REGIONAL VARIATION IN D1 SIGNALING PROTEIN LOCALIZATION

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prefrontal cortex (PFC), nucleus accumbens (NAc) and amygdala form a corticolimbic circuit that is involved in normal cognition, schizophrenia, anxiety and fear states, reward pathways and drug abuse. Dopamine, acting at the D1 family of receptors is critical to the individual and collective function of these brain regions. Studies of the cellular actions of these receptors have found variability in their effects within a region as well as variation between these brain regions. The goal of the work proposed here is to study the structural basis for this variability. The D1 family is comprised of two separate receptors, D1 and D5, which can not be distinguished by pharmacology. Regional differences in the availability of these receptors at pre- and postsynaptic sites would alter the action of D1 agonists at these sites. Both of these receptors are coupled to complex signal transduction systems. The localization of the components of these systems is tightly controlled and this localization is critical to function. This work is comprised of three aims: 1) Determine the localization of D1 and D5 in PFC, NAc and amygdala as well as any colocalization. 2) Determine the localization of three components of the D1 receptor signal transduction pathway in PFC, NAc and amygdala, as well as any colocalization. 3) Relate the localization of D1 and D5 to their signal transduction proteins. We use a rhesus monkey model for these studies for several reasons. A key component of the corticolimbic circuit, the PFC, shows significnant differences between primates and rodents. In particular, the dorsolateral region, of interest with regard to cognition and schizophrenia, has no clear homology in rat. The dopaminergic projections to PFC are organized differently in rats and primates. Furthermore, there is now evidence that the actions of monoamine neurotransmitters, such as serotonin and dopamine, vary between rodent and monkey, even in regions that are relatively homologus, such as the amygdala. Therefore, in order to produce results that can speak to the human illnesses in question, it is best to use a non-human primate model for these experiments. The results of these studies will shed light on conflicting physiological studies of D1 receptor action and advance our understanding of the effect dopaminergic drugs have on these important brain regions. This information is expected to add in the rational development of pharmacotherapies for the disorders associated with the corticolimbic circuit, including schizophrenia, substance abuse and anxiety disorders, including PTSD.