Research Paper on Validity of the Schizophrenic Mouse for Preclinical Research

Both models of specific symptoms or signs and models of the full syndrome are included within animal models that are used to study schizophrenia. With respect to both clinical responsiveness and phenomena to antipsychotic drugs, models are required to be evaluated scientifically in terms of their predictive and etiologic and construct validity. In assessment and development of an animal model, the specification of the purpose for which the model has been designed is important as the criteria that must be satisfied by the model to establish its validity is determined by the intended purpose of the model. In the cross-species validity of the model, the confidence can be increased by focusing on particular symptoms or signs instead of syndromes.

For schizophrenia, one of the most difficult things is to establish is the accuracy of the reproduction of the symptoms of a human condition by an animal model, which is also known as face validity. For establishing the predictive and constructive validity of this schizophrenic mouse model, behavioral measures have been used extensively. Impaired attentional, disruption of pre-pulse inhibition and horizontal locomotion are some of the behavioral measures that have been used. Addition to this, to establish the validity of this model, some others measures that have been used are molecular and cellular markers based on imaging studies and described changes in human postmortem.

To assess this model, changes in locomotors activity in mouse have also been used. From the psych stimulant model based on the dopamine hypothesis of schizophrenia, the original impetus for the use of locomotors activity measures has been derived. To characterize the effects of both N-methyl-D-aspartate NMDA) and dopaminergic psych stimulants, the measures of locomotors hyperactivity were used extensively. For the stereotyped behavior induced by amphetamine in humans, face validity was seen, as perseverative or stereotyped behaviors were stroked and locomotors hyperactivity were revealed by cross-species studies.

Further, molecular and cellular markets were used to establish the validity of this model. Additional to this, functional findings from imaging studies performed on schizophrenia patients were also used. In response to amphetamine in schizophrenia patients, an exaggerated dopamine release was demonstrated by these studies. Lastly, on the basis of its performance and whether a sound theoretical rationale is provided, this model was validated. In models of psychiatric disorders, these characteristics, i.e., performance and providing sound theoretical rational are referred to as construct and predictive validity.

Latent inhibition (LI) and pre-pulse inhibition of startle (PPI) were other measures that were also considered, as they are reliable indicators of schizophrenia. The disruptive effects of DA receptor agonists on PPI were also considered to depict the face validity of the model. Impaired in schizophrenia, a test of pre-attentional sensorimotor gating is referred to as PPI. In mouse and humans, the stimulus-evoked changes in PPI are similar and in both species, the PPI can be disrupted by the DA agonist Apo morphine. Some degree of both construct and predictive validity for this model was supported by an effect that was blocked by antipsychotics, i.e., the disruption in mouse by PPI through the directive influence of DA into the nucleus acumens (NAC). However, one of the limitations that were faced was the paucity of rigorous experimental data generated from clinical studies in establishing the predictive, etiologic and constructs validity of this schizophrenic mouse model.