Animal Models of Anxiety Disorders
Frederico G. Graeff and Hélio Zangrossi Jr
The last decades have witnessed a growing interest in the use and development of animal models in psychiatry. The demand for these models has been motivated by the ethical, methodological and economical constraints that restrain the study of neurobiological processes in human subjects. It is undeniable that animal experimentation has contributed to advances in psychopharmacology and to our understanding of brain mechanisms involved in psychiatric disorders. Suffice to remember that benzodiazepine anxiolytics have been discovered because of the taming effect of chlordiazepoxide observed in Cynomolgus monkeys by Randall (Randall et al, 1960). Also, hypotheses on the role of serotonin (5-HT) in anxiety were based on experimental work with conflict tests in rats and pigeons (Robichaud and Sledge, 1969; Graeff and Schoenfeld, 1970; Stein, Wise and Berger, 1973) as well as with aversive electrical stimulation of the rat dorsal periaqueductal grey matter (DPAG) (Kiser and Lebovitz, 1975; Schenberg and Graeff, 1978, Schiitz, de Aguiar and Graeff, 1985).
Early animal models of anxiety were developed when behaviourism was the main conceptual framework within experimental psychology, and before classifications of psychiatric disorders split pathological anxiety into distinct nosological entities (see later). These animal models of anxiety rely on either inhibition of ongoing behaviour elicited by conditioned stimuli that predicted unavoidable electric shock or on suppression of rewarded responding by electric-shock punishment. The first type of model is based on principles of associative or Pavlovian conditioning, and the second on instrumental or operant conditioning. Punishment tests also suggest clinically derived constructs that emphasize the role of inner conflict in pathological anxiety, and this may be the reason why these tests became known as conflict models. Early pharmacological analysis showed conflict models to have a higher predictive value than conditioned suppression and, as a result, punishment tests became paradigmatic for assaying anti-anxiety drugs (Kelleher and Morse, 1968).
Surprisingly, classical conflict tests failed to consistently detect the anxiolytic action of drugs that act primarily on the neurotransmission mediated by serotonin (5-HT), such as buspirone and ritanserin (Handley et al., 1993; Griebel, 1995). Such falsenegative results undermined the general confidence in conflict models, although many arguments may be summoned to their defence, as for instance the time course of drug action. Unlike benzodiazepine anxiolytics, the newer drugs need several weeks of continuous administration to become clinically effective, initial doses being sometimes anxiogenic (Nutt, 1991). Why, men, should one expect single administration of these agents to be anxiolytic in animal models? In spite of this, it became generally accepted that conflict tests were good only for anxiolytics that acted primarily on the neurotransmission mediated by γ-aminobutyric acid (GABA), which is the case for barbiturates and benzodiazepines.
A theoretical shift from behaviourism to ethology has also contributed to the discredit of conflict models, which have been criticized because of their artificiality and the confounding influence of appetitive drives, such as hunger and thirst, and of pain (Treit, 1985). As a result, a search for ethologically based animal models of anxiety has begun. The most widely used animal model of anxiety resulting from this trend has been the elevated 'X' or 'plus' maze, which is based on the natural fear that rats have for elevated, open spaces, represented by the two open arms of the apparatus (Handley and Mithani, 1984; Pelow and File, 1986). Coundess drugs have been assayed in this model, and the results obtained summarized in several comprehensive reviews (e.g., Handley et al., 1993; Rodgers, 1994; Griebel, 1995). Disappointingly, this model also failed to detect non-benzodiazepine anxiolytics. To do this, ethological analysis of behavioural items shown by the animals while exploring the elevated plus-maze has been added to the procedure (Cruz, Frei and Graeff, 1994; Rodgers and Johnson, 1995). However, with this modification one of the main advantages of the test, which is simplicity, is lost.
As these developments were taking place in basic research, the split of anxiety disorders into distinct diagnostic categories, a trend that was initiated by the DSM III classification of psychiatric disorders (American Psychiatric Association, 1980), became accepted worldwide. Even though present-day psychiatric classifications cluster symptoms empirically, they constitute a necessary starting point for systematic research. It is hoped that the evidence thus obtained will either validate or modify the original categories.
The following categories from the DSM IV classification of psychiatric disorders (American Psychiatric Association, 1994) will be considered in the present analysis. (1) Generalized anxiety disorder (GAD), a state of excessive anxiety or apprehension lasting for more man six months. Neurovegetative symptoms are often present, but relatively minor. (2) Panic disorder (PD), characterized by recurrent panic attacks, either unexpected or associated with particular situations. Panic attacks are sudden surges of intense fear or terror, desire of fleeing and feeling of imminent death, going crazy or loosing control. These subjective symptoms are accompanied by major neurovegetative changes, such as palpitation, hypertension, dyspnoea, difficulty in deep breathing, sweating, urge to void the bladder and increased peristalsis. This leads to worry about the next attack or anticipatory anxiety, and avoidance of places where a panic attack would be embarrassing. Ultimately, generalized avoidance or agoraphobia may ensue. Nevertheless, agoraphobia sometimes occurs without panic attacks. (3) Obsessive-compulsive disorder (OCD) characterized by intrusive, distressing thoughts (obsessions) and/or stereotyped or ritualized behaviour (compulsions) that must be performed in order to alleviate intense anxiety. (4) Specific phobias, which are irrational fears of either objects (animals, blood, pointed instruments) or situations (heights, closed environments). (5) Social