Animal Models in Depression Research Essay PDF

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What are the contributions of animal models in the understanding of depression?

Since the publication of Animal model of depression. I. Review of evidence: implications for research by McKinney & Bunney (1969), literature regarding animal models of depression has greatly risen. With depression established as one of the most significant public health issues (Wittchen et al., 2011), and projected to become the leading cause of disease burden globally by 2030 (WHO Report 2011), animal models provide the potential of neurological analysis at a finer molecular level, allowing us to better understand depression (Harro, 2018) – ultimately enhancing our capacity to treat it, through successful drug screenings. However, besides the controversies surrounding validity and the extent to which it is possible to model a human mental disorder in animals (Lemoine, 2016), the perceived lack of progress in the development of novel treatments and whether it can make a true breakthrough questions the contributions of animal models in the understanding of depression.

Depression is a heterogenous, multifaceted disorder with symptoms manifested at the psychological, behavioural, and physiological level; this presents a challenge of imitating the disorder in a laboratory setting (American Psychiatric Association, 1994). With many human symptoms of depression being described as having recurring thoughts of death or suicide or having excessive thoughts of guilt (DSM IV), it raises the notion of whether we can ever assume an animal is depressed. While it is impossible to model such symptoms that are exclusive within humans, other measures of depression such as helplessness, behavioural despair, and neurovegetative changes have shown to be replicated in laboratory animals (Krishnan & Nestler, 2011). Depression has been suggested to be a parallel to the evolutionary perspective of involuntary defeat strategy (IDS), which is triggered when an animal becomes aware of its hierarchal struggle for resources (Sloman, 2008).

The concept of validity in animal models is largely drawn from Willner’s (1984) conditions of face, predictive, and construct validity. Face validity refers to the degree of homogeny between the model and the disorder, accounting for symptoms and signs (Willner & Mitchell, 2002). Predictive validity should allow for the model to discriminate between true and false, and efficient and

inefficient treatments. Lastly, construct validity is satisfied if both theoretical and empirical unambiguous connections between the model and disorder can be established (Harro, 2018). It is also important to note that such aspects of validity are independent of one another, meaning that others are not necessarily satisfied if one is.

Roger Porsolt and colleagues first introduced the forced swimming test (FST) for mice and rats in the 1970s (Porsolt et al., 1977; 1978), which marked as a turning point for depression modelling for being one of the most widely and frequently used test (Cryan et al., 2002). In the FST, a mouse or rat is placed in an inescapable cylinder of water, and following an initial period of struggling, swimming, and climbing, the animal eventually displays a floating or immobile posture, which is interpreted as behavioural despair or entrapment that is shown to be reversed with the acute administration of available antidepressants (Cryan et al., 2005). Despite the increase of reports stating that immobility is anthropomorphically interpreted as depression (Molendijk & de Koet, 2015), a number of alternative interpretations have been proposed. De Pablo et al., (1989) and Enginar et al., (2016) proposed that the immobility reflects learning, such that having learned that escape from the water is impossible, the animal should maximise its chances of survival by conserving energy and hence staying immobile, though this would imply that antidepressants acts as an impairment to learning. Hence, Commons et al., (2017) suggested that the FST instead measures a stress-coping strategy, where the immobility reflects the switch from a predominantly active to predominantly passive behaviour under a stressful situation (Molendijk & de Koet, 2015). Hence, this translates to antidepressants serving to promote active coping strategies. The ability for the FST model to detect antidepressant-like effects from drugs allows for rapid screening of novel drugs (Rupniak, 2003).

Similar to the FST, the tail suspension test (TST) is based on the same notion that rodents develop an immobile posture subsequent to a period of initial escape-oriented movements, when placed in an inescapable, stressful situation. The stressful situation in the TST is induced by being hung by their tail in an incontrollable fashion, effectively removing the confound in FST induced by thermoregulation as water is not involved (Cryan & Mombereau, 2004). It has been found that rodents

undergo a longer period of active persisting in their escape if antidepressant treatments are administered before the test (Cryan et al., 2005). Additionally, the withdrawal from psychostimulants, which is associated with depressive-like behaviour in humans, increased immobility in the TST (Cryan et al., 2003). FST and TST studies have the capability of illustrating how the diversity of genes may play a role in regulating stress-induced immobility, suggested by the presence of knockout mice (KO) that displayed an increased immobility post screening. Such KO mice may have had confounded phenotypes by developmental compensatory effects, leading to the loss of gene of interest. For instance, it is found that the antidepressant-like phenotype of a certain KO mice is associated with a receptor mediated excitation in the hippocampus (Heurteaux et al., 2006), a change that is also observed subsequent to chronic treatment with a variety of antidepressants in humans (Haddjeri et al., 1998).

Despite the major advantage of FST and TST as a rapid test of antidepressant action, the models are strongly criticised in the sense that it is only sensitive to short-term antidepressant effects. Chronic treatments with antidepressants are usually required as a prerequisite for full clinical recovery in humans, though there is evidence that some initial behavioural changes occur in early antidepressant treatment in humans, that may be relevant to positive therapeutic outcome later (Katz et al., 1987).

Although a true breakthrough in antidepressant drug development may be required to convince the majority of critiques, animal models including the FST and TST serve as a helpful approach to better understand depression in humans. With the modern advancements in technology, a greater reliance and importance of animal models may arise – but for the time being, animal models are effective in allowing for the rapid screening of novel drugs, and to explore the role of genes and other neurobiological markers.

References

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