The role of ventral pallidal cannabinoid and opioid signaling in cross-sensitization between THC and cue-induced heroin seeking

摘要 大麻可以作为阿片类药物的治疗替代品，然而，使用非偶然性药物的临床前研究 四氢大麻酚暴露前和最近的流行病学研究表明，大麻的使用会增加以下风险： 未来的阿片类药物滥用反复药物暴露可导致对药物和药物的持续高反应性- 相关刺激。这种致敏的潜在神经适应被认为与以下因素有关： 慢性药物暴露后寻求药物的增加。滥用药物之间的交叉致敏也会发生 有些药物的交叉敏感性比其他药物好，表明不同的神经适应性取决于药物- 课然而，THC预处理后对海洛因反应性增强的神经生物学基础， 暴露是未知的。已经表明，对吗啡的敏化依赖于脑中的莫尔信号传导。 苍白球（VP），然而，缺乏慢性双重THC和海洛因自身的临床前模型， 给药（SA）阻碍了对THC诱导的神经适应性的详细研究， 可能导致与阿片类药物交叉致敏的途径。我将使用一种新开发的大鼠模型， THC和海洛因SA研究THC摄入是否增加未来海洛因自我给药和线索诱导 寻找海洛因我将研究退出后VP中CB 1 R和莫尔信号的神经适应性。 慢性THC和海洛因暴露，并将与慢性THC或海洛因诱导的适应进行比较 一个人我推测THC和海洛因暴露诱导CB 1和莫尔的通路特异性适应 在VP中增强D1传入和抑制D2传入的信号，这些交叉适应 有助于促进线索诱导的海洛因寻求THC预暴露后。

Abstract Cannabis could serve as a therapeutic alternative to opioids, however, preclinical studies using non-contingent THC pre-exposure and a recent epidemiological study indicate that cannabis use can increase the risk for future opioid abuse. Repeated drug exposure can lead to persistent hyper-reactivity to drugs and drug- associated stimuli. The underlying neuroadaptations of this sensitization are thought to be involved in increased drug seeking after chronic drug exposure. Cross-sensitization between drugs of abuse also occurs and some drugs cross-sensitize better than others, indicating distinct neuroadaptations depending on drug- class. However the neurobiological underpinnings of the enhanced responsiveness to heroin after THC pre- exposure are unknown. It has been shown that sensitization to morphine depends on MOR signaling in the Ventral pallidum (VP), however the lack of a preclinical model of chronic dual THC and heroin self- administration (SA) impedes a detailed investigation of THC-induced neuroadaptations within the reward pathway that could lead to cross-sensitization with opioids. I will employ a newly developed rat model of dual THC and heroin SA to study whether THC intake augments future heroin self-administration and cue-induced heroin seeking. I will investigate neuroadaptations in CB1R and MOR signaling in the VP after withdrawal from chronic THC and heroin exposure and will compare to adaptations induced by either chronic THC or heroin alone. I hypothesize that that THC and heroin exposure induce pathway specific adaptations in CB1 and MOR signaling which potentiate D1 afferents and inhibit D2 afferents in the VP and that these cross-adaptations contribute to facilitated cue-induced heroin seeking after THC pre-exposure.