對於古柯鹼上癮之病患而言，古柯鹼、與藥物相關聯的線索或壓力，皆會造成其強烈的心理渴求以及求藥行為。因此，如何去除病患對古柯鹼的心理渴求進而避免復發，乃治療古柯鹼成癮最大的挑戰。本實驗室過去發現，在公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，對於低劑量和高劑量古柯鹼引發場地制約偏好記憶有雙向調節的效果。我們因此首先探討利莫那班調節古柯鹼記憶是否有性別差異存在，並透過大麻素受體第一型來達成。我們接著探討，利莫那班對公鼠之古柯鹼記憶調節效果，是否藉由皮質酮或是內側前額葉皮質之多巴胺受體第一型和第二型來達成。研究結果發現，利莫那班對高劑量古柯鹼（20 mg/kg）的場地制約偏好之損害效果只存在於公鼠上，且大麻素受體第一型參與其中，而此效果在母鼠身上不存在。令人驚奇的是，利莫那班同時損害野生型公鼠以及大麻素受體第一型基因剃除的公鼠在極高劑量古柯鹼（40 mg/kg）之記憶，因此可能有其他機制參與其中。極高劑量古柯鹼（40 mg/kg）施打於予母鼠身上，很不幸地造成母鼠70%的死亡率。我們接著發現，單獨給予利莫那班或古柯鹼（10, 20 mg/kg）皆會促進皮質酮的分泌，然而利莫那班僅再次提升10 mg/kg 古柯鹼所促進的皮質酮量，對於20 mg/kg古柯鹼所增加的皮質酮毫無影響。此外，利莫那班對低或高劑量（10, 20 mg/kg）古柯鹼記憶之雙向調節作用在去除腎上腺之公鼠身上完全消失，此現象與皮質酮量在去除腎上腺後無法被藥物改變之現象相互呼應。最後，系統性或在內側前額葉皮質給予多巴胺受體第一型或第二型拮抗劑皆損害利莫那班對低劑量古柯鹼記憶之促進效果，表示內側前額葉皮質得的多巴胺受體第一型和第二型皆參與在利莫那班調節低劑量古柯鹼之相關記憶。

Goal of this study
We aimed to investigate the cannabinoid CB1 receptors and corticosterone and the dopaminergic D1 and D2 receptors mechanisms underlying the bidirectional effects of rimonabant on cocaine-induced CPP.
Methods
We used conditioned place preference to test the effects of rimonabant on cocaine-
associated memory. We also conducted adrenalectomy and ELISA to test
corticosterone level. Stereotaxic surgery is used for drug induction into mPFC.
Western blotting was used to quantify the protein expression.
Result
We found that the effect of rimonabant on 20 mg/kg cocaine-induced CPP exists in male mice and is mediated by CB1 receptors, but not in female mice, and rimonabant impairs 40 mg/kg cocaine-induced CPP memory in both wild-type and CB1 knockout male mice. Next, administration of rimonabant or cocaine (10 or 20 mg/kg) alone increased corticosterone. However, rimonabant only potentiates 10 mg/kg cocaine increase of corticosterone, but not that of 20 mg/kg cocaine. Moreover, rimonabant’s effects on low- and high-dose cocaine CPP are abolished by ADX, which is correlated with blunted corticosterone level following ADX. Finally, systemic or intra-mPFC administration of the D1 and D2 antagonists impaired the facilitating effect of rimonabant on memory consolidation of 10 mg/kg cocaine-induced CPP. These results indicate that both D1 and D2 receptors in the mPFC are involved in the rimonabant’s effect on cocaine-associated memory.

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