Social isolation: effects on the stress axis and stimulant self-administration

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): People suffering from post-traumatic stress disorder (PTSD) are 3 times more likely to abuse psychostimulants than people in the general population. This is alarming, since estimates indicate that 8% of adults have abused stimulants in their lifetime. Identifying common substrates of both PTSD and drug addiction can provide a useful perspective on drug abuse treatment in patients with PTSD. Early life stress contributes to the development of both PTSD and drug addiction, and can be modeled in rodents by employing social isolation during the early post-weaning period. Isolation enhances susceptibility to stress-related pathologies as assessed by animal models of depression and anxiety, as well as increasing vulnerability to stimulant self- administration. Conversely, environmental enrichment during development buffers against both anxiety and stimulant self-administration. Although alterations in the stress axis are likely involved in the effect of isolaton on drug self-administration, the distinct neurobehavioral mechanisms of stress in drug abuse vulnerability induced by social isolation are largely unknown. Acute stress has the ability to increase drug seeking as measured by enhanced acquisition of self-administration, and also causes reinstatement of drug seeking. Therefore, relative to enriched rats, it is hypothesized that rats raised in isolation and subjected to an acute stressor will acquire cocaine self-administration more rapidly and will demonstrate greater stress-induced reinstatement due to a sensitized stress axis. Specific Aim 1 will measure the acquisition of cocaine self- administration after an acute stressor, and measure stress-induced reinstatement of self-administration in rats raised in an isolated condition (IC), standard condition (SC), or an enriched condition (EC). An adapted single prolonged stress model (SPS), considered a type of acute stressor, will be used to model PTSD. Corticosterone, the major stress hormone in rodents, and its receptor, the glucocorticoid receptor (GR), are implicated in stress-induced acquisition and reinstatement. Differences in levels of corticosterone or GR have the potential to underlie addiction and anxiety-related pathologies such as PTSD. Given the importance of GR and corticosterone in both stress and drug abuse, Specific Aim 2 will determine if this hormone/receptor system is altered by acute stress in IC, SC, and EC rats. GR expression levels will be quantified in brain areas involved in drug abuse after SPS administration in IC, SC, and EC rats. These areas will include the amygdala, medial prefrontal cortex, orbitofrontal cortex, nucleus accumbens, and dorsal striatum. Additionally, levels of free corticosterone will be measured in response to SPS in rats raised in these different housing conditions. These experiments are important because co-morbidity of PTSD and stimulant addiction is a serious social and health problem. Understanding the neurobiological basis of a common risk factor, early life stress, can aid in the development of addiction treatment strategies targeting this at-risk group and can help design both psychosocial and pharmaceutical interventions that ameliorate an overly sensitive stress axis.