Social buffering and vulnerability to nicotine reward

说明(由申请人提供)：对于吸烟和尼古丁依赖，需要更好的预防和干预策略。这一领域的进展取决于对成瘾不同阶段(包括成瘾初期)所涉及的生物学和行为机制的了解。最初的吸毒经历通常发生在青春期，几乎总是在为行为提供社会强化的同龄人在场的情况下，但涉及社会影响毒品起始的神经机制却鲜为人知。动物模型表明，在青少年中，社会互动增强了包括尼古丁在内的常见滥用药物的回报效果。尼古丁和其他滥用药物通过激活下丘脑-垂体-肾上腺(HPA)轴来提高皮质类固醇(CORT)水平，HPA轴是身体对应激源的反应。在应激文献中，社会缓冲是一种众所周知的现象，在应激文献中，同种刺激的存在通过减轻对应激的负面生理和行为反应来促进从应激刺激中更好地恢复。压力和奖励都会激活大脑中的中皮质边缘通路，这些通路参与处理情绪刺激并将其转化为动机行为。这些通路和HPA轴是相互调节的。最近，我们的实验室发现，尼古丁诱导的皮质醇升高会因社会环境而减弱。因此，我们假设，在尼古丁的最初体验中，社交缓冲通过抑制HPA轴和调节中皮质边缘处理，使青少年对药物最初的焦虑效应更具弹性，从而导致奖励显著增加。为了验证我们的假设，我们将研究尼古丁诱导的HPA轴激活和在开放领域中单独测试的大鼠和熟悉的配对大鼠的焦虑相关行为。然后，我们将检验这种最初的药物体验是否使第一次注射后与另一只大鼠在一起的大鼠的下一次药物体验比那些单独使用条件性位置偏好(CPP)模型的大鼠更有回报。最后，我们将使用即刻早期基因蛋白产物Fos的表达作为标记来测量处理应激刺激所涉及的大脑区域的激活。神经激活的检查将主要集中在识别纹状体床核内的兴奋性和抑制性细胞 终末(BNST)，大脑中高度参与焦虑处理的区域。我们预测，接受社交互动和尼古丁结合的大鼠将在旷场测试中表现出较少的焦虑样行为，表现出减弱的皮质醇反应，表现出增强的药物-CPP，并表现出较少的压力和焦虑相关脑结构的激活。这些发现将有助于阐明最初接触毒品时社会和尼古丁奖励相互作用的机制。这一信息意义重大，并可能为制定新的药物滥用预防和干预策略提供信息，因为一个人发现第一次药物经验的回报程度被认为可以预测药物滥用和依赖的倾向。

DESCRIPTION (provided by applicant): There is a significant need for better prevention and intervention strategies for smoking and nicotine dependence. Progress in this area relies upon understanding the biological and behavioral mechanisms involved in various stages of addiction, including initiation. Initial drug experiences typically take place in adolescence and nearly always in the presence of peers who provide social reinforcement for the behavior, yet the neural mechanisms involved in social influences on drug initiation are poorly understood. Animal models demonstrate that in adolescents, social interactions enhance the rewarding effects of commonly abused drugs, including nicotine. Nicotine and other drugs of abuse elevate corticosteroids (CORT) via activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is the body's response to stressors. Social buffering is a well- known phenomenon in the stress literature in which the presence of a conspecific promotes better recovery from stressful stimuli by alleviating negative physiological and behavioral responses to stress. Stress and reward both activate mesocorticolimbic pathways in the brain, which are involved in processing emotional stimuli and translating it into motivated behavior. These pathways and the HPA axis are reciprocally regulated. Recently, our lab has found that nicotine-induced CORT elevation is attenuated by a social context. Therefore, we hypothesize that social buffering during initial the experience with nicotine renders adolescents more resilient to initial anxiogenic effects of the drug by inhibiting the HPA axis and modulating mesocorticolimbic processing, resulting in increased reward salience. To test our hypothesis, we will investigate nicotine-induced HPA-axis activation and anxiety-related behavior in an open field in rats tested alone versus in familiar pairs. We will then examine whether this initial drug experience renders the next drug experience more rewarding in rats that were with another rat following their first injection relatie to those that were alone using the conditioned place preference (CPP) model. Finally, we will measure activation of brain regions implicated in processing stressful stimuli using expression of the immediate early gene protein product, Fos as a marker. Examination of neural activation will be focused primarily on identifying excitatory and inhibitory cells within the bed nucleus of stria terminals (BNST), a region of the brain highly implicated in anxiety processing. We predict that rats that receive social interaction in combination with nicotine will demonstrate less anxiety-lik behaviors in the open field test, show an attenuated CORT response, display enhanced drug-CPP, and exhibit less activation of stress and anxiety-related brain structures. The findings will aid in elucidating the mechanisms involved in social and nicotine reward interactions during initial drug exposure. This information is significant and may inform the development of new prevention and intervention strategies for drug abuse because the degree to which one finds the first drug experience rewarding is thought to predict the propensity for drug abuse and dependence.