研究背景
甲基安非他命是一種全球濫用的中樞神經興奮劑。由於其高度的成癮性，在我國被歸類為二級毒品。根據一一一年衛生福利部彙編的年度藥物濫用案件暨檢驗統計資料統計，(甲基)安非他命濫用之通報個案為第二多，僅次於海洛因。吸食者不但需要面對嚴重的成癮及犯罪責任，甲基安非他命對其身體的影響更是重要問題。即使停止使用甲基安非他命，患者仍可能經歷一系列的戒斷症狀，包括精神疾病、情緒不穩、易怒，及對藥物的渴望所延伸出的暴力行為。這些負面影響不僅涉及患者個人的健康，還可能對家庭和社會帶來嚴重後果。遺憾的是，儘管臨床上存在行為療法，藥物治療多以消極的支持性療法為主，目前並沒有被廣泛認可的藥物治療方法。
研究目的
由於在社會新聞以及科學文獻中觀察到甲基安非他命戒斷可能會引發人類暴力行為的出現，因此，本研究的宗旨在於建立甲基安非他命戒斷後期產生暴力行為的動物模型，並且釐清參與其中神經迴路，以利結合到臨床，找到合適的藥物治療策略。
研究方法
在本研究當中，我們結合化學遺傳學、神經迴路操控、免疫螢光染色及不同動物行為模式之分析方法確立甲基安非他命戒斷後期，對實驗鼠之中樞神經系統的影響。最後結合藥物，找到合適的治療策略。
研究結果
由實驗結果觀察到，對甲基安非他命成癮的老鼠，再強迫其戒斷十天以後，有顯著增加的暴力行為之相關動作，例如:咬入侵者大於十五次的比例，由原先尚未使用甲基安非他命之前的11.11%，到戒斷後期增加到61.11%。證明我們建立起了由甲基安非他命戒斷後期所誘導攻擊行為的動物模型。接著透過回溯標定實驗，找到參與此攻擊行為，並且會投射到下視丘腹內側核(Ventromedial hypothalamus, VMH)的腦區，包含了腹側海馬迴(Ventral hippocampus, vHip)及基底外側杏仁核(Basolateral amygdala, BLA)等。利用化學遺傳學方式將AAV(rg)-hSyn-hM4Di-mCherry注射至VMH，以微量注射CNO藥物至vHip，抑制了hSyn-hM4Di小鼠vHip興奮及抑制性神經元的神經活性，結果發現可有效降低因甲基安非他命之戒斷，而誘導攻擊相關動作的次數。然而，將AAV(rg)-hSyn-hM4Di-mCherry注射至VMH，以微量注射CNO藥物至BLA，抑制了hSyn-hM4Di小鼠BLA興奮及抑制性神經元的神經活性，結果發現無法有效降低因甲基安非他命之戒斷，而誘導攻擊相關動作的次數。此結果顯示了vHip投射至VMH的神經迴路與甲基安非他命戒斷，所誘導的攻擊行為之相關性。腹腔注射血清素1B受體(5-HT1B receptor)的促效劑，於甲基安非他命戒斷之小鼠體內，也能有效降低其攻擊行為次數。而微量注射血清素1B受體的促效劑，於甲基安非他命戒斷之小鼠的雙側vHip，也能有效降低其攻擊行為次數。
研究重要性
我們建立了一個由甲基安非他命戒斷，會誘導攻擊行為的動物模型，並發現vHip投射至VMH是參與此行為的重要神經迴路。透過使用血清素1B受體的促效劑可以改善這種攻擊行為。這些研究結果為毒品戒斷症狀提出了一個新的治療方向。

Background
Methamphetamine (MeAM) is an illicit psychostimulant abused globally. Due to its high addictive potential, it is classified as a Schedule II narcotic in our country. According to the annual drug abuse case reports and examination statistics compiled by the Ministry of Health and Welfare in 2022, MeAM abuse cases were the second most reported, surpassed only by heroin. Withdrawal from MeAM is associated with psychosis, rapid mood swings, and violent behaviors, posing a significant public health concern. Unfortunately, despite the availability of behavioral therapies in clinical settings, pharmacological treatments are mostly limited to palliative supportive care. Currently, there are no widely recognized pharmacological treatment methods.
Purpose
Due to observations in social news and scientific literature that methamphetamine withdrawal may trigger violent behavior in humans, this study aims to establish an animal model of violence induced by prolonged methamphetamine withdrawal. Additionally, it seeks to elucidate the neural circuits involved, facilitating the translation to clinical practice to find appropriate pharmacological treatment strategies.
Methods
In this study, we combined chemogenetics, neural circuit manipulation, immunofluorescence staining, and analysis of various animal behavior models to investigate the effects of prolonged methamphetamine withdrawal on the central nervous system of experimental mice. Finally, we integrated pharmacological approaches to identify suitable treatment strategies.
Results
Experimental results revealed that mice withdrawn from MeAM exhibited a significant increase in violent behaviors. The population proportion of mice with aggressive behaviors exceeding 15 times increased from the initial 11.11% to 61.11% at the prolonged withdrawal stage. This demonstrates that we successfully established an animal model of aggression induced by prolonged MeAM withdrawal. The retrograde tracer was injected into the VMH which colocalized with c-Fos cells and transported to the CA1 of the ventral hippocampus (vHip) and the basolateral amygdala (BLA). Human M4 muscarinic receptor (hM4D(Gi)) which fused with a mCherry fluorescent protein was introduced into the VMH using retrograde adeno-associated viruses (AAV(rg)-hSyn-hM4D(Gi)-mCherry). Cannulas were implanted into the bilateral vHip. Mice that received CNO or DCZ infusion in the vHip both exhibited a reduced number of attacks compared to those infused with a vehicle. In contrast, there was no difference in aggressive behaviors between mice receiving CNO or vehicle infusion in the BLA. This result indicates the involvement of the neural circuit projecting from the vHip to the VMH in methamphetamine withdrawal-induced aggression. Lastly, the administration of 5-HT1B receptor agonists anpirtoline or CP93,129 (i.p. or microinjection into the vHip) attenuated aggressive behaviors.
Significance
In our study, we have established an animal model of MeAM-induced aggressive behaviors during MeAM withdrawal. Our results demonstrated that vHip-VMH rather than BLA-VMH is responsible for MeAM withdrawal-induced aggressive behaviors and 5-HT1B receptor could be a therapeutic target for the treatment. These findings suggest a new therapeutic direction for treating drug withdrawal symptoms.

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