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Animal Models of Psychiatric Disorders
Author Paul Kenyon

 

Measuring animal behaviour under laboratory conditions - the Skinner box
An area of psychology called psychopharmacology or behavioural pharmacology is concerned with measuring the effects of drugs on behaviour. Exploring the effects of drugs on operant schedules of reinforcement has a long tradition in psychopharmacology. Here is some of the technology used by psychopharmacologists.

Skinner box 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 set-up by the experimenter.

Electric shock can be delivered to the animal's feet through the floor of the box which consists of a grid of parallel metal rods. Food or water can be delivered through a food trough beside 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.

In many studies the animal's bar presses and the delivery of stimuli are recorded on a cumulative recorder.


Cumulative recorder: Diagrammatic representation
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).

This animation shows the process:

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.


Rationale for animal models of human behaviour

model-train.jpg (3429 bytes) 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 a psychiatric disorder is an attempt to capture the essence of the condition, but it does not claim to reproduce the human condition in an animal. Depression, schizophrenia and anxiety are probably uniquely human conditions. One 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-scream.jpg (4979 bytes)

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.

Steps in the construction of an animal model
1 Drug X has a behavioural effect in humans that resembles human pathology e.g. drug X produces depression when given to humans
2 Drug X produces similar behavioural effects in animals, allowing for any species differences in behaviour
3 Drug X produces specific biochemical effects in animals
4 Thus the biochemical effects produced in animals provide data relevant to the behavioural effect of drug X in humans
5 If the behavioural effect of drug X in humans has the same characteristics as pathological behaviour, then the biochemical changes produced by drug X in animals may also provide data relevant for the understanding of the abnormal human behaviour.

Depression:The catecholamine theory of mood

The catecholamine theory of mood suggests that:

The catecholamine-depleting drugs tetrabenazine and reserpine have been explored for their ability to produce animal models of depression. Here are some stills from an animation showing the effects of these drugs on catecholamines.

You can download the movie - which has audio effects and larger images.

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

Rationale for the tetrabenazine/reserpine animal model of depression
1 About 15% of humans treated with reserpine for hypertension develop depression
2 Reserpine and TBZ disrupt conditioned and unconditioned behaviour in animals
3 Reserpine and TBZ produce profound depletion of catecholamines
4 Thus the depletion in CAs may be related to human depression - this is the CA theory of Mood
5 The depression produced by reserpine in humans is similar to 'naturally occurring' depression. Thus CA depletion may be responsible for 'naturally occurring' depression.

Sidman avoidance schedule
In order to explore this model of depression, rats that had been trained on an avoidance schedule in a Skinner box were injected with reserpine or tetrabenazine. Avoidance schedules of reinforcement are very useful to psychopharmacologists because the rat's motivation remains relatively stable during a test session. In contrast, on schedules of reinforcement maintained by food rewards the 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 schedule 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.

clock.jpg (6432 bytes)For example, 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!



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 is a cumulative record showing 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 effects of 2.0 mg/kg TBZ

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

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 antagonize 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 combination 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
Tetrabenazine and imipramine


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

  Antagonism of tetrabenazine at
Antidepressant group 0.2 mg/kg 2.0 mg/kg
Tricyclics Yes No
MAOIs No Yes

One further 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.

You can read a fuller account of The Catecholamine Theory of Mood


Learned helplessness theory of depression

Martin Seligman is responsible for learned helplessness theory which had a major influence on psychological research into depression in the 1970s. Seligman discovered helplessness by accident whilst studying the effects of inescapable shock on active avoidance learning in dogs.

Seligman restrained dogs in a Pavlovian harness and administered several shocks (UCS) paired with a conditioned stimulus (CS) - this is the conventional CS-UCS pairing procedure used to study classical conditioning . Then these dogs were placed in a shuttlebox where they could avoid shock by jumping over a barrier. The shuttlebox was used to study the role of operant conditioning in learning. Most of the dogs failed to learn to avoid shock.

Seligman argued that prior exposure to inescapable shock interfered with the ability to learn in a situation where avoidance or escape was possible. Seligman introduced the term learned helplessness to describe this phenomenon.


Learned helplessness and human depression

Seligman argues that there are similarities between the symptoms of depression in humans and learned helplessness

Symptoms of depression Corresponding symptom in learned helplessness
depressed mood helplessness
lack of interest in, and pleasure from, almost all activities cognitive representation of uncontrollability
decreased appetite leading to weight loss helpless animals eat less & loose weight
insomnia or hypersomnia I know of no study on this point
psychomotor agitation or retardation helpless animals are passive in face of shock
feeling without energy lack of response initiation
feelings of worthlessness and guilt perception that individual cannot control their environment
inability to think clearly or concentrate effectively, indecisiveness cognitive representation of uncontrollability
thoughts of death, suicidal thoughts helpless animals may die in traumatic situations

The motor activation deficit explanation of learned helplessness

One aspect of helplessness and depression posed problems for Seligman's theory - its physiological basis. Seligman points out similarities between the physiological basis of depression and helplessness:

Physiology of depression Physiology of learned helplessness
  • Depression is associated with a deficiency of catecholamines
    (particularly norepinephrine) at central receptor sites. This is the catecholamine theory of mood
  • Helpless rats have lowered levels of norepinephrine in the brain

Weiss believes that 'learned helplessness' is produced by some form of stress-induced 'debilitation' involving a temporary reduction in brain norepinephrine levels. He called this the motor activation deficit hypothesis (Weiss & Glazer, Psychosomatic Medicine, 37, p501, 1975).

You can read a fuller account of this controversy in Depression and Learned Helplessness


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

Comparison of amphetamine psychosis and paranoid schizophrenia

An early 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.

Similarities between amphetamine psychosis and paranoid schizophrenia Differences between amphetamine psychosis and paranoid schizophrenia
Clear sensorium Strong sexual stimulation and stereotypic compulsive behaviour in amphetamine psychosis
High incidence of auditory hallucinations Failure to display flattened affect in amphetamine psychosis
Phenothiazines (and other antipsychotics) are highly efficacious in treatment Lack of formal thought disorder in amphetamine psychosis

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).


Rationale for animal model of schizophrenia

One of the first animal models of schizophrenia involved the use of drugs that increased the release of dopamine in the brain. Here is the logic for an animal model that involved injecting rats with amphetamine.

Rationale for the amphetamine animal model of schizophrenia
1 Amphetamine induced psychosis is similar to paranoid schizophrenia
2 Amphetamine affects conditioned and unconditioned animal behaviour 
3 Amphetamine releases DA from presynaptic nerve terminals
4 Thus the release of DA may be related to schizophrenia - this is the DA hypothesis of schizophrenia
5 Amphetamine-induced psychosis is similar to 'naturally occurring' paranoid schizophrenia. Thus DA hyperactivity may be responsible for 'naturally occurring' schizophrenia.



Amphetamine-induced stereotypy as an animal model of schizophrenia

Effect of amphetamine on unconditioned behaviours 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 exemplified by this cat !

This diagram shows that 'stereotypy' increases as a function of increasing dose of amphetamine Relationship between Stereotypy Scores and amphetamine dose
  • 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-antagonism may detect antipsychotic drugs

Antipsychotic drugs such as chlorpromazine are thought to exert their therapeutic 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 dopamine activating these receptors and consequently the postsynaptic 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 antagonize 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).

You can read a fuller account of the DA theory of schizophrenia


Anxiety: The Geller-Seifter paradigm as an animal model of anxiety

The Geller-Seifter paradigm was developed to screen drugs for their ability to control human anxiety. The technique involves training rats in a Skinner box on two different schedules of reinforcement.
  • Under the VI (variable interval) schedule, each bar-press is reinforced by sweetened milk at irregular intervals.
  • Under the CRF (continuous reinforcement) schedule every response is reinforced by the delivery of sweetened milk, but in addition, each response is punished by the delivery of a brief, inescapable electric shock to the animal's feet.

The switch from VI to CRF is signalled by a tone or light. The CRF schedule may produce 'anxiety' in the rat by placing it in a 'conflict' situation.

This diagram shows the performance of a rat in the Geller-Seifter paradigm after a saline injection (upper panel) and following the injection of a benzodiazepine (lower panel) .

The effect of the benzodiazepine is revealed in performance on the CRF schedule of reinforcement where the rat is presented with a conflict between bar-pressing for a guaranteed reward, but at the cost of an inevitable electric shock to its feet

Important points to note:

  • the drug does not affect performance on the VI component
  • performance on the CRF (punished) schedule is increased by the anti-anxiety drug
    Schedule of reinforcement
    VI (unpunished) CRF (punished)
Injection Saline high, stable response rate no responding
Benzodiazepine no change to high, stable response rate increased response rate


Correlation of rat punishment potency with clinical potency
Correlation of rat punishment potency with clinical potency There is a very strong correlation ( r=.987 ) between the dose of drug that needs to be given to a patient to control their anxiety, and the dose of the same drug that reduces conflict in animals.

In this diagram

This suggests that there may be a common biochemical basis for the effect of the drugs in humans and animals. One of the first theories to explore this idea was Stein's theory that the anti-anxiety effect of benzodiazepine drugs involved the serotoninergic system in the brain.

Refer to an earlier lecture on anxiety for discussion of the specificity of benzodiazepine effects on the Geller-Seifter paradigm.


Seminar discussion topics

Read Hitzeman (2000) Animal models of psychiatric disorders and their relevance to alcoholism which is available online to familiarize yourself with the following concepts and techniques:

Face validity

phenotypes and endophenotypes
prepulse inhibition of the acoustic startle response

Predictive validity

Etiological validity

Genetic validity

Reliability

  • inter-laboratory reproducibility
  • test-retest reliability; carry-over effects
Animal models of schizophrenia
  • prepulse inhibition
  • latent inhibition
  • catalepsy
  • hallucinogens
  • acute and chronic amphetamine -drug sensitization
  • NMDA: N-methyl-D-aspartate

Animal models of depression

  • reserpine
  • learned helplessness
  • behavioural despair

Animal models of anxiety and fear

  • conditioned and unconditioned fear
  • open-field test
  • light-dark transition
  • elevated plus maze
  • fear potentiated startle

Read Geyer and  Markou (2000) Animal Models of Psychiatric Disorders: which is available online and consider the following points:


Read Barrett and Miczek (2000) Behavioral Techniques in Preclinical Neuropsychopharmacology Research which is available online and consider the following points:


References and supplementary resources

Copyright Dr. C.A.P. Kenyon 1994-2006