Estrogen and Cocaine Sensitization in the Female Rat

雌性大鼠的雌激素和可卡因致敏作用

• 批准号: 7501367
• 负责人: Annabell C. Segarra
• 金额: $ 35.05万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7501367
• 关键词: Acute; Address; Affect; Agonist; Animals; Area; Autoradiography; Behavioral; Binding; Biochemistry; Blood; Brain; Brain Mapping; Chemicals; Cocaine; Cocaine Dependence; Cocaine HCl; Collaborations; Conscious; Daily; Data; Development; Dose; Drug Addiction; Drug Kinetics; Estradiol Benzoate; Estrogens; Female; Functional Magnetic Resonance Imaging; Future; Goals; Health; Image; Intervention; Laboratories; Lead; Ligands; Literature; Magnetic Resonance Imaging; Measures; Monitor; Motor Activity; Neurobiology; Neurons; Nucleus Accumbens; Opioid; Opioid Receptor; Opioid Receptor Binding; Pharmaceutical Preparations; Physiology; Prefrontal Cortex; Rattus; Research; Sex Characteristics; Signal Transduction; Site; Structure; System; Testing; Withdrawal; Woman; behavioral sensitization; day; design; dosage; drug of abuse; in vivo; innovation; kappa opioid receptors; male; men; neurobiological mechanism; new technology; novel therapeutics; receptor binding; receptor function; research study; response; stereotypy; therapy development

Drug addiction is a national health problem. Interestingly, men and women have different sensitivities to the development of cocaine addiction that are unrelated to differences in the pharmacokinetics of the drug. There is substantial literature pointing to estrogen as a critical chemical signal affecting cocaine sensitization in the female. The studies in this proposal are designed to elucidate estrogen's mechanism of action in cocaine sensitization. It is hypothesized that estrogen facilitates cocaine sensitization by: (1) sensitizing components of the mesocorticolimbic system to repeated cocaine administration (2) altering the interaction between the opioid and dopaminergic systems. Previous studies from our laboratory indicate that estrogen and opioids interact to regulate the behavioral response to cocaine in the female rat. To investigate the mechanisms involved we have formulated the following specific aims: (1) It is hypothesized that estrogen facilitates cocaine sensitization by blunting cocaine-induced neuronal activation in rostral mesocorticolimbic brain structures such as the nucleus accumbens (NAc) and prefrontal cortex. (2 and 3) It is anticipated that repeated cocaine enhances mu and decreases kappa opioid receptor function in the nucleus accumbens. To address specific aim 1, ovariectomized rats without (OVX) and with (OVX-EB) estrogen will be injected for 5 days with cocaine hydrochloride (15 mg/kg), challenged on day 13 with the same dose of cocaine and brain activity monitored by fMRI. To address specific aims 2 and 3, we will measure changes in mu and kappa opioid receptor binding in OVX and OVX-EB rats in response to acute and repeated cocaine and after withdrawal and reinstatement. An additional group of animals will be treated with specific mu and kappa opioid agonists and antagonists during repeated cocaine administration and after reinstatement and tested for behavioral sensitization. The progressive daily increase in locomotor activity elicited by the same dosage of cocaine will be used as an indicator of cocaine sensitization. Opioid ligands that induce changes in behavioral sensitization will be used in experiments that image cocaine-induced changes in BOLD signal by functional MRI (fMRI). At the conclusion of the in vivo studies, the brains will be studied for assessment of opioid (mu and kappa) receptors by regular and functional autoradiography. The proposed research is innovative because it capitalizes on the new technology of fMRI to identify sites in the brain that respond to acute and repeated cocaine administration. The results obtained will be significant because they will provide neurobiological data for the development of new therapeutic strategies in the treatment of drug addiction taking into consideration the differences in the physiology and biochemistry of men and women.

吸毒成瘾是一个国家健康问题。有趣的是，男人和女人对可卡因成瘾的发展具有不同的敏感性，这与该药物的药代动力学差异无关。有大量文献将雌激素指向影响女性可卡因敏化的关键化学信号。该提案中的研究旨在阐明雌激素在可卡因敏化中的作用机理。假设雌激素通过以下方式促进可卡因的敏化，（1）将中皮质糖系统的成分敏化，以重复可卡因给药（2）改变相互作用 在阿片类药物和多巴胺能系统之间。我们实验室的先前研究表明，雌激素和阿片类药物相互作用以调节女性大鼠对可卡因的行为反应。为了研究所涉及的机制，我们已经提出了以下具体目的：（1）假设雌激素通过使可卡因诱导的可卡因诱导的神经元激活促进可卡因的敏化，例如，鼻层中性杂质脑结构，例如Accumbens（NAC）和前核核细胞核（NAC）和核核细胞核。 （2和3）预计重复可卡因会增强MU并降低伏隔核中的Kappa阿片受体功能。为了解决特定的目标1，将不含（OVX）和（OVX-EB）雌激素的卵巢切除型大鼠注射5天的盐酸可卡因（15 mg/kg），并在第13天对可卡因和可卡因和可卡因和可卡因剂量进行了质疑。 fMRI监测的大脑活动。为了解决特定目标2和3，我们将测量OVX和OVX-EB大鼠在急性和重复可卡因以及撤回和恢复后的MU和Kappa阿片受体结合的变化。在重复可卡因施用期间，恢复原状并测试了行为敏化后，还将用特定的MU和Kappa阿片激动剂和拮抗剂对另一组动物进行治疗。相同剂量可卡因引起的运动活性的每日逐渐增加将用作可卡因敏化的指标。诱导行为敏化变化的阿片类药物配体将用于可卡因诱导的功能MRI（fMRI）大胆信号的变化的实验。在体内研究结束时，将研究大脑，以评估阿片类药物（MU和KAPPA）受体，并通过常规和功能性放射自显影。拟议的研究具有创新性，因为它利用了fMRI的新技术来识别大脑中对急性和反复可卡因给药反应的地点。获得的结果将是重要的，因为考虑到男性和女性的生理学和生物化学差异，它们将为制定药物成瘾的新治疗策略提供神经生物学数据。