Animal models of anxiety

Prog. Neuro-Psychophamacol. vo1.5, pp. 143-157 Pergamon Press Ltd, 1981. Printed in Great Britain.

0364-7722/81/0701-0143$05.00/O

ANIMAL MODELS OF ANXDTY

Jeffrey A. Gray, Nicola Davis, Joram Feldon, J. Nicholas P. Rawlins and Susan R. Owen

Department of Experimental Psychology Oxford, England

(Final form, February 1981)

1. 2. 3 . 4. 4.1. 4.2. 5.

Contents

Abstract 143

The psychology of anxiety as deduced from the action of anxiolytics 143 The neural substrate of anxiety 144 Behavioural tolerance to the adequate stimuli for anxiety 145 The neural substrate of behavioural tolerance 151 The septo-hippocampal system 151 Ascendingmonoaminergicpathways 153 Conclusions 155 References 156

Abstract

A theory of anxiety and the psychological action of anti-anxiety drugs is presented (a) on a general theory of learning which postulates that emotional behavlour is

based the

outcome of an interaction between two basic learning processes (classical and instrument- al conditioning); and (b) on experiments on the behavioural effects of anti-anxiety drugs (benzodiazepines, barbiturates, alcohol) in animals.

The theory proposes that the effective stimuli for anxiety are stimuli associated with punishment, stimuli associated with frustrative non-reward, and novel stimuli; the behavioural conseqeuences of anxiety are an inhibition of ongoing behaviour, increased arousal, and increased attention to novel features of the environment. Physiological experiments suggest that the neural substrate of anxiety thus defined includes the septo-hippocampal system (SHS) and its monoaminergic inputs from the brain stem, especially the dorsal ascending noradrenergic bundle (DANB). The SHS-DANB system is also concerned with aspects of the development of behavioural tolerance for non-reward or punishment; and the anti-anxiety drugs, under certain conditions, block the development of this tolerance.

Keywords: anti-anxiety drugs, dorsal ascending noradrenergic bunlde, septo-hippocampal system, tolerance for stress.

Abbreviations: Continuous reinforcement (CRF); Dorsal ascending noradrenergic bundle (DANB); Partial punishment (PP); Partial punishment effect (PPE); Partial reinforcement (PRF); Partial reinforcement extinction effect (PREE); Septo-hippocampal system (SHS).

1. The Psychology of Anxiety as Deduced from the Action of Anxiolytics

The word 'model', as it is used in psychopharmaoclogy, is elastic. At one extreme it denotes isolated items of behaviour which bear only a superficial resemblance, if any, to the human condition modelled, but which display important principles of drug action. At the other extreme it stretches to cover rather general theories of the underlying processes

143

144 .l. A. Gray et al.

which control the relevant human condition. The work described here lies close to the latter end of this spectrum of meanings. We shall not present a particular form of behaviour as a 'model' of anxiety or of the action of the anti-anxiety drugs (benzodiasepines, barbiturates, alcohol), but rather a theory of anxiety which has been derived from a.general consideration of the great range of reported behavioural effects of these agents.

Since both the theory (Gray, 1976, 1977a, 1978) and the drug effects on which it is based (Gray, 197713) have been described in considerable detail, we shall here be brief - indeed,

dogmatic + and set out only its main lines. This will allow us to concentrate on some of the problems to which our research is currently directed.

The theory of the psychological effects of the anti-anxiety drugs which we have developed is a natural extension of the pioneering work of Neal Miller (1951, 1964) on alcohol and the barbiturates. Like his work it draws heavily on the general theory of learning (Gray, 1975) in order to define the action of these drugs and the newer benzodiasepines. Since the behavioural ef,fects of the three classes of drugs, as observed in a remarkably wide variety of behavioural tasks and animal species (Gray, 1977b), differ only in points of detail (and in what may be regarded, from the point of view of anti-anxiety action, as side-effects), it is possible to advance a single theory to cover them all.

According to this theory (Gray, 1977b), the anti-anxiety drugs counteract the behavioural effects of three major classes of stimuli: a) stimuli associated with punishment; b) stimuli associated with frustrative nonreward, as this term is used by Amsel (1962); and c) novel stimuli. Note that this formulation is intended to imply that these drugs do not affect behavioural reactions to other important classes of stimuli, e.g. those associatr with reward or the active avoidance of punishment. In particular, the anti-anxiety drugs do not alter the effects of punishment (nor probably those of nonreward) once those aversive events have actually occurred, but only the effects of stimuli which warn the animal that they are likely to occur.

If these are the classes of stimuli whose behavioural effect- J are counteracted by the anti-anxiety drugs, we may now ask what behavioural reactions they produce in experimental animals. Once again, rather than describe a long list of particular behavioural changes (for which there is in any case not time), we shall be dogmatic and theoretical. Stimuli

associated with punishment, stimuli associated with nonreward and novel stimuli cause three major changes in behaviour: a) they inhibit ongoing behaviour, b) they increase the level of arousal, and c) they increase attention to novel features of the environment (Gray, 1975, 1977b). All these behavioural changes are counteracted by the anti-anxiety drugs (Gray, 1977b).

One now makes use of this description of the behavioural effects of these drugs to con- struct a psychological theory of anxiety. In order to distinguish between constituents of this theory, on the one hand, and the clinical concept of anxiety to which it is meant to correspond, on the other, we have introduced the term 'behavioural inhibition system'. This denotes a hypothetical set of structures in the C.N.S. which receives information concerning the presence of the classes of stimuli described above and organizes behavioural responses t0 them (Fig. 1). Ex hypothesi activity in the behavioural inhibition system constitutes anxiety, and the an=-anxiety drugs reduce activity in the behavioural inhibition system. Thus the system pictured in Fig. 1 is a 'model' both of anxiety and of the action of the anti-anxiety drugs.

There is, however, one important feature of the action of these agents which is not captured in Fig. 1. Not only do they impair the immediate response to the adequate stimuli for anxiety (i.e., the classes of stimuli shown to the left of Fig. l), they also impair the animals' ability to develop behavioural tolerance to such stimuli. This finding is of both clinical and theoretical importance. Clinically, it implies that drug therapy may interfere with the development of behavioural mechanisms which might allow one to cope with anxiety-provoking stimuli. Theoretically, it implies that the same system which responds acutely to the adequate stimuli for anxiety is also responsible for the development of behavioural tolerance to them. We have been particularly interested in the latter possibility, and much of our recent research has been directed to it. Before describing this research, however, it will be necessary to indicate briefly the neural structures in the real brain which, we believe, discharge the functions of the behavioural inhibition system

2. The Neural Substrate of Anxiety

Brevity again compels dogmatism. A variety of evidence from lesion, stimulation and

Animal models of anxiety 145

'DIE BEHAVIOURAL INHIBITION SYSTEM

Inputs outputs

Signals of Punishment

Signals of Nonreward

Novel Stimuli

t

Impair

Anti-Anxiety Drugs

Fig. 1. The behavioural inhibition system: a model for anxiety

neuropharmacological studies (Gray, 1970; McNaughton et al., 1977; Gray et al., 1978) suggests that the neural structures which correspond (at least in part) to the behavioural inhibition system include the septal area and the hippocampus (which are so intimately related that they are best considered as a unitary 'septo-hippocampal system'), and the noradrsnergic and serotonergicafferents which these structures receive from nuclei in the brain stem (the locus coeruleus and raphe nuclei, respectively). Figures 2-5 present a schematic diagram of the interconnections between these various areas.

3. Behavioural Tolerance to the Adequate Stimuli for Anxiety

We have used two main methods to study the development of behavioural tolerance to the adequate stimuli for anxiety.

a) The partial reinforcement extinction effect (PREE). It is well known that, if animals are rewarded on only a random proportion of trials on

which they perform a response (a 'partial reinforcement' - PP.F - schedule) they subsequently show greater resistance tc extinction than animals rewarded on every trial (a 'continuous reinforcement' - CRF - schedule). This is the PREE. Using rats given food reward for running in an alley we have shown that the PP.EE is (under favourable behavioural conditions) completely blocked if training is conducted under the influence of small doses of amylobarbitone sodium (20 mg/kg i.p.) or chlordiazepoxide HCl (5 mg/kg i.p.1 (Gray, 1969; Feldon et al., 1979; Feldon and Gray, in press: Figures 6-S).

b) The 'partial punishment effect' (PPE). This second method for studying behavioural tolerance is similar in essential features to

the PREE but makes use of electric shock as a punishment rather than nonreward. Two groups of rats are again trained to run in an alley for food reward, given on a CRF schedule to all animals. One group is also subjected to electric shocks in the goal box of the alley, on a random proportion of trials, initially of low intensity but gradually increasing to about 0.3 mA (a 'partial punishment' - PP - schedule). Both groups are now given shock at 0.3 mA in the goal box on every trial ('continuous punishment'). The PP group is more resistant to the disruptive effect of this relatively high-intensity shock than is the control group (Fig. 9). This is the PPE; and, like the PREE, it is blocked if training is

146 J. A. Gray et al.

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Fig. 2. Lamellar organization of the hippocampus: (a) Lateral view of the rabbit brain with the parietal and temporal neocortex removed to expose the hippocampal formation. The lamellar slice indicated has been presented separately in (b) to show the proposed circuitry alv, alveus; ento, entorhinal cortex; fim, fimbria; pp. perforant path; Sch, Schaffer collateral. Modified by J. N. P. Rawlins from Andersen et al. (1971).


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Fig. 3. Interrelations between the septal area, the hippocampus and the locus coeruleus. Fim, fimbria; fern, fornix. As well as the noradrenergic input to the septo-hippocampal system from the locus coeruleus (see Fig. 41, there is a serotonergic input from the raphe nuclei (see Fiy. 5).

148 J. A! Gray et al.

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4. Saggital representation of the rat brain, showing the principal ascending and descending noradrenergic pathways. Cell bodies in the locus coeruleus (A61 give rise to pathways (- - -1 innervating all cortical areas of the brain. The dorsal bundle arising from A6 also innervates areas of the amygdala and anterior hypothalamus, while a short descending pathway innervates lower brain-stem nuclei. (From Livett, 19731.

Fig.

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5. Diagrammatic representation of the main projections of the serotonin axons to the septo-hippocampal complex. AL, ansa lenticularis; CB; cingulum bundle; D, dorsal and V, ventral hippocampus; DR, dorsal raphe; DT, diagonal tract; F, fornix column, FI, fimbria; L, lateral and M, medial septal nucleus; MFB, medial forebrain bundle; MR, median raphe; TSHT, septo- hypothalamic tract. (From Axmitia, in Elliot and Whelan 1978, p- 81).


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Fiq. 6. Runninq speed in the straight alley during extinction at one trial a day as a function of continuous reinforcement (CRF) or partial reinforcement (PRF) associated with injections of 5 mg/kg chlordiazepoxide (CDP) or saline placebo. Drug injections were given durinq acquisition only. (From Feldon and Gray, in press).

Fig. 7. Running speed in the straight alley. Drug injections were given only during extinction. (From Feldon and Gray, in press). Abbreviations as in Fig. 6.

150 S. A. Gray et oz.

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Speeds in goal section of alley during testing with food and 0.3 mA shock punishment on every trial (at one trial per day) as a function of partial punishment or no punishment ('controls') during training and treatment with 5 mg/kg chlordiazepoxide ('drug') or saline. The point 'C' on the abscissa is the final day of training (without shock). Saline-saline: saline during both training and testing Saline-drug: saline during training, drug during testing. Drug-saline: drug during training, saline during testing. Drug-drug: drug during both training and testing. (From Davis et al., in press).


conducted under the influence of amylobarbitone sodium (Dyck et al., 1975) or chlordiazepoxide (Davis et al., in press) (Fig. 9).

In the PREE, then, animals exposed to nonreward develop tolerance to the response- suppressant effect of nonreward (i.e., extinction); and in the PPE animals exposed to electric shock develop tolerance to the response-suppressant effects of this punishment. In neither case is the behavioural tolerance thus developed limited to the aversive event used in training: a PP schedule increases resistance to extinction, and a PP.F schedule increases resistance to the punishing effect of shock (Brown and Wagner, 1964). Miller (1976) has coined the phrase 'toughening up' to denote this development of general

behavioural tolerance to stress (which can also be demonstrated in experiments on cross- tolerance between shock and intense cold: Weiss et al., 1975). It seems that the anti- anxiety drugs in some way prevent an animal from 'toughening up'.

4. The Neural Substrate of Behavioural Tolerance

In pursuance of our hypothesis that the action of the anti-anxiety drugs is mediated, in part,by the septo-hippocampal system, we have been examining the role of these structures in the PREE. We have found that certain lesions reproduce the full pattern of action of the anti-anxiety drugs on the PREE, while others reproduce only part of this pattern.

To understand the results we have obtained it is first necessary to consider in a little more detail the findings shown in Figs. 6-9. Both in the PREE and in the PPE it is possible to distinguish between an action of chlordiasepoxide given during acquisition (on a PRF or PP schedule) and an action of the drug given during testing (in extinction or continuous punishment, respectively). If the drug is given during testing there is an overall increase in resistance to extinction or punishment, but the difference between PRF and CRF groups or PP and CRF groups is preserved (Figs. 7,9). This is consistent with the hypothesis that the anti-anxiety drugs block the behavioural inhibition produced by the threat of ncnreward (in extinction) or punishment (in continuous punishment). If the drug is given during acquisition there is a blockade of the PREE and PPE. produced by a lowering of resistance to subsequent extinction (in PPF-trained animals) or punishment (in PP-trained animals) relative to undrugged controls (Figs. 6 and 9). If the drug is given during both acquisition and extinction, the two effects combine: the PREE and PPE are blocked and there is an increase in resistance to extinction or punishment in CRF-trained animals (Figs. 8 and 9).

4.1 The septo-hippocampal system

If we now turn to the septo-hippocampal system,the following patterns of results emerges. Septal lesions which encroach upon both the medial and lateral nuclei produce the same changes in the PREE as an anti-anxiety drug present during both acquisition and extinction (Gray et al., 1972; Henke, 1974, 1977: Fig. 10). But lesions restricted either to the

medial septal area or the lateral septal area produce, respectively, the pattern of results found when an anti-anxiety drug is injected during extinction only or during acquisition only. That is to say, medial lesions increase resistance to extinction but leave the PREE intact (Fig. ll), while lateral lesions abolish the PREE exclusively by reducing resistance to extinction in PPF-trained animals (Fig. 12.; Feldon and Gray, 1979a,b).

In an effort to understand this pattern of results we have made use of the known input- output relations between the septal nuclei and the hippocampus. The medial septal nuclei project heavily to the hippocampus and control the hippocampal theta rhythm (Stumpf, 1965; Swanson and Cowan, 1976). The lateral nuclei receive the major sub-cortical outflow of the hippocampus (Swanson and Cown, 19761. We therefore proposed the hypothesis illustrated in Fig. 13 (Gray et al., 1978). According to this hypothesis, signals of impending nonreward are received in the medial septal nuclei and conveyed thence to the hippocampus by the same input which produces the theta rhythm. The hippocampus now inhibits the nonrewarded behaviour while attempting to determine the best behavioural strategy under the changed circumstances. (This period of behavioural inhibition and uncertainty would, ex hypothesi, be experienced subjectively as anxiety.) Under the conditions of a PRF schedule the best strategy is, in fact, to overcome the behavioural inhibition caused by nonreward and to continue with the partially reinforced response. To achieve this the hippocampus sends impulses to the lateral septal nuclei, which in turn alter the medial septal input to the hippocampus, thus cancelling the instruction to inhibit the nonrewarded behaviour.


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Fig. 11. Running speed in the straight alley during extinction at one trial a day as a function of continuous (CRF) or partial (PRF) reinforcement and medial septal lesions or sham operations ('control'). (From Feldon and Gray, 1979a).


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Fig. 12. Running speed in the alley during acquisition and extinction at one trial a day as a function of continuous (CRF) or partial (PRF) reinforcement and lateral septal lesions or sham operations ('control'). (From Feldon and Gray, 1979a).

This hypothesis gives rise to the prediction that destruction of the hippocampus should produce the same effects as a lesion destroying both the medial and the lateral septal areas Although previous data relevant to this prediction were equivocal, we have recently completed an experiment which leaves no doubt on the matter: under behavioural conditions which are optimal for disc!.osing the effects of large septal lesions on the PRRE (Henke, 1974) hippocampal destruction acts in the same manner: resistance to extinction is decreased in PRF-trained animals, increased in CRF-trained animals and the PREE is abolished (Rawlins et al., 1980; Fig. 14).

4.2 Ascending Monoaminergic Pathways

These data suggest the possibility that the chief site of action of the anti-anxiety drugs is in the hippocampus itself. This would account for the fact that destruction of the hippocampus produces the same changes in the PREE as does an injection of an anti-anxiety drug throughout both acquisition and extinction. However, other data suggest that the key site of action of tnese agents consists in the input pathways to the septo-hippocampal system, particularly those from the locus coeruleus (noradrenergic) and the median raphe (serotonergic).

154 S. A. Gray et al.

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Fig. 13. Gray et al. 's (1978) counter-conditioning model. text for explanation.

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Fig. 14. Running speed in the alley during extinction at six trials a day as a function of continous (CRF) or partial (PRF) reinforcement and hippocampectomy (HPC). Cortical control lesions (CC) or sham operations (SO). A-7 and A-8: the last two days of

acquisition. (From Rawlins et al., 1980).

The hypothesis that the anti-anxiety drugs (in particular, the benzodiazepines) influence behaviour by impairing serotonergic mechanisms has been proposed by a number of workers and is supported by evidence from psychopharmacological (Graeff and Schoenfeld, 1970; Stein et al., 1973) and histochemical (Lidbrink et al., 1972; Corrodi et al., 1971) experiments. More recently, Tye et al. (1977) have shown that the anti-punishment effects of the benzodiazepines in a Skinner box test (where barpressing is first rewarded but then suppressed by punishing electric shock) are mimicked by an injection of the specific neurotoxin, 5, 7- dihydroxytryptamine, just rostra1 to the raphe nuclei, which causes a loss of over 80 per cent of serotonin in the forebrain.


The hypothesis that the anti-anxiety drugs act on forebrainnoradrenergicmechanims is less widely entertained, though It too is supported by the histochemical observations of Fuxe's group (Lidbrink et al.. 1972). Our own experiments rather strongly suggest an involvement of the dorsal ascending noradrenergic bundle, in which the noradrenergic efferents from the locus coeruleus travel to the forebrain (Ungerstedt, 1971), in the action of these drugs. This inference was first drawn from neuropharmacological results (Gray et al., 1975; McNaughton et al., 19771 which we shall not describe here. More recently, we have shown that destruction of the dorsalnoradrenergicbundle by local injection of the specific neurotoxin, 6-hydroxydopamine, causing a loss of over 90 per cent of forebrain noradrenaline, produces the same pattern of change in the PP.EE as total septal or total hippocampal destruction (Owen, 1979; Owen et al., 1979: Fig. 15).

M Control-CR o--o Control -PR - Lesion -CR o---o Lesion -PR

” A” 1 2 3 5 DAYS DF EXTItKTIDN

Fig. 15. Speeds in the goal sectron of the alley as a function of continuous (CR) or partial (PR) reinforcement and destruction of the dorsal

ascending noradrenergic bundle ('lesion') or sham operation ('control'). The point 'A' on the abscissa is the last day of acquisition. (From Owen 1979).

5. Conclusions

At present, therefore, there is good reason to believe that the anti-anxiety drugs alter behaviour by impairing the serotonergic and the noradrenergic inputs to the septo-hippocampal system. The question naturally arises as to the particular functions which might be discharged by each of these two projections. One possibility is that the serotonergic fibres carry signals about impending punishment to the septo-hippocampal system, while the noradrenergic fibres carry signals about impending nonreward. This would account for the results Tye et al.(1977) obtained in their experiments on punishment and our results (Owen et al., 1979) using the PREE (Fig. 15.).

However, matters do not appear to be so simple. First, the dorsal noradrenergic bundle 1s also involved in responses to novelty: we have found that the same lesion (produced by 6-hydroxydopamine) which eliminated the PREE impairs such responses in the same way as do the anti-anxiety drugs (Owen et al., 1979). Second, we have succeeded in increasing resistance to extinction in the alley by injection of p-chlorophenylalmine, which blocks synthesis of seorotonin, and this effect was reversed by subsequent injection of 5- hydroxytryptophan, which restores synthesis of serotonin (Rickwood and Gray, unpublished


results). Finally, the experiments of Weiss's group (Weiss et al., 1975) on 'toughening up' in response to repeated electric shock have demonstrated an involvement of brain noradrenaline in this phenomenon.

Thus the exact demarcation of responsibility between serotonergic and noradrenergic mechanisms in mediating responses to the adequate stimuli for anxiety and the effects of the anti-anxiety drugs remains an open question. It is probable that both are concerned; and also that, of their various forebrain projections, it is the ones to the septo- hippocampal system which are of most importance. These issues, and the data which bear on them, are discussed in detail elsewhere (Gray, 1981).

Acknowledgements This work is supported by the UK Medical Research Council.

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Animal models of anxiety