Sex Differences in Endocannabioid-Mediated Behaviors

描述（由申请人提供）：压力相关障碍，如重度抑郁症是严重的精神疾病，影响超过2000万美国人。内源性大麻素，A9-THC的类似物，是涉及调节压力和焦虑的神经调质。该提案的长期目标是确定内源性大麻素系统在情绪障碍的病因学和病理生理学中的功能。具体的假设是，慢性轻度应激，抑郁症的动物模型，差异调节CB 1受体水平在大鼠的性别特异性的方式，这种差异的基础上更高的脆弱性，女性抑郁症。这一假设是基于以下观察：1）抑郁症在女性中的发病率是男性的两倍2）慢性轻度压力下调雄性大鼠的大麻素受体CB 1，3）CB 1受体的破坏增加了对压力和焦虑的行为反应，4）破坏CB 1受体也增强了获得性恐惧的获得并损害了对获得性恐惧的消退。实验的三个具体目的是：1）确定慢性轻度应激是否对雄性和雌性大鼠海马中CB 1受体水平有差异调节。2)确定慢性轻度应激是否调节对依赖于露营的恐惧条件反射的反应。3)确定慢性轻度应激对恐惧条件反射的调节是否具有CB 1受体依赖性。在三周的慢性轻度应激方案后，将使用Western免疫印迹法评估海马CB 1受体水平。恐惧条件反射将按照既定的经典条件反射方案进行。

DESCRIPTION (provided by applicant): Stress-related disorders such as major depressive disorder are serious mental illnesses that affect over 20 million Americans. Endocannabinoids, analogs of A9-THC, are neuromodulators implicated in regulating stress and anxiety. The long-term objective of this proposal is to determine the function of the endocannabinoid system in the etiology and pathophysiology of mood disorders. The specific hypothesis is that chronic mild stress, an animal model of depression, differentially regulates CB1 receptor levels in a gender-specific manner in rats and that this difference underlies the higher vulnerability of females to depressive disorders. This hypothesis is based on the following observations: 1) Depressive disorders are twice as prevalent in women than men 2) Chronic mild stress downregulates the cannabinoid receptor, CB1, in male rats, 3) Disruption of CB1 receptor increases behavioral responses to stress and anxiety, and 4) Disrupting CB1 receptors also enhances the acquisition and impairs extinction to acquired to fear. The three specific aims to be tested are: 1) To determine if chronic mild stress differentially regulates CB1 receptor levels in the hippocampus of male and female rats. 2) To determine if chronic mild stress modulates responses to hippocampal-dependent fear conditioning. 3) To determine if the chronic mild stress modulation of fear conditioning is CB1 receptor dependent. Hippocampal CB1 receptor levels will be assessed using Western immunoblotting following three-weeks of a chronic mild stress protocol. Fear conditioning will be performed with established classical-conditioning protocols.