古柯鹼 (cocaine) 是一個心理興奮劑，具備高度成癮性進而影響成癮者的健康和生活機能，因此關於古柯鹼成癮的治療，一直是臨床上很關心的議題。當古柯鹼成癮者接觸到壓力、古柯鹼相關情境或古柯鹼藥物本身時，容易使既有的古柯鹼相關記憶再次被提取，造成病患強烈的心理渴求以及求藥之行為。因此，我們要如何壓抑甚至抹除病患對古柯鹼的相關記憶，進而避免重複用藥，乃是本實驗的最大目標。我們實驗室過去發現，在雄性小鼠身上系統性給予或是在內側前額葉皮質微量注射利莫那班 (rimonabant)，對於低劑量和高劑量古柯鹼引發場地制約偏好記憶 (cocaine-induced conditioned place preference, CPP) 有雙向調節的效果。我們首先探討利莫那班調節古柯鹼記憶是否透過大麻素受體第一型 (cannabinoid receptor type 1, CB1) 來達成。接著，我們探討利莫那班對雄性小鼠之古柯鹼記憶調節效果是否藉由多巴胺受體第一型和第二型 (dopamine receptor D1、D2) 來達成。第三，我們將光遺傳學技術應用在多巴胺合成酵素酪氨酸羥化酶 (tyrosine hydroxylase, TH) 之基因轉殖鼠 (TH-Cre mice) 上，探討利莫那班調節古柯鹼記憶是否透過腹側被蓋區 (ventral tegmental area, VTA) 投射到內側前額葉皮質 (medial prefrontal cortex, mPFC) 之多巴胺神經迴路來達成。最後，由於利莫那班在臨床使用上產生許多副作用，如噁心、焦慮以及增加自殺風險等，因而限制了其臨床應用性，我們進一步研究在臨床上已證實具備抗焦慮和治療癲癇等功能之大麻二酚 (cannabidiol, CBD)，是否可以取代利莫那班來調節古柯鹼記憶。我們的研究結果發現，利莫那班對於低劑量古柯鹼 (10 mg/kg) 的場地制約偏好有促進效果，此重複了我們實驗室過去的研究發現，我們進一步發現大麻素受體第一型受體的促進劑WIN 55,212-2 (WIN) 可以阻斷利莫那班的記憶促進效果，我們因此推論大麻素受體第一型CB1至少參與在利莫那班的記憶調節效果。此外，利莫那班損害高劑量古柯鹼 (20 mg/kg) 場地制約偏好之記憶，但當我們單獨施予WIN時，對於高劑量古柯鹼場地制約偏好記憶也產生損害，因此當WIN和利莫那班同時給予時，WIN無法反轉利莫那班之記憶損害效果。我們接著發現，在低高劑量古柯鹼相關記憶上，系統性或在內側前額葉皮質微量注射多巴胺受體第一型D1拮抗劑 (SCH23390, SCH) 或多巴胺受體第二型D2拮抗劑 (sulpiride, Sulp)，僅有Sulp會阻斷利莫那班的記憶調節效果，此一結果證實了多巴胺受體第二型D2參與在利莫那班的記憶調節效用。我們接著發現，使用光遺傳學技術興奮TH-Cre小鼠之腹側被蓋區 (VTA) 投射到內側前額葉皮質 (mPFC) 的多巴胺酬償迴路可以有效抑制利莫那班促進低劑量古柯鹼之記憶；然在高劑量古柯鹼記憶之實驗，由於利莫那班在TH-Cre小鼠身上無法複製先前之損害效果，因此興奮此一迴路之效用無法顯現。最後，我們發現，大麻二酚與利莫那班相似，雙向調節了低高劑量古柯鹼場地制約偏好之記憶。我們接著檢視大麻二酚是否也透過大麻素受體第一型CB1來達到其調控效果，結果發現，WIN可以有效抑制大麻二酚在低劑量古柯鹼相關記憶之促進效果；然而，儘管 WIN單獨使用時抑制了高劑量古柯鹼，WIN依然有效回復了大麻二酚的記憶抑制效果，由此可推論大麻素受體第一型CB1參與在大麻二酚之雙向記憶調節效用。總結來說，利莫那班對於古柯鹼相關記憶之調節同時有大麻素受體第一型CB1以及巴胺受體第二型D2之參與，且VTA投射到mPFC之多巴胺神經迴路扮演重要角色，由於大麻二酚亦透過大麻素受體第一型CB1來調節古柯鹼相關記憶，極可能可以在臨床上取代利莫那班的治療效果。

Goals of this study
We aimed to investigate the mechanisms of cannabinoid CB1 receptors and the dopaminergic D1 and D2 receptors underlying the bidirectional effects of rimonabant on cocaine-induced conditioned place preference (CPP).
Methods
We used conditioned place preference to examine the effects of rimonabant on cocaine-associated memory. Stereotaxic surgery was performed for infusing drugs into the medial prefrontal cortex (mPFC). The optogenetic technique was used for investigating the ventral tegmental area (VTA)-to-mPFC dopaminergic projecting pathway.
Results
We found that the rimonabant has bidirectional effects on cocaine-induced CPP) memory in male mice and is mediated by CB1 receptors. Next, rimonabant’s bidirectional effects are mediated by the dopamine D2 receptors. Moreover, by using optogenetic approach in the tyrosine hydroxylase (TH) transgenic mice (TH-Cre mice), we found that activation of the VTA-to-mPFC dopaminergic projecting pathway decreases the facilitatory effect of rimonabant on low-dose cocaine-induced CPP. Finally, systemic administration of the cannabidiol (CBD) also has bidirectional effects on cocaine-induced CPP memory and is mediated by CB1 receptors. These results indicate that CB1 and D2 receptors in the mPFC and VTA-to-mPFC dopaminergic pathway are involved in the rimonabant’s effect on cocaine-associated memory.

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