Trpc4 as a Gene Target for Addiction and the Effects of Stressor Controllability and Addiction on Anxiety and Depression in Rodent Models

Drug addiction, anxiety, and stress have several commonalities. One is that they all pose a substantial burden on individuals and society, both psychologically and financially. Another is that they have overlapping brain regions and/or neural pathways that are implicated in their etiologies. Consequently, these neuropsychiatric disorders are often exhibited concurrently or sequentially with one another. For these reasons, it is of clinical importance to better understand the mechanisms driving these disorders and how they interact with each other. The following studies aim to shed light onto these topics. We first investigated the Trpc4 gene as potential target for drug addiction and anxiety. The Trpc4 gene was selected based on it expression pattern in the brain and its function. The gene is abundantly expressed in regions that receive extensive dopamine (DA) input from the brain’s reward circuitry. These regions are highly involved in mood regulation and reward-seeking. The TRPC4 ion channel is the product of the Trpc4 gene, and is known for increasing neuronal excitability. These unique properties make Trpc4 an intriguing candidate for addiction and anxiety. Indeed, we found that rats lacking the Trpc4 gene showed an increase in anxiety-like phenotypes and a decrease in cocaine-seeking compared to wild-type rats. Next, we examined how repeated cocaine exposure and stressor controllability effect anxiety. Stress is a leading risk factor in developing such disorders as drug addiction and anxiety. However, it is known that the degree of control one has over a stressful situation is predictive of the outcome. Controllable stress has been shown to mitigate the negative effects induced by uncontrollable stress. We found that repeated cocaine exposure does not interfere with this phenomenon, even after a drug withdrawal period. These studies and previously published studies on the effects of stressor controllability all used rat models. To further our understanding of these concepts, we next wanted to determine if a mouse could be used in order to take advantage of the multitude of transgenic strains available. However, based on our results, it appears that mice are not an ideal organism to study the effects of stressor controllability on neuropsychiatric disorders