Value of Animal Models for Predicting CNS Therapeutic Action

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

“…Equally important is the increasing reliance on automatically-recorded numbers as opposed to the collaboration of visual observation of changes in behaviour and automated recording that has characterised behavioural pharmacology (Barrett, 2006;Irwin, 1968). Nevertheless, automation plays an important role in safety pharmacology and toxicology where potentially harmful side effects of a new chemical entity needs to be identified early first during the process of lead optimisation and certainly before the compound is progressed to clinical development (Hamdam et al, 2013;McArthur, 2010b). Physiological parameters such as heart rate, body temperature, EEG are easily automated and can be combined with automated measures of locomotor activity, feeding, and drinking to provide an accurate temporal profile of the effects of a drug candidate on the general well-being of an experimental animal.…”

“…Notwithstanding the "me-too" nature of psychoactive drug discovery, manipulations of neurochemical systems were key activities that helped in the development of our understanding of the neurobiology of behaviour and established the validity and value of animal models (McArthur, 2010b;Millan et al, 2015). The contribution of other neurochemical systems to normal and pathological behaviour were further elucidated; of which the noradrenergic system, serotonin, and glutamate perhaps have been the most prominent.…”

“…The clinically-active standards, as was discussed previously, are based on neurochemical mechanisms of action identified and developed over the past 70 years, and unfortunately not always active as positive controls in clinical trials (Hooper and Amsterdam, 1998). This form of validation of the model is known as pharmacological isomorphism (McArthur, 2010b) and ultimately leads to a tautology, that is, proving its existence by referring to itself.…”

“…Analogous procedures used to assess associative learning, for example, show remarkable consistency in species as diverse as zebra fish (Champagne et al, 2010), rodents (Delotterie et al, 2015;Talpos et al, 2014), primates, (Weed et al, 1999) and humans (Robbins et al, 1994). Further, these procedures and the changes in behaviour that they elicit can be mapped on to neural systems, provide validity to behavioural constructs (Markou et al, 2013;Young et al, 2013) and are an integral part of the drug discovery and development process (Decker, 2006;Markou et al, 2008;McArthur, 2010b;Millan, 2008).…”

“…Nevertheless, while animal models are fundamental to the understanding of behaviour from a physiological and psychological perspective (McArthur, 2010b), these results, are at best considered useful to progress a compound into clinical development within the biopharmaceutical industry, but are usually considered irrelevant by clinical investigators evaluating the potential efficacy of drug candidates in clinical trials (Lasagna, 1999;Littman and Williams, 2005;McArthur, 2010a).…”