Main Research Interests & Developments
THE NEONATAL QUINPIROLE MODEL OF SCHIZOPHRENIA
Negative and positive symptoms associated with schizophrenia can be attributed to varying levels of dopamine in specific brain regions. Evidence suggests low levels of dopamine in the prefrontal cortex is responsible for the asociality and blunted effect of schizophrenia. Exceedingly great levels of dopamine in mesolimbic region neurons is likely responsible for the delusions and hallucinations experienced by those suffering from schizophrenia. Such augmentation of the dopamine D2 receptor is thought to originate from a disturbance in the nucleus accumbens cortical pathway. Taken together, this information elucidates dopamine as the premier target for designing a model of schizophrenia.
Quinpirole is a selective dopamine D2 receptor agonist that acts as the primary psychoactive drug in our rodent model of schizophrenia. Rat pups are administered 1 mg/kg of quinpirole from post-natal day (PND) one to PND twenty-one. This results in lifelong supersensitization of the D2 receptor that is also passed on to offspring (F1 generation). The supersensitization is marked by an extremely enhanced behavioral response to quinpirole that is consistent with phenotypes associated with schizophrenia. |
SUBSTANCE ABUSE COMORBIDITIES IN SCHIZOPHRENIA
Roughly 75% of those diagnosed with schizophrenia are chronic smokers, making nicotine a relevant target for analyzing behavior and developing alternative symptom relief.
Evidence suggests that schizophrenics seek the effects of nicotine in an effort to alleviate stress and negative symptoms associated with the disorder, i.e. anhedonia or blunted effect. |
Alzheimer's Disease |
Current medications for Alzheimer's Disease (AD) do not have sufficient efficacy towards treatment of behavioral deficits and neuropathology associated with AD. The Brown Lab in collaboration with P2D Bioscience Inc. in Cincinnati, OH is developing a first-in-class treatment for AD. Our drug is an orally-effective combination that targets both innate immunity and the dopamine transport (DAT) inhibitor. Recent studies suggest that TNFα and DAT inhibitors are orally effective treatments for Alzheimer's Disease (AD) in preclinical AD transgenic mouse models. The studies we are currently conducting will determine if our compound is an effective treatment for AD using three transgenic animal models of AD. The rationale is a rigorous evaluation for our lead compound across different models of AD pathology. Across several experiments, we will determine if chronic oral treatment, which is administered through the diet, will significantly improve behavioral deficits and AD associated pathophysiology in these animal models. |