Sex Differences in Endocannabioid-Mediated Behaviors

描述(申请人提供)：与压力相关的疾病，如严重的抑郁障碍，是严重的精神疾病，影响着2000多万美国人。内源性大麻素是A9-THC的类似物，是调节压力和焦虑的神经调节剂。这项建议的长期目标是确定内源性大麻系统在情绪障碍的病因学和病理生理学中的作用。具体的假设是，慢性轻度应激，一种抑郁症的动物模型，以性别特有的方式对大鼠的CB1受体水平进行不同的调节，这种差异是女性更容易患抑郁症的基础。这一假说基于以下观察：1)抑郁症在女性中的流行程度是男性的两倍；2)慢性轻度应激下调了雄性大鼠的大麻素受体CB1，3)CB1受体的中断增加了对压力和焦虑的行为反应，4)CB1受体的中断也增强了获得性恐惧的获得性，并损害了对获得性恐惧的消退。要测试的三个具体目标是：1)确定慢性温和应激是否对雄性和雌性大鼠海马区的CB1受体水平进行了差异调节。2)确定慢性轻度应激是否调节对海马区依赖的恐惧条件反射的反应。3)确定恐惧条件反射的慢性轻度应激调节是否依赖CB1受体。在为期三周的慢性轻度应激方案后，将使用免疫印迹法评估海马区CB1受体的水平。恐惧的条件反射将通过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.