Anxiety Author Paul Kenyon Overview Learning objectives Measuring human anxiety Anxiety disorders defined in DSM-111-R Benzodiazepines The Geller-Seifter paradigm Explanation of cumulative record Acute and chronic effects of benzodiazepines Effect of major and minor tranquillizers on conflict Effects of benzodiazepines Effects of chlorpromazine Serotonin synthesis Effects of drugs on 5-HT Serotonin depletion disrupts conflict behaviour Some comments and caveats References Supplementary information Further reading Visit the SALMON Bookshop for recommended books on this topic

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Overview:

Learning objectives

After studying the material on this page you should be able to:

• recognize items used in Spielberger's state anxiety scale
• understand the relationship between state anxiety scale scores and percentile ranks
• be able to convert state anxiety scale scores to percentile ranks and vice versa
• name 5 anxiety disorders defined in DSM-111-R
• name 2 benzodiazepines
• describe the Geller-Seifter paradigm
• draw a diagram to show the effects of placebo and benzodiazepine treatments on responding in the Geller-Seifter paradigm
• distinguish acute from chronic effects of anti-anxiety drugs on the Geller-Seifter paradigm
• distinguish between the effects of major and minor tranquillizers on the Geller-Seifter paradigm
• draw a diagram of the synthesis of 5-HT, include relevant enzymes
• state what drugs you would use to test the 5-HT theory of anxiety, and why
• evaluate the rationale for animal models of human behaviour

Learning Activity: Measuring human anxiety

Anxiety is an unpleasant psychological state involving tension, nervousness, fear and worry often accompanied by physical symptoms such as trembling, dizziness and heart palpitations. We all experience anxiety from time to time in response to specific challenges in our environment. But there are individual differences in how people react to specific stressors. In addition people vary in how anxious they are over longer periods of time.

Spielberger calls these two types of anxiety:

• state anxiety - a measure of an individual's emotional reactions to a stressor. It is by characterized by subjective, conscious feelings of tension, apprehension, nervousness and worry.
• trait anxiety - refers to the extent to which a person views the world as threatening or dangerous, and in the frequency that state anxiety is experienced.

Learning Activity: Measuring State Anxiety

Before we start a warning : The information provided on this page 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 anxiety. It should not be used as part of any experimental investigation of anxiety. Bear in mind that this is an educational exercise. You do not have to answer the questionnaire truthfully. You may decide that you do not want to know your personal score on this scale. This is perfectly reasonable. You can answer the questions "as if" you were a highly anxious person, or vice versa. This will not interfere with the educational purpose of the exercise.

The purpose of this activity is to:

• Present the items used in Spielberger's state anxiety scale.
  
• Show the relationship between scale scores and population percentile ranks
• Show the relationship between individual questions and scale scores

The first exercise on this page consists of three steps:

1. Select your sex (interpretation of the scale is sex-dependant)
2. Fill in the questionnaire
3. Determine the percentile rank for your score

Please complete each step before moving on.

Sex	Select a sex male female
Statement	Possible responses
I feel calm	Select statement Not at all Somewhat Moderately Very much
I am tense	Select statement Not at all Somewhat Moderately Very much
I feel upset	Select statement Not at all Somewhat Moderately Very much
I feel frightened	Select statement Not at all Somewhat Moderately Very much
I feel nervous	Select statement Not at all Somewhat Moderately Very much
I am relaxed	Select statement Not at all Somewhat Moderately Very much
I am worried	Select statement Not at all Somewhat Moderately Very much
I am confused	Select statement Not at all Somewhat Moderately Very much
State Anxiety Score =

The second exercise tests your understanding of the relationship between sex, anxiety state scores and percentile ranks.

The percentile rank indicates the percentage of scale scores in a population that lie below any particular score. For example, a male scoring 17 on the state anxiety scale has a percentile rank of 75. This means that 75% of males have a score lower than 17.

• Use the 'floating rulers' to determine the relationship between scale scores and percentile ranks
• Answers selected from the 'drop-down' choices are automatically checked
• If you make a mistake, use the 'floating rulers' and 'drop-down' menu to correct your answer

Sex	State Anxiety Score	Percentile	Correct?
Male	17	Select percentile 95 75 50 25 5
Male	Select score 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32	50
Male	12	Select percentile 95 75 50 25 5
Female	17	Select percentile 95 75 50 25 5
Female	Select score 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32	50
Female	12	Select percentile 95 75 50 25 5

Relationship between state anxiety score and individual scale items

If you look carefully at the items that make up the state anxiety scale you will notice two items:

• I feel calm
• I am relaxed

that contrast with the other items on the scale.

These non-anxiety items were included to make the scale sensitive in measuring low levels of anxiety.
This table - which shows how responses on each item are scored - indicates how each statement contributes to the overall state anxiety score.
An individual's score is calculated by adding together their score for each scale item.

Anxiety disorders defined in DSM-111-R

		We all experience anxiety from time to time. Without anxiety we would be careless, lazy and aggressive. But anxiety can become more intense than is justified by the real threat to the individual. A person can become overwhelmed by anxiety in the absence of any obvious stressor. When anxiety becomes so debilitating that it interferes with a person's life-style, work and interpersonal relationships, it is classed as a mental disorder. The Diagnostic and Statistical Manual, Third Edition- Revised (DSM-III-R) was published by the American Psychiatric Association in 1987. It lays out definitions for 313 distinct mental disorders which include the following five types of anxiety disorder:
		Panic disorder (panic attacks) - rapid-onet attacks of extreme fear and feelings of heart palpitations, choking and shortness of breath. Phobic anxiety is triggered by a particular object, for example; spiders, snakes, heights, or open spaces. Obsessive-compulsive disorder - uncontrollable recurring anxiety-producing thoughts and uncontrollable impulses. For example compulsive hand-washing, checking that doors are locked, counting steps whilst walking, or avoiding places or objects. Generalized anxiety disorder - extreme feeling of anxiety in the absence of any clear cause Post-traumatic stress disorder (PTSD) - recurrent recollections of a traumatic event of unusual clarity which produce intense psychological distress. It is estimated that about 13% of Americans suffer from anxiety at some time during their lifetime. Many of these people have been helped by drug treatments. Lickey and Gordon (1991) provide a detailed but very readable description of the diagnosis of various forms of anxiety.

Benzodiazepines

In the 1960s the treatment of anxiety was revolutionized by the introduction of the benzodiazepine anti-anxiety drugs: Librium (chlordiazepoxide) introduced in 1960 Valium (diazepam) introduced in 1962 Librium and valium are tradenames for medicines. Tradenames are written on the label of bottles containing tablets. Chlordiazepoxide and diazepam are generic names used in textbooks and scientific articles. These drugs are also called anxiolytics or minor tranquillizers to distinguish them from major tranquillizers such as the antipsychotic drug chlorpromazine.

The number of prescriptions written in USA peaked in the mid 1970s

• 100 million in 1975 at cost of 500 million dollars
• declined to 70 million in 1979

There is still a need to discover effective anti-anxiety drugs because current medicines cause addiction in some people.

The Geller-Seifter paradigm

Tests on animals are an important part of the process involved in discovering new medicines to treat mental illness. Psychology has an important role in this endeavour because psychologists are trained in the techniques required to measure behaviour.

The next part of the lecture explores a behavioural technique that was developed to screen drugs for their ability to control human anxiety.

A technique introduced by Geller and Seifter, 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.

When a rat has been trained on the Geller-Seifter paradigm the cumulative record shows:

• stable and relatively high rates of responding during the VI unpunished component,
• but low levels of suppressed responding during the CRF punishment component.

Geller & Seifter found that anxiolytic drugs (drugs that reduce anxiety in humans)

• increased the rate of responding in the punishment component,
• but had relatively little effect on unpunished responding.

This specific effect of the drug on the CRF schedule is very important because it shows that benzodiazepines are not simply increasing the rats' overall rate of responding.

Explanation of cumulative record

If you are unsure how a to interpret a cumulative record run the animation to see how a cumulative recorder represents the rate of rat's lever pressing. The slope of the tracing made by the response marking pen is a function of how many responses are made in a fixed time period. The greater the response rate the steeper the slope. A flat tracing indicates that the rat has not pressed the lever in the Skinner (operant) box. The animal injected with saline shows a flat tracing during the CRF component in the diagram above. In contrast response rate was high, and there is relatively little variability in response rate under drug and saline conditions under the VI schedule of reinforcement.

Acute and chronic effects of benzodiazepines

This page is Java enhanced.
You will need a Java-capable browser to view its applet This figure shows the actual cumulative records from a rat treated with the anti-anxiety benzodiazepine drug Oxazepam .
The cumulative records are shown for the last control day and drug days as indicated. The slopes of these curves indicate response rates.

The recording pen reset after every 3 minutes. The numbers indicate the number of of punished responses that occurred during 3-minute tone periods and the responses are indicated by short upward stokes of the pen. Downward strokes indicate rewarded responses that occurred during the unpunished periods. Note that the full 'anxiolytic' effect of the drug takes several days to emerge. For example, the rat makes fewer punished responses on days 1,2 and 3 than on days 12 and 22. Also the cumulative records show that unpunished responding tends to be depressed on the first few days of treatment and gradually recovers over the course of the experiment.

This distinction between the acute and chronic effects of the drug will be explored in more detail in a future lecture .

I have embedded a Java applet in the page that allows you to magnify this image so that you can examine the animals behaviour in detail. The horizontal and vertical scroll bars enable you to move around the image.

Effect of major and minor tranquillizers on conflict

An important question to raise at this point is "Are the effects of benzodiazepine drugs on the Geller-Seifter paradigm unique to anti-anxiety drugs?". The first step to answering this question is to compare the effects of major and minor tranquillizers on punished responding in the CRF component oif the Geller-Seifter paradigm.

Dose response effects of chlordiazepoxide on Geller-Seifter paradigm

This graph shows the effects of increasing doses of the benzodiazepine drug chlordiazepoxide on punished and unpunished responding. Notice how at low and intermediate doses of the drug, the rate of punished responding increases whilst there is very little effect on unpunished responding.

This suggests that the drug is having a specific effect on 'anxiety' rather than a general effect on response rate. However at very high doses both punished and unpunished behaviours are affected - there is a general decline in response rate - indicating a non-specific / 'sedative' effect of the drug on the animals' behaviour

Dose response effects of chlorpromazine on Geller-Seifter paradigm
This graph shows the effects of increasing doses of the antipsychotic / major tranquillizer drug chlorpromazine on punished and unpunished responding.

Notice that there is no evidence of a specific increase in punished responding at any dose of the drug. At higher doses there is a massive decline in both punished and unpunished bar pressing which reflects the 'sedative' effect of the drug.

This result supports the idea that only anti-anxiety drugs increase responding during the CRF component of the Geller-Seifter paradigm.

These results are examples of a body of evidence which shows that the pattern of responding (increase in punished responding with little change in unpunished response rate) in rats treated with benzodiazepines is specific to benzodiazepine drugs, and is not seen in animals treated with other classes of psychoactive compounds.

This is a very important finding which suggests that the Geller-Seifter paradigm may be a good animal model for studying the biological bases of anxiety. The next step would be to try to understand whether anxiolytics work by affecting particular neurochemical systems.

Serotonin synthesis

It has been suggested that serotonin (5-HT) mediates the effects of punishment on behaviour, and that benzodiazepines exert their anxiolytic effects via serotonin. I do not propose to go into details of this hypothesis this year, but this serotonin hypothesis provides a convenient 'hook' to begin our exploration of serotonin neurotransmission within the brain.

The 5-HT hypothesis suggests that antianxiety drugs reduce activity at serotonin receptor sites within the brain.

The diagram below shows the steps involved in 5-HT synthesis.

You should learn the steps involved in serotonin synthesis because we will use this information a number of times during the course.

Serotonin pathways in the brain

Cell bodies of the serotonin pathway  are located in Raphé nucleus which is part of the brainstem area. These neurons send long axons to higher centers in the brain including the neocortex and the limbic system (e.g., the amygdala and hippocampus).A second pathway for serotonin neurons  descends down the spinal cord; these neurons control muscle activity.

Effects of drugs on 5-HT

You should be familiar with the strategy adopted by psychopharmacologists investigating a theory such as the 5-HT theory of anxiety: Briefly the effects of drugs that exert an influence over the 5-HT system are examined in an animal model of the human condition such as the Geller-Seifter paradigm. The basic idea being that drugs that reduce serotoninergic activity should increase punished responding in the Geller-Seifter paradigm i.e. exert an anxiolytic effect drugs that increase serotoninergic activity should reduce punished responding in the Geller-Seifter paradigm i.e. exert an anxiogenic effect In fact early tests of this theory were promising. PCPA which blocks the enzyme tryptophan hydroxylase and thereby depletes the brain of 5-HT, has anti-punishment effects comparable to benzodiazepines.

Serotonin depletion disrupts conflict behaviour

This diagram shows the effect of serotonin (5-HT) depletion on conflict behaviour in the Geller-Seifter paradigm.

PCPA is a drug which inhibits the enzyme tryptophan hydroxylase. As a consequence, 5-HT synthesis is stopped and the amount of serotonin available for neurotransmission within the brain is reduced.

PCPA increases bar-pressing during the CRF component of the conflict test. This is consistent with the suggestion that serotonin is involved in the effects of punishment on behaviour.

In a future lecture we will examine the possibility that benzodiazepines work via the serotoninergic system.

Some comments and caveats

Despite the impression that may be growing as you study these lectures, drugs seldom affect behaviour by working on just one neurotransmitter system. Normally drugs affect several neurotransmitters at once, and they often have more than one mode of action e.g. amphetamine affects catecholamine release and reuptake. Therefore it is generally accepted that the effects of psychoactive drugs involve several neurochemical processes. Furthermore neurotransmitter systems interact with each other, so that drug effects may 'cascade' through several systems.

Nevertheless, drugs that are useful to psychopharmacologists tend to have relatively specific effects on one neurotransmitter system, and theories of the biological bases of mental illness tend to focus on specific neurotransmitter systems. This is certainly true of current work linking DA to schizophrenia. If you have read recent research on the biology of depression you may have gathered that the earlier CA theory of depression has lost favour and increasingly attention is focussed on the role of serotonin in depression. Often attention is narrowed down within a neurotransmitter system so that research focusses on particular receptor subtypes or particular neurotransmitter pathways within the brain.

At several points in these lectures we have presented animal models of mental illness. These animal models often serve several functions. For example they may be used as the basis of screening tests for new drugs, or as starting-off points on the road to understanding the biological basis of a particular human condition. The strengths and weaknesses of the various models should be clear to you but you should bear in mind that a model is only as good as the knowledge that went into its construction.

There is a danger when animal models are used for drug screening that they may only reveal new medicines that work in a very similar way to the drugs used to construct the model in the first place. For example drugs that work as anxiolytics in the Geller-Seifter paradigm may do so simply because they have the same biochemical effects as benzodiazepines. This is all very well and good provided that the biological reason why benzodiazepines work in the animal model is the same as the way the drugs work to reduce human anxiety. If they differ, then a potentially important source of new and better drugs will be missed. Imagine a drug screening test that relied on the colour of the drug. Say- for the sake of argument - that all benzodiazepine molecules were blue. If a chemist synthesized a new molecule that was blue it would clearly be very dangerous to conclude that this new medicine would reduce anxiety in humans!

References 

• Geller and Seifter (1960), Psychopharmacologia, 1, 482-492.
• Lickey and Gordon, (1991). Medicine and Mental Illness, Freeman, New York.
• Spielberger, C.D. (Ed), Anxiety and Behaviour . New York: Academic Press, 1966.
• Spielberger, C.D. (Ed), Anxiety: Current Trends in Theory and Research . New York: Academic Press, 1972
• Spielberger, C.D., Understanding Stress and Anxiety . London: Harper & Row, 1979.