The Translocator Protein in Stress and Anxiety

The translocator protein, or TSPO, is an evolutionarily conserved protein with many purported functions including cholesterol transport. Recently, its role in stress and anxiety disorders has been heavily investigated. Evidence suggests that since TSPO is involved in cholesterol transport it may be able to regulate stress and anxiety through the production neurosteroids. The overall aim of the thesis was to further clarify the role and the importance of TSPO in stress and anxiety. Chapter 3 demonstrates that in response to chronic doses of HU210, a cannabinoid agonist, testicular TSPO is decreased in an age-dependent manner. At the doses used, HU210 has previously been shown to be anxiogenic and reduce testosterone levels. The overall results suggest that decreases in TSPO expression is better explained by decreases to testicular steroidogenesis rather than the anxiogenic effect of HU210. Chapter 4 documents the first known existence of TSPO knockout mice, confirmed by PCR and ligand binding experiments. TSPO knockout mice were healthy and fertile and did not display any overt dysfunction or abnormalities. The existence of TSPO knockout mice challenges the previously reported importance of TSPO particularly towards steroidogenesis. Chapter 5 assesses anxiety-like behaviours in TSPO knockout mice, and finds no significant differences between knockout and wildtype mice suggesting that TSPO is not involved in anxiety-like behaviours under normal conditions. Together, these results challenges our understanding of the framework in which TSPO is involved in stress and anxiety regulation. The successful generation of the TSPO knockout mice directly contradicts the previous belief that TSPO is essential for steroidogenesis and thus life. Further research, particularly in non-steroidogenic tissues, may assist in understanding the functional roles of TSPO and allow for TSPO to be effectively developed as a target for anxiolytic intervention