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Schizophrenia Author Paul Kenyon Overview & Learning Objectives Lecture Outline Schizophrenia: fact and fiction Impact of drugs on treatment of mental illness Drugs used to treat schizophrenia Side effects of antipsychotic drugs The DA theory of schizophrenia Drugs used to test DA hypothesis Animal model of schizophrenia Comparison of amphetamine psychosis and paranoid psychosis

Developing an animal model of schizophrenia Amphetamine affects a variety of behaviours Measuring amphetamine effects on behaviour Amphetamine-antagonism detects antipsychotic drugs? Effect of pimozide on stereotypy and locomotion in animals Effect of clozapine on stereotypy and locomotion in animals References Supplementary information Further reading Visit the SALMON Bookshop for recommended books on this topic

Lecture Outline
The lecture will outline the rationale for the amphetamine model of schizophrenia and describe problems the model encountered in dealing with the behavioural effects of modern 'atypical' antipsychotic drugs.

Dopamine has been associated with two disorders: a deficiency of DA in the corpus striatum has been found in Parkinson's patients; an excess of DA in limbic forebrain may be involved in schizophrenia.

DA and amphetamine are structurally similar and amphetamine displaces DA from synaptic vesicles.

In humans, amphetamine causes amphetamine psychosis which is similar, but not identical to, paranoid schizophrenia . Therefore amphetamine psychosis may be a model of paranoid schizophrenia.

Chlorpromazine (CPZ) is a drug used to treat schizophrenia and amphetamine psychosis. CPZ blocks DA's access to postsynaptic receptor sites.

An animal model of schizophrenia has been developed. This involves injecting animals, usually rats, with amphetamine. The drug produces an increase in locomotion and an increase in so-called stereotyped behaviour. A behaviour is said to be stereotyped when it is is repeated in an apparently meaningless fashion.

Antipsychotic drugs are tested for their ability to antagonise these behavioural effects of amphetamine; thus the model is often called the amphetamine-antagonism test .

Some antipsychotic drugs, the so-called classic antipsychotics, such as pimozide block both the increased locomotion and the increased stereotyped behaviours produced by amphetamine. In fact this ability of classic antipsychotics to block the effects of amphetamine is the rationale for using the amphetamine-antagonism test to detect antipsychotic potential in a new drug.

However classic antipsychotics have a number of very undesirable side effects on the control of movement (Extra Pyramidal Side Effects - EPS ) such as dystonia and tardive dyskinesia.

Recently a new type of antipsychotic medication has appeared - atypical antipsychotics - these drugs are effective clinically and produce fewer EPSs.

However atypical antipsychotics do not antagonise all the effects of amphetamine in rats.

In addition atypicals have side effects e.g agranulocytosis - a potentially lethal condition associated with clozapine that requires close patient monitoring.

Consequenly there is still a need for psychologists to develop an effective animal model of antipsychotic potential.

Schizophrenia: fact and fiction

Fiction: Schizophrenia means that you have a split personality.
One common misconception is that schizophrenia means 'split personality'. Schizophrenia sometimes causes people to hear voices, behave unusually, or become fearful, but people with schizophrenia have one personality, just like everyone else.
Fact: Schizophrenia can be inherited
Schizophrenia occurs in about 1% of the population. Researchers have found that schizophrenia runs in families. Identical twins are studied with particular interest, since researchers have discovered that if one twin has schizophrenia, there is a 50% chance that the other twin will develop the illness.

Impact of drugs on the treatment of mental illness

This picture was painted in 1735 by William Hogarth as the last stage in a 'Rake's Progress' and shows Bethlem hospital in London - the world's oldest institution devoted to caring for people with mental disorders since 1247. Mental illness and its treatment play on some deep-seated fears and anxieties. At one time the only treatments available were based on trying to calm the florid symptoms of madness, and involved the use of straightjackets, insulin shock, brain surgery, or powerful sedative drugs - the 'chemical cosh'.

Even though the treatment of mental illness was revolutionized by the introduction of drugs such as chlorpromazine in 1956, there is still concern in some quarters about taking drugs to alleviate mental illness on the grounds that they

• may be addictive,
• involve a violation of human rights or
• produce side effects that are worse that the original illness.

Some people argue that mental illness is a form of 'social construction' to label, stigmatise and isolate individuals who do not conform to a social norm.

You will be able to form informed opinions on these questions as you progress through your degree course.

Drugs used to treat schizophrenia

are called: antipsychotics / neuroleptics / major tranquilisers
There are two types of antipsychotic medicine: classic and atypical antipsychotics

Examples of classic antipsychotics:

• the phenothiazine drugs:
  • chlorpromazine
  • thioridazine
• the butyrophenone drug:
  • haloperidol
• the diphenylbutylpiperine drug
  • pimozide

Examples of atypical antipsychotics:

• clozapine
• sulpiride
  

Side effects of classic antipsychotics

Unfortunately 'classic' antipsychotic drugs such as chlorpromazine and haloperidol produce serious side effects which include: Acute dystonia - uncontrolled movements of face, neck, tongue Oculomotor crisis - uncontrollable eye movements Akathisia - restlessness & agitation Parkinson's disease - slow movement, shuffle, facial tremor Tardive dyskinesia

Tardive dyskinesia means "late appearing movement disorder". It involves erky movement of the tongue and face, eventually entire body affected.

Consequently there is a pressing need to develop effective anti-psychotic drugs without adverse side effects. Atypical antipsychotics are less likely to cause this type of side effect. This research is built upon an hypothesis about the biochemical basis of schizophrenia.

The DA theory of schizophrenia

According to the DA (dopamine) theory,

• schizophrenia is associated with increased activity at dopaminergic receptor sites
• antipsychotic drugs exert their clinical effect by reducing increased DA activity.

which leads to predictions that:

• drugs which increase DA activity should produce schizophrenia
• drugs which decrease DA activity should reduce schizophrenia

Drugs used to test DA hypothesis

The idea that schizophrenia is associated with abnormal neurotransmitter activity can be investigated by using drugs that interfere with the metabolism of DA in the brain which include:

• amphetamine - releases DA from DA neurons
• chlorpromazine - blocks DA at receptor sites
• apomorphine - mimics DA at receptor sites
• 6-OHDA - a neurotoxin which destroys DA cells when it is injected into brain
• L-DOPA a DA precursor

There is evidence that increased DA hyperactivity can lead to psychotic episodes in otherwise healthy people.

As you know, Parkinson's disease is associated with a profound loss of DA in the nigrostrial system. Treatment consists of administering the DA precursor L-DOPA which is converted into DA in the nigrostriatal system.

Some patients who receive too much L-DOPA may experience hallucinations, delusions and paranoia that disappear when the dose of L-DOPA is reduced. These psychotic symptoms may be due to an increase in DA activity within the mesolimbic DA pathway which lies close to the nigrostriatal system.

Comparison of amphetamine psychosis and paranoid schizophrenia

Another clue that schizophrenia might involve increased dopaminergic activity was provided by the observation that people who take high doses of amphetamine for many days can develop amphetamine psychosis - a drug-induced mental state which could be mistaken for paranoid schizophrenia.

Although it is now clear that amphetamine psychosis and paranoid schizophrenia are not identical, the similarities between the states motivated research designed to explore the biochemical and behavioural effects of amphetamine in animals in order to understand the role of dopamine in behaviour and to develop medicines to treat schizophrenia.

Here are some images from a movie showing that amphetamine releases catecholamines (especially dopamine) from synaptic vesicles in nerve terminals. Note that amphetamine causes a massive release of DA from synaptic vesicles within the presynaptic nerve ending which causes the postsynaptic neuron to fire.

You can download the complete movie (size c1.6MB).

Animal model of schizophrenia

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 schizophrenia is an attempt to capture the essence of the condition, but it does not claim to reproduce the human condition in an animal. Schizophrenia 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 schizophrenia involved the use of drugs that increased the release of dopamine in the brain. Here are the steps that encouraged neuroscientists to develop an animal model that involved injecting rats with amphetamine.

Developing an animal model of schizophrenia

An animal model of schizophrenia has been developed which involves injecting animals -usually rats - with amphetamine. Amphetamine produces an increase in locomotion and an increase in so-called stereotyped behaviour. A behaviour is said to be stereotyped when it is is repeated in an apparently meaningless fashion. The cardinal features of stereotypy: repetition of the behaviour the invariance of the repetition i.e. the behaviour is the same each time it is emitted the apparent purposeless nature of the behaviour are exemplifed by this cat ! I also believe that locomotion can be repetitive,but that debate must wait another lecture in the course! Points to ponder Can you think of any human stereotyped behaviours? Is thinking behaviour? If yes, how could you operationally define thinking and measure stereotyped-thinking?

This diagram shows that 'stereotypy' increases as a function of increasing dose of amphetamine.   Stereotypy rating scales express the degree of stereotypy as a single number. Stereotypy scores increase with increasing dose of amphetamine Stereotypy scales 'lump-together' different behaviours

Amphetamine affects a variety of behaviours

This diagram shows the underlying complexity of behaviour that stereotypy rating scales attempt to capture as a single number.It shows the effect of increasing doses of amphetamine on conditioned and unconditioned behaviours.

• Note how - as the dose of amphetamine is increased - the fundamental nature of the rats' behaviour changes. For example, at 3mg/kg amphetamine rats engage in a lot of rearing and locomotion, but very little sniffing and licking.
• Above 5mg/kg of the drug, gnawing, biting, sniffing, licking and rythmic head movements are the main behaviours. The rat is virtually immobile - it does not walk around or rear - when it is given a large dose of amphetamine.

Measuring amphetamine effects on behaviour

We can further illustrate the meaning of this figure by setting up an imaginary experiment in which dogs are injected with saline or increasing doses of amphetamine (of course it would be very difficult to justify this type of experiment on dogs). Imagine that we are able to measure three behaviours:

• walking
• tail-wagging and
• ear-flapping

Notice that as we increase drug dose, the intensity of these behaviours change. As we increase dose the intensity or frequency of each behaviours tends to increase. But importantly the rate of increase varies between the behaviours.

Frequency of behaviour
Tail wagging	medium	fast	fast	slow	absent	Equivalent rat behaviour
						Rearing
Drug dose	Saline (Control)	1.0 mg/kg	3.0 mg/kg	5.0 mg/kg	10.0 mg/kg
The behaviour tail-wagging is seen at a medium rate even under saline (control) conditions, this behaviour increases after a low dose of amphetamine (1.0 mg/kg), but declines with higher doses of the drug and is totally absent under the highest dose (10.0 mg/kg). This pattern of change is similar to the changes seen in the rats' rearing behaviour under increasing doses of amphetamine.

Intensity of behaviour
Walking	slow	medium	fast	fast	absent	Equivalent rat behaviour
						Conditioned responding
Drug dose	Saline (Control)	1.0 mg/kg	3.0 mg/kg	5.0 mg/kg	10.0 mg/kg
In contrast walking is slow under control conditions, is fastest under intermediate doses of the drug ( 3-5.0 mg/kg), but slows down under the highest dose. This is similar to the effect of increasing doses of amphetamine on rats' rearing behaviour.

Frequency of behaviour
Ear flapping	absent	absent	absent	slow	fast	Equivalent rat behaviour
						Sniffing & licking
Drug dose	Saline (Control)	1.0 mg/kg	3.0 mg/kg	5.0 mg/kg	10.0 mg/kg
Finally, ear-flapping is absent under low doses of amphetamine, but is emitted at a high rate under the highest doses (5-10.0 mg/kg) of the drug. Thus ear-flapping resembles sniffing and licking behaviour in the rats.

It is very difficult to measure the effects of any drug on behaviour. We have just seen that the behaviours that are affected by amphetamine change as the dose of the drug is increased. If we focussed on just one behaviour e.g. tail-wagging in the dog or rearing in the rat, we might conclude that intermediate doses (3mg/kg) increased the frequency of this behaviour, but high or low doses had virtually no effect. In contrast if only measured sniffing and licking in the rat or ear-flapping in the dog, we would conclude that only high doses of amphetamine (10 mg/kg) increased the frequency of this behaviour.

One approach to this problem is to use a rating scale that lumps all behaviours together and simply tries to measure the stereotyped nature of the animals' behaviour. This is a popular approach but it ignores underlying changes in different behaviours. To some extent this simple approach has been successful. It is used in the conventional amphetamine-antagonism test where the investigator is interested in the ability of antipsychotic drugs to antagonise amphetamine-induced stereotypy. If a new drug shows this ability it is taken as a sign that it may be useful in the treatment of schizophrenia. We will now explore the background to this approach.

Amphetamine-antagonism detects antipsychotic drugs?

Antipsychotic drugs such as chlorpromazine are thought to exert their theraputic effects by blocking DA receptors. Here are some images from a movie showing this effect of chlorpromazine on postsynaptic receptors. Notice that chlorpromazine attaches to receptor sites in the postsynaptic membrane normally occupied by dopamine released from the presynaptic neuron. This prevents amphetamine activating these receptors and consequently the post-synaptic neuron does not fire.

You can download the complete movie (size c1.4MB).

A well established screening test for novel antipsychotic drugs involves examining their ability to antagonize the effects of amphetamine on animal behaviours. Here are some images from a movie showing how chlorpromazine may antagonise the effects of amphetamine by blocking postsynaptic receptor sites so that they cannot be activated by the large amount of DA released by an injection of amphetamine.

In this simulation chlorpromazine is injected first and occupies postsynaptic receptor sites. Then amphetamine is injected. This mimics the arrival of an action potential at the nerve ending and causes the release a large number of DA molecules from the presynaptic neurone. But this released DA cannot activate the postsynaptic receptors because they are occupied by chlorpromazine molecules. Consequently, the postsynaptic neurone does not generate an action potential. The released DA is broken down by enzymes in the synaptic cleft, or is reabsorbed into the presynaptic neurone.

You can download the complete movie (size c1.8MB).

Effect of pimozide on amphetamine-induced locomotion and stereotypy
The next diagrams show the effects of pimozide (a classic antipsychotic) on locomotion and stereotypy produced by increasing doses of amphetamine. Note that pimozide

• reduces amphetamine-induced locomotion and
• reduces amphetamine-induced stereotyped behaviours

These results are consistent with the hypothesis that reduction of amphetamine-induced behaviours is an indication of a drug's antipsychotic potential.
 

A common feature of the so-called classic antipsychotics - such as pimozide - is their ability to block both the increased locomotion and the increased stereotyped behaviours produced by amphetamine. In fact this ability of classic antipsychotics to block the effects of amphetamine is the rationale for using the amphetamine-antagonism test to detect antipsychotic potential in a new drug.

However as we discussed above classic antipsychotics have a number of very undesirable side effects on the control of movement (Extra Pyramidal Side Effects - EPS ) such as dystonia and tardive dyskinesia.

Recently a new type of antipsychotic medication has appeared - atypical antipsychotics - these drugs are effective clinically and produce fewer EPSs. How do these drugs perform in the amphetamine-antagonism test?

Effect of clozapine on amphetamine-induced locomotion and stereotypy
The next diagram shows the effects of clozapine ( an atypical antipsychotic) on locomotion and stereotypy produced by increasing doses of amphetamine. Note that clozapine

• reduces amphetamine-induced locomotion but
• enhances amphetamine-induced stereotyped behaviours

These results are NOT consistent with the hypothesis that reduction of amphetamine-induced behaviours is an indication of a drug's antipsychotic potential
 

Although clozapine is a very useful antipsychotic medication - it is effective and poses less risk of extrapyramidal side effects than the older classic drugs - nevertheless it can have serious side effects e.g agranulocytosis - a potentially lethal condition involving the immune system that requires close patient monitoring.

Consequenly there is still a need for psychologists to develop effective animal models to test new chemicals for antipsychotic potential. Several years ago research here at Plymouth was directed towards this goal. The fruits of this work will be described in subsequent lectures.

References

• Davis, American Journal of Psychiatry, 1976, 133, 208-214.
• Leonard, (1997). Fundamentals of Psychopharmacology, 2nd Edition, Wiley, Chichester.
• Lickey & Gordon, (1991) Medicine and Mental Illness, Freeman, New York.
• Moore & Kenyon, (1994), Psychopharmacology, 114, 123-130.
• Robertson & MacDonald, (1985). Eur. J. Pharmacol., 36, 181-188.
• Sharp et al, (1986). Eur. J. Pharmacol., 129, 411-415.