Master of Science – Research
School of Health Sciences
De Santis, Michael, The effects of antipsychotics aripiprazole, bifeprunox and haloperidol on body weight regulation and dopamine markers, Master of Science – Research thesis, School of Health Sciences, University of Wollongong, 2012. http://ro.uow.edu.au/theses/3759
[extract] The mental illness of schizophrenia has a much clouded pathophysiology; however a clear link to the dopamine neurotransmitter system has been uncovered. Although the mental illness is still poorly understood, treatment of the positive and negative symptoms along with the cognitive deficits has seen significant improvement, with three generational developments of antipsychotic drugs. The most-recent 3rd generation of antipsychotic drugs, in particular the drug Aripiprazole, has seen a much lower incidence of detrimental side-effects observed than with previous generations, alongside therapeutic efficacy in treating schizophrenia symptoms. These beneficial effects were previously attributed to its partial agonist mechanisms of action, particularly actions at dopamine D2 receptors, which resulted in an attempt to develop other drugs with a D2 partial agonist action, including the drug Bifeprunox. Clinical trials of other partial D2 agonists such as Bifeprunox, however, showed that they did not have the same therapeutic efficacy as Aripiprazole, and Bifeprunox was subsequently rejected by the U.S. Food and Drug Administration (FDA).
The present study has subsequently aimed to investigate potential differences in the effects of the dopamine D2 receptor partial agonist drugs Aripiprazole and Bifeprunox, as well as the D2 receptor antagonist Haloperidol. The effects on various dopamine synthesis and re-uptake markers, as well as the concentration of dopamine itself, in the mesolimbic and nigrostriatal dopamine pathways in the rat model were investigated. Forty-eight male Sprague-Dawley rats were divided into four groups and fed orally (0.3g/feed) with Aripiprazole (0.75mg/kg, 3 times per day), Haloperidol (0.1mg/kg, 3 times per day) or Bifeprunox (0.8mg/kg, 3 times per day), or vehicle for either one or ten weeks. Body weight, food and water intake was measured weekly. Brain tissue was obtained via microdissection to examine the expression levels of the dopamine synthesis and re-uptake markers p-TH (60kDa), TH (58kDa) and DAT (80kDa) via western blotting in the substantia nigra (SN), caudate putamen (CPu), ventral tegmental area (VTA) and nucleus accumbens (NAc); concentration levels of DOPA and dopamine (DA) were also examined via Gas Chromatography-Mass Spectrometry in the CPu and NAc.