Advances In Modelling Depression And Anxiety In Mice Notes

Advances in modeling depression and anxiety in mice

GOOD FIRST QUOTE TO OPEN ESSAYS:

Charles Darwin, The Descent of Man, 1871:

“Nevertheless the difference in mind between man and the higher animals, great as it is, certainly is one of degree and not of kind. We have seen that the senses and intuitions, the various emotions and faculties, such as love, memory, attention, curiosity, imitation, reason, etc., of which man boasts, may be found in an incipient, or even sometimes in a well-developed condition, in the lower animals.”

• While Darwin emphasized in his thesis that “the difference between the mind of the lowest man and that of the highest animal is immense”, his writings provided a foundation ideology for the development of the modern scientific fields of ethology and comparative psychology, in which behaviour in animals is studied to gain insight into the neural processes underlying behaviour in humans

• Psychiatry as a field has proven to be among the least penetrable clinical discipline for productively amalgamating knowledge of human pathology with animal behaviour to develop satisfactory in vivo animal models for evaluating novel treatment approaches

• Due to the growing costs of clinical trials, there is a growing emphasis on first obtaining proof that a new chemical entity designed to alter the function of a specific target will do so in a predictable and safe manner

• Of central importance to this approach is the availability of valid preclinical animal models for evaluating the potential efficacy of novel pharmacotherapeutics

Defining depression and anxiety

• There are various diagnostic tools that are used to identify and evaluate depression

• These include the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association and rating instruments such as the Hamilton Depression Scale

• The hallmark of anxiety disorders is a “marked, persistent, and excessive or unreasonable fear” that is experienced to a degree that significantly interferes with everyday life

• These criteria are important to bear in mind because, unlike a depressive episode, a transient anxiety response to real danger is an appropriate, adaptive response in patients and non-patients alike

• Another difference with depression is that DSM-IV classification of clinical anxiety distinguishes between numerous subdisordres of anxiety, the most common being generalized anxiety disorder, panic disorder, specific phobia, social phobia, OCD, PTSD

• These disorders are largely distinguished from one another by the nature of the stimulus provoking the anxiety

• Moreover, although there is epidemiological comorbidity between anxiety disorders, they are, to some degree, differentially responsive to different classes of anxiolytic drug treatments, suggesting discrete neurobiological and genetic aetiologies

• Psychiatrists have several rating scales to quantify anxiety severity, primarily the Hamilton Rating Scale for Anxiety and the Clinical Global Impression Scale

• Historically, depression and anxiety disorders have been regarded as separate clinical entities, since different drug treatments have been used to treat the disorders, usually tricyclic antidepressants and benzodiazepines respectively

• However, clinically, there is considerable comorbidity between the 2 disorders

• The issue of comorbidity has important implications for the treatment of these conditions in that drugs that are effective in both anxiety and depression would be particularly beneficial and cost effective, and there has been more focus on the development of such drugs in recent years

• SSRIs can successfully treat both depression and certain anxiety disorders

Why the mouse?

• Historically, research in non-humans, mostly rodents, has been central to efforts to understand the neural systems mediating emotion, how these systems dysfunction under pathological conditions and how they can be therapeutically modulated

• For decades the rat was the species of choice in preclinical research – rats perform well in many of the cognitive and operant tasks that are the pillars of modern behavioural pharmacology

• Size and robustness of the rat, compared with the smaller mouse, aids the application of invasive techniques such as catheterisation and cannula implantation

• HOWEVER, in the past decade, as in other biomedical disciplines, there has been an explosion in the use of mice in neuropsychiatric research

• The key driving force behind this has been the development and application of novel molecular technologies such as gene targeting, which enable researchers to engineer precise genetic alterations to study the neural basis of behaviour

• The mouse is uniquely amenable to these techniques

• Mice are also easy to breed and house in large numbers

• As a result, whereas mice were certainly commonly used in behavioural pharmacological research before the application of these techniques, the proliferation of KO, KI and transgenic mice has force researchers to quickly embrace the mouse in their research programmes

Manipulating mice

• About 80 different mutant lines have been reported to have phenotypes interpreted as abnormal “depression-related” or “anxiety-related” behaviour

• In some cases these phenotypes were predictable from existing knowledge regarding the role of the gene/gene product in emotional behaviour and served to reinforce and refine existing hypotheses regarding the importance of certain systems in mediating these behavioiurs

• For example, the antidepressant-related phenotype found in noradrenaline transporter (NET) KO mouse fits the profile of antidepressant efficacy of drugs that antagonize NET

• However, there are also numerous examples of phenotypic abnormalities in KO and transgenic mice that potentially reveal novel mechanisms that subserve emotion

• Such findings in mutant mice are particularly valuable when more traditional approaches (e.g. selective agonists, antagonists) to study the specific function of a gene product are impractical

• For example, the...

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