Alterations in gene expression at key points in the addiction cycle

Abstract

Addiction is a disease in which individuals cannot control their need for drugs, despite negative health and social consequences. While previous research has delineated the brain circuitry mediating the addiction process, molecular mechanisms responsible for drug-mediated behaviors remain elusive. Therefore, in this thesis, I sought to examine alterations in gene expression during key transition points in the addiction cycle, reward and exinction. Using microarray analysis, cocaine-mediated effects on gene expression changes were investigated in the nucleus accumbens (NAc) following reward and the amygdala (AMYG) following extinction in the conditioned place preference paradigm. In addition, the role of the environment was examined at the reward time point; following extinction, the role of cyclic-AMP response element binding protein (CREB) was examined. While cocaine had a minimal effect on gene expression in both microarrays, the environment played a significant role in altering gene expression following reward and the CREB genotype impacted gene expression in the AMYG. This global gene analysis at two key transition points furthers our understanding of molecular alterations involved in mediating the addiction process. Stress is one of the primary causes of relapse back into drug seeking. Therefore, I also examined the role of acute and prolonged cocaine withdrawal on behavioral, endocrine and molecular outputs of stress responsivity to further understand the mechanisms behind stress-induced relapse. While no alterations in behavior were observed, corticosterone levels were augmented in cocaine-experienced mice following both acute and prolonged withdrawal, indicating a hyperactive hypothalamic-pituitary-adrenal axis that develops and persists well after drug is removed. Corticosterone releasing factor mRNA levels in the AMYG, as well as brain derived neurotrophic factor (BDNF) mRNA levels in the ventral tegmental area and NAc, were increased after stress exposure following prolonged withdrawal only in cocaine-treated mice, suggesting that alterations in the regulation of these genes occurs during the withdrawal period and may sensitize gene expression to a stressor. Taken together, these data indicate that alterations in endocrine pathways and gene expression can occur well into the withdrawal period