Are Animal Models Relevant in Modern Psychiatry?

Examples of animal models in psychiatry

Behavioral despair. The behavioral despair model is commonly used to screen candidate antidepressants. Like other TCAs, imipramine(Drug information on imipramine) was screened using the Porsolt forced swim test. In this test, the animal (a rat or a mouse) is placed in a container with cold water and is forced to swim until exhausted; it is then briefly taken out of the water. This is repeated until the animal reaches a state of helplessness and stops swimming. Although immobility time is reduced by antidepressant agents such as imipramine, significant strain differences have been reported.²³

The Porsolt forced swim test has been criticized on the grounds that the state of helplessness is more a strategy of survival than a sense of “despair.” The increased immobility simply demonstrates a positive behavioral adaptation, in which the animal has learned that it cannot escape and is conserving energy until it is removed from the water. In addition, while the test is reported to distinguish antidepressants and neuroleptics from anxiolytics, false positives have been reported for a number of other compounds, including stimulants, convulsants, anticholinergics, pentobarbital, and opiates.^24,25

Canine acral lick dermatitis. This is considered by some researchers to be a suitable animal model for the study of obsessive-compulsive disorder (OCD) in humans.²⁶ However, most cases of acral lick dermatitis in animals have an underlying allergic cause; if the allergen is eliminated, the condition resolves. In humans, OCD is an anxiety disorder characterized by intrusive thoughts, unrelated to allergies. Although SSRI treatment may be effective for both acral lick dermatitis in animals and OCD in humans because of a shared neurotransmitter response, this does not confer homology on the animal model. According to Nonneman and Woodruff,²⁷ “If every aspect is fully isomorphic between the animal model and the human condition, including cause and mechanism, the model is homologous.” Clearly, the OCD dog model does not fulfill these criteria. In addition, the dog model ignores the existence of a genetic component and the presence of comorbidities, which are thought to play an important role in human OCD.^28,29

Transgenic mice and the study of anxiety-like endophenotypes. Humans and mice share approximately 97% of their working DNA and approximately 24,000 genes per body cell.³⁰ In light of these facts, scientists have turned their attention to the study of differential gene expression patterns in genetically altered mice to investigate anxiety through the corticotropin-releasing hormone system, the serotonin system, and the GABA system.³¹ However, because genes work in networks and animals are examples of complex systems, small changes at the gene level can have major consequences for the individual. Thus, it is irrelevant to point to observed similarities in genetic makeup (including transgenes) between species, since the details of the differences are in the interactions between conserved genes, not in the genes themselves.³²

As Hirst and colleagues³³ have shown in the example of the serotonin system, it is unlikely that serotonin type 6 knockout mice will be useful for validating the serotonin type 6 receptor as a therapeutic target because of unexpected species differences in both receptor regional distribution and pharmacological profiles. It is now evident that slight variations in rodent and human amino acid sequences can lead to unexpectedly large differences in the pharmacology of the receptors, with potentially disastrous effects for drug development. What has not been clearly documented until the study by Hirst and colleagues is that mouse receptors could be significantly different from rat receptors.

Role of non-human primates in psychiatric and neurological research. The use of non-human primates by Harlow and associates³⁴ to demonstrate the effects of maternal deprivation has been well documented. In experiments conducted between 1957 and 1963, they removed baby rhesus monkeys from their mothers and observed the effects of partial and total social isolation. Some of the monkeys were kept in solitary confinement for up to15 years. These studies have been criticized on both ethical and methodological grounds.¹⁵