NE norepinephrine )

Dopamine pathways in rat brain
DA pathways originate from groups of cells in the rostral areas of the brain. These groups were given the titles A8, A9, and A10 by the Swedish neuoanatomists Falck and Hillarp who developed ways of visualizing catecholamine cells in the brain in the 1960s.

DA neurones are organised into pathways in the brain.

• The nigrostriatal system runs from the substantia nigra (A9) forwards to the caudate, putamen, and globus pallidus, these 3 structures are called the corpus striatum.
• The mesolimbicocortical sytem run from the ventral tegmental area (A10) forwards to the nucleus accumbens, amydala, septum, olfactory nuclei,

Relatively few brain cell contain DA. There are over 10 billion cells in the human brain, only 1 million contain DA. Nevertheless, they play an important role in our behaviour.

For example, increased DA activity in the mesolimbicocortical has been implicated in schizophrenia. The nigrostriatal system is damaged in Parkinson's disease. Drugs with addictive potential release DA in the nucleus accumbens.

Noradrenalin pathways in rat brain

The nuclei that give rise to noradrenergic pathways lie in the pons and medulla. They travel forwards in a dorsal and ventral noradrenergic bundle which come together to form the medial forebrain bundle as the pathways traverse the hypothalamus.

This lecture explores the theory that depression is associated with reduced activity in this pathway.

Synthesis of Dopamine & Noradrenalin
Here is a very important diagram.

• The catechalamine neurotransmitters dopamine and noradrenalin are manufactured in the brain from the precursors - tyrosine and DOPA.
• Tyrosine is converted into DOPA by the enzyme tyrosine hydroxylase.
• Notice that dopamine is both a neurotransmitter, and a precursor in the production of noradrenalin.
• The difference between dopaminergic and noradrenergic neurones is the presence of the enzyme dopamine-beta-hydroxlase in noradrenergic neurones.

It is important to learn the steps in this metabolic sequence because many drugs that are used to investigate the role of neurotransmitters in behaviour work by interfering with particular steps in this process.

Notice the subtle molecular changes brought about by the enzymes involved in catecholamine synthesis. The term metabolism is used to describe the chemical processes involved in the manufacture and breakdown of neurotransmitters.

Effects of drugs on catecholamines

You will recall this diagram from the previous lecture on neurotransmission. It shows that neurotransmitters are stored in vesicles which are transported to nerve endings where they are released by an action potential travelling down the axon.

There are a number of ways in which drugs interfere with catecholamine metabolism:

• by inhibiting enzymes responsible for converting precursor molecules
• by disrupting the storage of neurotransmitters in synaptic vesicles
• by inhibiting the reuptake of neurotransmitters from the synaptic cleft

These drugs have been used to study the effects of increasing and decreasing neurotransmitter levels on behaviour

• alpha-methyl-para-tyrosine and disulphiram inhibit enzymes involved in CA synthesis
• reserpine and tetrabenazine make synaptic vesicles 'leaky' so that they escape into the pre-synaptic terminal where they are broken down by the enzyme monoamine oxidase
• amphetamine causes a massive release of neurotransmitter into the synaptic cleft
• iproniazid and other MAOI's inhibit the enzyme monoamine oxidase
• imipramine and drugs blocks the reptake of neurotransmitters from the synaptic cleft into the pre-synaptic nerve terminal

Predictions from the Catecholamine Theory of Mood

The catecholamine theory makes the following predictions:

• Drugs wich destroy CAs should produce depression
• Drugs which increase CAs should alleviate depression

Drugs used to test the Catecholamine Theory of Mood

You now have a body of knowledge that can be used to test the catecholamine theory of mood.

At first glance you might be tempted to use only those drugs that are associated with clear predictions - for example reserpine and pargyline - to test the theory. But it would be premature to dismiss the dopamine-beta-hydroxylase inhibitors as useful agents. The catecholamine theory does not distinguish between the roles of DA and NA in depression. Using a dopamine-beta-hydroxylase inhibitor may help to make the relative roles of these two neurotransmitters in depression.

Rationale for animal models of human behaviour

Psychologists use animal models to test biological theories of human behaviour. A model is a simple representation of a complex system. For example, a model aeroplane or train looks similar to the real thing but lacks all the features of the full size object. An animal model of depression is an attempt to capture the essence of the condition, but it does not claim to reproduce the human condition in an animal. Depression is a uniquely human condition. The purpose of an animal model is to discover novel medicines that combat the abnormal behaviour in the animal model which could be then be used to alleviate human suffering.

The development of an animal model often begins with the accidental discovery that a drug produces abnormal behaviour in otherwise normal people. Psychologists interested in the biological bases of abnormal behaviour then follow these five steps to determine whether it would be worthwhile using the drug to construct an animal model of the abnormal human behaviour.

One of the first animal models of depression involved the use of drugs that reduced catecholamine levels in the brain. Here are the steps that encouraged neuroscientists to develop an animal model that involved injecting rats with reserpine or tetrabenazine.

The next part of the lecture explores the tetrabenazine/reserpine animal model of depression. Here are some stills from an animation showing the effects of reserpine on transmitters.

Skinner box
At this stage in the lecture you are armed with a theory of depression, and knowledge of the drugs which can be used to test predictions made by the theory. We now need to consider how we can measure the effects of drugs on an animal's behaviour. An area of psychology called psychopharmacology is concerned with the effects of drugs on behaviour. Exploring the effects of drugs on operant schedules of reinforcement has a long tradition in psychopharmacology. But first we must explore the technology used by psychopharmacologists.

This picture gives an idea of the facilities available in an operant chamber, or Skinner box.

The box is equipped with a lever; responses on the lever are recorded on a cumulative recorder (see below). Reinforcements in the form of food, water or electric shock can be delivered according to the contingencies of reinforcement setup by the experimenter.

Electric shock can be delivered to the animals feet through the floor of the box which consists of a grid of parallel rods. Food or water can be delivered through a food trough to one side of the lever.

The box is equipped with lights and a speaker for the delivery of stimuli which can come to control the rat's behaviour.

Cumulative recorder: Diagramatic representation

How a cumulative recorder works. The paper unrolls (yellow roller) under the two pens at a constant speed (normally 5mm/min, but speeded up in this demonstration).

Each bar-press moves the response marking pen a small increment to the left along a brown steel bar . Note that when the pen reaches the left hand edge of the paper, it is automatically reset to the baseline on the right hand side. An automatic reset is indicated by a vertical line running from left to right of the paper. Automatic resets can be programmed to occur at fixed time intervals e.g. every 15 minutes. Reinforcements are indicated by a short blue diagonal slash on the cumulative record.

The relative angles of successive slopes gives a visual indication of the regularity in response rate. Steep slopes reflect high response rates and vice versa.

Sidman avoidance schedule
Avoidance schedules are very useful to psychopharmacologists because the rat's motivation does not change during a test session. A rat may grow less hungry during a long test session because it is receiving food pellets for pressing the lever. In contrast, the motivation to avoid shock does not wane with the passage of time.

A rat working on a Sidman avoidance schule has no external signal to mark the onset of shock. A shock is delivered to the rat that lasts 1-2 seconds at regularly spaced intervals (the shock-shock interval; normally 5 seconds). The presentation of shock can be delayed by a fixed time interval ( the response-shock interval, normally 20 seconds) if the rat presses a lever.

The library has us all on a Sidman avoidance schedule. You can borrow a book for 14 days. If you take it back before the loan period is up, you can sign it out for another 14 days. If you don't take it back within 14 days you start to get fined. Every day you keep the book beyond the loan period the fine rises. Thus the library is operating a 14 day response-shock (borrow-return) interval, and a 1 day shock-shock (fine-fine) interval. A smart person who was a slow reader would return the book to the library every 13-14 days and keep renewing the loan period.

Well trained rats can show very accurate time discriminations - responding every 19 seconds and rarely getting shocked; we don't really know how they do this, but they certainly don't wear Rolex!

The library has a book by Murray Sidman "Tactics of Scientific Research" in which he describes this behaviour in some detail, and more importantly lays out the behaviourists' approach to the study of behaviour which you will find is very different to the line taken in your course on Experimental Design & Statistics!

Tetrabenazine: An animal model of depression?
Tetrabenazine (TBZ) depletes catecholamines (NA & DA) and was used to test the Catecholamine Theory of Mood.

The picture below illustrates the effects of tetrabenazine on the avoidance behaviour of a rat trained to avoid electric shock on a Sidman avoidance schedule. Compare control (A-1,A-2) performance (steady response rate) with the effects of 2.0 mg/kg TBZ (B1-B3). Response rate declines dramatically about 25 min after injection of the drug.

The next set of cumulative records shows the protective effects of iproniazid - a monoamine oxidase inhibitor (MAOI) - against tetrabenazine.  Note how response rate is actually increased following pretreatment with iproniazid and tetrabenazine. This effect is outlined in red on the diagram.

These results were reported by G.A. Heise and E. Boff (1960) J.pharmacol. exper. Therap., 129, 155-161, and are described by David Warburton in his book Brain Behaviour and Drugs, Wiley, 1975 which is available in the library. David supervised my PhD research which involved the use of TBZ, and David himself was a PhD student with George Heise in Indiana. I am grateful to both these great teachers for introducing me to the biological bases of behaviour.

We can now use some of our knowledge about CA synthesis and the drugs that affect it, to test the hypothesis that CAs are responsible for the short period of behavioural excitation following TBZ injection in rats pretreated with a MAOI.

The next slide shows the effect of injection the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) on responding in MAOI+TBZ treated animals. Note how the period of behavioural excitation following TBZ (outlined in blue on the diagram) is abolished by the AMPT injection. This result tells us that one of the CAs - dopamine or noradrenalin - is involved in this effect. But which catecholamine: DA or NA?

The next slide shows the effect of injection the dopamine-beta- hydroxylase inhibitor, disulphiram on responding in MAOI+TBZ treated animals. Note once again how the period of behavioural excitation following TBZ (outlined in blue on the diagram) is abolished by the disulphiram injection. This result suggests that NA is responsible for the behavioural excitation following MAOI treatment.

Tetrabenazine and imipramine

At this point in the story you might think we have succeeded in producing a pretty good animal model of human depression that could be used to test novel drugs for antidepressant potential. The logic would be that if a new drug reversed the disruption of conditioned avoidance behaviour produced by 2.0 mg/kg TBZ then it would be a potential candidate for clinical trials in humans. But there is a sting in the tail of this story.

The first thing we need to do is ask whether other antidepressant drugs reverse TBZ-induced behavioural disruption in our rat model. We already know that tricyclic drugs such as imipramine are effective antidepressants. Unfortunately imipramine does not antagonise the effects of 2.0 mg/kg TBZ.

But imipramine does interact with TBZ in an interesting way. A very low dose of TBZ (0.2 mg/kg) on its own does not interfere with conditioned avoidance behaviour. When this low dose of TBZ is given in comination with imipramine, a period of behavioural excitation is seen - but not until 2.25 hours after the TBZ injection.
This effect is illustrated in the next diagram. The late period of excitation is outlined in red.

Summary of TBZ antagonism studies
Here is a summary of the current state of our slightly battered animal model of human depression.

That's as far as we can take the story in this module of the 'ups and downs' encountered trying to construct simple models of complex human emotional states. One obvious problem with this model is the issue of theraputic-lag. It been known for some time that the antidepressant effects of drugs like imipramine take some time to develop - typically 21 days or more. This is clearly at variance with the rapid changes of behaviour seen in the animal model we examined. But don't get too depressed.

Bear in mind that I am not aiming to give you 'cut and dried' answers to the biology of depression. Instead, I am trying to introduce you to a way of exploring possibilities in a scientific manner. At the end of the day there are no clear-cut answers. We have some good clues to what is going on, but the truth - whatever that is - eludes us. This is what makes it an exciting research area!

The research I have described was carried out some time ago and there have been significant changes in our theoretical understanding of depression at a biological level which we explore at a later stage in your course.

You can read more about contemporary research at Depression Central which describes itself as follows: "This site is Internet's central clearing house for information on all types of depressive disorders and on the most effective treatments for individuals suffering from Major Depression, Manic-Depression (Bipolar Disorder), Cyclothymia, Dysthymia and other mood disorders. "

Names of common drugs used to treat disorders of mood

• Depression
  • Tricyclic antidepressants
    • amitriptyline (Elavil)
    • desipramine (Norpramin)
  • MAO inhibitors
    • phenelzine (Nardil)
  • selective 5-HT reuptake inhibitors
    • fluoxetine (Prozac)
• Mania
  • Mood stabilisers
    • lithium (Lithonate)