The olfactory bulbectomised rat as a model of depression

Abstract

Bilateral olfactory bulbectomy results in changes in behavior, and in the endocrine, immune and neurotransmitter systems, that simulates many of those seen in patients with major depression. The olfactory system in the rat forms a part of the limbic region in which the amygdala and hippocampus contribute to the emotional and memory components of behavior. However, the loss of olfaction alone, which results from bulbectomy, is not the major factor that contributes to the behavioral abnormalities as peripherally induced anosmia does not cause the same behavioral changes. Thus it would appear that bulbectomy causes a major dysfunction of the cortical-hippocampal-amygdala circuit that underlies the behavioral and other changes. These neuroanatomical areas also seem to be dysfunctional in the patient with major depression. Chronic, but not acute, administration of antidepressants largely corrects most the behavioral, endocrine, immune and neurotransmitter changes that occur following bulbectomy. Thus the olfactory bulbectomized rat is not only a model for detecting antidepressant activity but also one for exploring the inter-relationships between these systems that are also dysfunctional in patients with major depression.

Introduction

Since the accidental discovery of the first antidepressants some 40 years ago, numerous attempts have been made to develop animal models of depression that would be predictive of antidepressant activity in novel compounds. McKinney and Bunney (1969) were the first to establish widely accepted criteria for an animal model of depression when they proposed that the minimum requirement for such a model involved:

• A similarity in the behavior of the animal to the symptoms seen in patients with depression

• The behavioral changes occurring in the animal can be objectively measured

• The behavioral changes can be reversed by any treatment that is therapeutically effective (antidepressants, electroconvulsive shock, sleep deprivation etc.)

A major impetus to the development of a rat model arose from the need of the pharmaceutical industry to screen novel compounds for potential antidepressant activity. One of the first models to be widely used to detect drugs that resembled the tricyclic antidepressants or the monoamine oxidase inhibitors was the reserpine antagonism test (Danysz et al., 1991). A major disadvantage of the reserpine test was that it failed to detect novel antidepressants, such as mianserin, that lacked monoamine re-uptake inhibitory properties. Furthermore the reserpine model detected antidepressants following their acute administration by contrast to the clinical situation where antidepressant activity is only apparent after chronic treatment.

Such limitations resulted in the search for rodent models that simulated the major features of clinical depression that were precipitated by environmental stress either acutely (for example the forced swimming test and the tail suspension test (Porsolt, 2000), or chronically (for example, the chronic mild stress test (Vergnes and Kempf, 1982)). Rodent models were also developed based on specific lesions of the limbic system. Of these, the bilateral olfactory bulbectomized (OB) rat achieved some attention following the observation by Cairncross and colleagues (Jancsar and Leonard, 1981) that the irritability initiated by the lesion was attenuated by the chronic, but not the acute, administration of amitriptyline.

An obvious limitation of any rodent model arises because the core symptoms of major depression (low mood, anhedonia, feelings of guilt, suicidal thoughts, etc.) are species specific and may ultimately depend on the complexity of the brain. Nevertheless, while recognizing such limitations it is possible to select key aspects of the depression syndrome that are present in the rodent model and that may reflect the same dysfunctional anatomical substrates occurring in the brain of the depressed patient. For example, anhedonia is a core symptom of depression and a relevant rodent model could exhibit this behavior by a reduction in the intake of sweetened milk (Jancsar and Leonard, 1981). An increased sensitivity to a stressful environment is another characteristic of depression that may be simulated in the rodent by an increase in anxiety-dependent behaviors (Song et al., 1994). Besides such behavioral similarities, it is also possible to demonstrate that endocrine, immune and neurotransmitter changes found in patients with depression also occur in the rodent model (Kelly et al., 1997). Most importantly, for a rodent model to have predictive validity, it is essential that the chronic administration of all types of therapeutically effective antidepressants should normalize most biological dysfunctions in the animal model.

With these criteria in mind, this review will be restricted to the bilateral olfactory bulbectomized (OB) rat model, as this appears to fulfil many of the criteria necessary for a successful animal model of depression. It should be emphasized that several extensive reviews have been published recently that critically assess the different rodent models of depression (O'Neill and Moore, 2003, Redrobe et al., 1998, Willner, 1991, Leonard, 1989, Cryan et al., 2002, Nestler et al., 2002).