Brattleboro (BB) rats have a single gene mutation causing abnormal vasopressin production. Preliminary findings from the PI's laboratory indicate that the BB rat may be developed as an animal model of schizophrenia-relevant information processing abnormalities that has unique strong features and practical advantages compared to existing animal models including: 1) genetically based (i.e., non-induced), stable deficits in prepulse inhibition (PPI), startle habituation, and cognitive function that are analogous to schizophrenia, 2) reversal by drugs with antipsychotic efficacy, 3) the ability to distinguish established antipsychotic drugs with distinct clinical profiles (e.g., """"""""typical"""""""" versus """"""""atypical""""""""), 4) sensitivity to drugs that produce antipsychotic-like effects via non-traditional mechanisms (e.g., neuropeptides), 5) the ability to model the chronic time course associated with optimal therapeutic effects of antipsychotic drugs, 6) pathophysiology features that are analogous to schizophrenia (e.g., D2 receptor elevation), and 7) an apparent etiology (vasopressin deficiency) for these deficits that has not been well studied, and may therefore provide new insights into mechanisms contributing to schizophrenia. In a series of proposed experiments (Specific Aim 1) the sensitivity and specificity of the reversal of BB PPI deficits for drugs with antipsychotic efficacy will be further assessed. This will be done by testing several established typical and atypical antipsychotics, non-antipsychotic psychotropic drugs, as well as novel antipsychotics with non-conventional mechanisms (i.e., aripiprazole, amisulpride). A separate set of experiments (Specific Aim 2) will be aimed at characterizing the extent of the homology between BB rats and schizophrenia patients by assessing if the BB rat also exhibits antipsychotic-sensitive deficits in latent inhibition and social memory, whether their schizophrenia-like deficits are due to genetic versus parenting factors (via cross-fostering), and if they exhibit a schizophrenia-like ontological emergence. A third set of studies (Specific Aim 3) will investigate the mechanisms underlying BB PPI deficits by: 1) examining the effects of selective dopamine and serotonin antagonists, 2) measuring brain levels of dopamine and serotonin receptors, and 3) examining whether central vasopressin replacement restores PPI. The successful development of this animal model could significantly enhance the understanding of the underlying causes of schizophrenia-associated abnormalities and improve drug discovery.
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| Feifel, David; Shilling, Paul D (2010) Promise and pitfalls of animal models of schizophrenia. Curr Psychiatry Rep 12:327-34 |
| Feifel, D; Mexal, S; Melendez, Gilia et al. (2009) The brattleboro rat displays a natural deficit in social discrimination that is restored by clozapine and a neurotensin analog. Neuropsychopharmacology 34:2011-8 |
| Feifel, David; Melendez, Gilia; Priebe, Kristianne et al. (2007) The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats. Behav Brain Res 181:278-86 |
| Shilling, Paul D; Kinkead, Becky; Murray, Tiesha et al. (2006) Upregulation of striatal dopamine-2 receptors in Brattleboro rats with prepulse inhibition deficits. Biol Psychiatry 60:1278-81 |
