Insights into the role of the dopamine D1 receptor in brain function: Studies using a gene deletion model

grantor: University of TorontoDopamine receptors are widely expressed throughout the central and peripheral nervous systems and regulate many key functions of the brain. Five dopamine receptors have so far been cloned and classified into two main classes known as D1-like (D1 and D5) and D2-like (D2, D3 and D4) based on similarity in structure, pharmacology and coupling. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of these individual dopamine receptor subtypes remain unclear. The D 1 receptor subtype is highly expressed in the striatum, nucleus accumbens and prefrontal cortex, brain regions shown to modulate many functions ranging from locomotion to reward, cognition and emotion. To study the potential ' in vivo' role of the dopamine D1 receptor in the regulation of specific brain functions and drug induced behaviors, we used mice lacking the functional D1 receptor gene. In these mice the D1 receptor gene was deleted by means of homologous recombination. Based on the behavioral analysis of D1 receptor-deficient mice, we demonstrate that the D1 receptor is an abundant protein that plays a crucial role in mediating higher brain functions including some aspects of cognition (spatial learning and memory), appetitive motivation (operant responding for sucrose), alcohol seeking behavior and locomotor responses to alcohol and amphetamine. In addition, we have defined, for the first time, a role for the D1 receptor in the normal extinction of conditioned fear responses. However, D1 receptor does not appear to be essential for basal locomotor activity, working memory, sweet-taste preference or acquisition and expression of fear responses. These findings have great importance in furthering the understanding of the role of D1 receptors in brain functions.Ph.D