Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation

The work proposed for this award addresses the critical intersection between two of the Fiscal Year 2014 (FY14) Peer Reviewed Medical Research Program (PRMRP) Topic Areas: Metabolic Disease and Psychotropic Medications. Our studies also target an identified FY14 PRMRP research priority/gap in the Psychotropic Medications category as we will study mechanisms by which antipsychotic drugs (APDs) cause metabolic disease. Specifically, APDs treat numerous psychiatric disorders ranging from schizophrenia to post-traumatic stress disorder. However, these medications also cause substantial metabolic side effects including weight gain, insulin resistance, hypertension, elevated cholesterol, as well as increase the risks for developing type II diabetes and cardiovascular disease . Veterans are increasingly affected by these side effects since up to 78% of some Veteran's Affairs populations are treated with APDs and the prevalence of APD-induced metabolic dysfunction in Veterans is more than twice that of the general population. To date, however, the mechanisms for these APD-induced metabolic disturbances are poorly understood. Thus, given the severity of this growing health problem and its applicability to active military personnel, Veterans, and their families, the central critical question in this proposal is: What are the underlying biological mechanisms by which APDs cause weight gain and metabolic dysfunction? Significantly, all APDs cause these side effects to differing degrees and ultimately reduce life expectancy. Though multiple targets for these drugs have been implicated, the single known unifying property of all clinically effective APDs is their blockade of a specific class of drug targets: dopamine D2 (D2R) and D3 (D3R) receptors, suggesting a potential role for these proteins in mediating APD metabolic side effects. D2R and D3R are found in the hypothalamus, a brain region that regulates appetite and metabolism. Surprisingly, these APD targets were also recently discovered in regions outside the brain that are also critical to metabolic regulation including insulin-producing beta islets of the pancreas. Based on this, our main hypothesis is that D2R and D3R mediate the metabolic side effects of APDs both centrally in the hypothalamus and peripherally in the pancreas. However, the precise contributions of these peripheral and central D2R and D3R receptors to APD-mediated metabolic dysregulation are unknown. To disentangle these mechanisms, we have created the first tissue-specific D2R knockout (KO) mice targeting either hypothalamus or pancreatic beta islets to selectively eliminate D2R expression only in the respective organ; we are now producing similar tissue-specific D3R KO mice. Additionally, we have also developed new and highly sensitive optical and biochemical assays to rapidly measure effects of D2R and D3R on insulin release in real time. Using these new tools, we propose an innovative multidisciplinary approach combining whole animal in vivo metabolic studies, imaging, and biochemistry to determine the precise molecular mechanisms by D2R and D3R in the brain and pancreas that contribute to APD-induced metabolic side effects. In our first specific aim, we will identify the respective contributions of hypothalamic D2R and D3R to APD-induced weight gain and metabolic dysregulation in vivo. We will use our new hypothalamus-specific D2R and D3R KO mice to first determine whether the absence of these receptors in the hypothalamus is sufficient to mimic the effects of APD treatment on weight gain and appetite. We will then treat the hypothalamic KO mice with APDs to ascertain whether APD-induced weight gain and insulin resistance are attenuated using in vivo metabolic analyses. In parallel, the second specific aim will determine the specific contributions of pancreatic beta islet D2R and D3R to APD-induced metabolic disturbances using our new beta islet-specific D2R and D3R KO mice. As with the hyp