Cason Angie M, Kohtz Amy, Aston-Jones Gary
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, New Jersey, United States of America.
PLoS One. 2016 Jun 30;11(6):e0158577. doi: 10.1371/journal.pone.0158577. eCollection 2016.
Locus coeruleus norepinephrine (LC-NE) and corticotropin releasing factor (CRF) neurons are involved in stress responses, including stress's ability to drive drug relapse. Previous animal studies indicate that female rats exhibit greater drug seeking than male rats during initial drug abstinence. Moreover, females are more sensitive to the effect of stress to drive drug seeking than males. Finally, LC-NE neurons are more sensitive to CRF in females compared to males. We hypothesized that increased drug seeking in females on extinction day one (ED1) is due to increased response to the stress of early withdrawal and is dependent upon the increased response of LC in females to CRF. We predicted that LC-NE neurons would exhibit Fos activation on ED1, and that blocking CRF1 signaling would decrease drug seeking on ED1 measured by responding on an active lever previously associated with cocaine self- administration. After chronic cocaine self-administration, female and male rats underwent a test for initial extinction responding by measuring lever pressing in the absence of cocaine. Prior to this Extinction Day 1 (ED1) session, rats were injected with vehicle or the selective CRF1 antagonist (CP) to measure effects of CRF antagonism on drug seeking during early abstinence. ED1 increased corticosterone in female rats, in proportion to lever responding in male and female, indicating that ED1 was stressful. Pretreatment with CP decreased cocaine seeking on ED1 more effectively in female compared to male rats. This increase in responding was associated with an increase in activation of LC NE neurons. Together, these findings indicate that stress, and signaling at CRF receptors in LC, may be involved in the increased drug seeking during initial abstinence.
蓝斑去甲肾上腺素（LC-NE）和促肾上腺皮质激素释放因子（CRF）神经元参与应激反应，包括应激驱动药物复吸的能力。先前的动物研究表明，在最初的药物戒断期间，雌性大鼠比雄性大鼠表现出更强的觅药行为。此外，与雄性相比，雌性对压力驱动觅药行为的影响更敏感。最后，与雄性相比，雌性的LC-NE神经元对CRF更敏感。我们假设，雌性在消退第一天（ED1）觅药行为增加是由于对早期戒断应激的反应增加，并且依赖于雌性LC对CRF反应的增加。我们预测，LC-NE神经元在ED1会表现出Fos激活，并且阻断CRF1信号会减少在先前与可卡因自我给药相关的活动杠杆上的反应所测量的ED1觅药行为。在慢性可卡因自我给药后，雌性和雄性大鼠通过测量在无可卡因情况下的杠杆按压进行初始消退反应测试。在这个消退第一天（ED1）实验之前，给大鼠注射溶剂或选择性CRF1拮抗剂（CP），以测量CRF拮抗对早期戒断期间觅药行为的影响。ED1使雌性大鼠的皮质酮增加，与雄性和雌性的杠杆反应成比例，表明ED1具有应激性。与雄性大鼠相比，CP预处理在雌性大鼠中更有效地减少了ED1的可卡因觅药行为。这种反应的增加与LC NE神经元激活的增加有关。总之，这些发现表明，应激以及LC中CRF受体的信号传导可能参与了初始戒断期间觅药行为的增加。
