Rex M. Philpot, Ph.D. - US grants

Emerging evidence supports the idea that adolescence is a unique developmental period during which time individuals are more likely to experiment with drugs of abuse and are at greater risk for subsequent addiction. There is a strong correlation between the onset of nicotine addiction at an early age and addiction to alcohol as well as a heightened vulnerability to addiction to either ethanol or nicotine when use is initiated during adolescence. When the brain is exposed to drugs of abuse, adaptive changes take place that contribute to the addictive process. Evidence demonstrates that many drugs alter the expression and activity of two major transcription factors, viz., cAMP response element binding protein (CREB) and AFosB (a truncated form of FosB) and that these alterations lead to the expression of genes thought to mediate the addictive process. Although studies have suggested that CREB and AFosB may represent a common cellular target for the action of addictive drugs, few studies have focused on the cellular consequences of exposure to nicotine and subsequent vulnerability to alcohol, targeting the two most widely used/abused and coabused compounds in the adolescent population.

Project Summary Choline (Ch) is an essential nutrient necessary for the synthesis of acetylcholine (ACh), a neurotransmitter that plays a key role in cognitive processes. There is strong evidence that choline supplementation (+Ch) can improve learning and memory in individuals suffering from cognitive deficits, however the benefits of +Ch have not been assessed for the prevention of chemotherapy-related cognitive deficits (CRCDs). CRCDs occur in up to 75% of survivors and studies suggest that these deficits can persist for greater than 20 years following treatment, interfering with daily functioning, the ability to return to work and reducing quality of life. Findings suggest that the manifestation of CRCDs involve reductions in estrogen and/or tumor- and chemotherapy-associated increases in pro-inflammatory cytokines, but it is unclear how these consequences translate into long lasting cognitive deficits in cancer survivors. The proposed studies will model CRCDs using cyclophosphamide (CYP) and doxorubicin (DOX), agents used to treat breast cancer, to induce deficits in the working, spatial and/or procedural memory of mice with breast cancer (MMTV-PyVT mice). This model will be used to investigate the hypothesis that CRCDs result from chemotherapy-related decreases in estrogen-mediated regulation of high affinity choline uptake and ACh synthesis, processes that contribute to cognitive decline. Further, because central cholinergic function regulates cytokine activity, the relationship between altered cholinergic function and increases in pro-inflammatory cytokines during and following chemotherapy, will be assessed. Aim 1 will use a longitudinal design to verify that choline supplementation (+Ch) can prevent CYP+DOX-induced deficits in the spatial memory of MMTV-PyVT mice, determine whether these benefits extend to other cognitive domains affected by chemotherapy and determine if +Ch can prevent CYP+DOX-induced increases in circulating pro-inflammatory cytokines. Aim 2 will investigate the central mechanisms mediating the effects of CYP+DOX, using a cross sectional approach to determine if CYP+DOX administration impairs high affinity choline uptake and ACh synthesis and if these effects can be prevented by increasing dietary choline. In addition, the effects of CYP+DOX and +Ch on pro-inflammatory cytokine expression in the central nervous system will be determined. Results will determine if chemotherapeutic agents produce CRCDs in animals with breast cancer as a consequence of impaired cholinergic function. In addition, studies will establish the relationship between these adverse effects and the effects of chemotherapeutic agents on circulating estrogen and pro-inflammatory cytokines. Further, studies will determine whether +Ch can prevent CRCDs by increasing cholinergic function, reducing pro-inflammatory cytokines, or both. Lastly, studies will evaluate the impact of +Ch on tumor growth and the effectiveness of chemotherapy. These findings will identify a mechanism mediating the occurrence of CRCDs and establish +Ch as a viable intervention, setting the stage for clinical studies of CRCD treatment approaches.