神經心理疾病患者在受到壓力的狀況下容易引發突發性的攻擊行為，流行病學的相關數據也表示早期生活壓力對成年後對於壓力的耐受性有顯著的影響。同時也發現在美國通過醫療用大麻合法化法案的州，其殺人和攻擊的犯罪率似乎有下降的趨勢。在人體內也有會自發生成的內源性大麻素，內源性大麻素與大麻葉中的大麻素最大的不同點在於內源性大麻素沒有大麻素的成癮性以及情緒上的副作用，而只有與大麻素相似的醫療成份。人體內表現最多的內源性大麻素主要是花生四烯酸乙醇胺和花生四烯酸甘油胺，並且具有兩種受體，稱為CB1和CB2受體。CB1在中樞神經系統中最豐富，並且會抑制腺苷酸環化酶作用。此外，內源性大麻素逆行刺激突觸前CB1受體，然後抑制鈣離子通道活化或刺激鉀離子通道，從而減少神經遞質的釋放。臨床前研究報導，CB1受體的受損增加了囓齒類動物暴力行為的發生。此外，許多實驗研究表明CB1受體功能改變會影響情緒控制。所以我們欲研究CB1受體在面對急性壓力下是否能夠調節攻擊行為。在本研究中，我們使用斷奶後社會隔離的動物模型來誘導小鼠的攻擊行為。相較於群居小鼠，隔離小鼠只表現較多的威嚇行為，而無直接的咬嚙攻擊。如進一步給予急性壓力，則可發現隔離小鼠會明顯用咬的攻擊BALB/c小鼠。我們在急性壓力前注入利用腹腔注射CB1受體致效劑ACPA或WIN-55,212-2 (CB1受體致效劑)後，隔離小鼠明顯減少異常攻擊行為，效果可以持續24小時。但在群居小鼠注射CB1受體致效劑後並沒有明顯的變化。由於腹側海馬迴會調節邊緣系統並影響主要調控攻擊行為的下丘腦。我們利用腦顯微手術將ACPA或WIN-55,212-2 (CB1受體致效劑)在急性壓力前注入隔離小鼠的海馬迴內，結果發現明顯減少異常攻擊行為。相反，沒有參與攻擊行為的丘腦注入致效劑後沒有行為上的改變。而利用shRNA技術減少隔離小鼠海馬迴內的CB1受體蛋白表現後，也發現隔離小鼠的攻擊行為明顯上升。此外，我們發現隔離小鼠的CB1蛋白表現量與群居小鼠相比沒有差異。CB1會表現在於隔離小鼠腹側海馬中的glutamate神經元或GABA神經元。我們還發現CB1受體致效劑治療改變了神經傳遞物質的濃度，它增加了血清素濃度並降低了多巴胺濃度。CB1受體致效劑治療還增加ERK和p70S6K磷酸化。CB1受體致效劑治療24小時後，ERK和p70S6K磷酸化會回復到基礎值。接下來，我們通過CB1敲除實驗再次證實隔離小鼠中的CB1受體。但利用shRNA技術減少群居小鼠海馬迴內的CB1受體蛋白表現後，群居小鼠的攻擊行為並沒有改變。總結上述的實驗結果，面對壓力時隔離小鼠易有攻擊行為，之後更進一步去操弄海馬迴內的CB1受體，我們發現海馬迴內CB1受體在遭受急性壓力的狀況下的會調節攻擊行為，使社會隔離小鼠減少攻擊行為。通過控制CB1R改善攻擊性行為可能為治療精神病理學開闢了一個新方向。

Accumulating epidemiological evidence shows that early life stress has long-term effects on the susceptibility to subsequent stress exposure during adulthood. Previous reports from human studies suggest that early life stress significantly contributes to the development of excessive and impulsive aggression. Moreover, statistical results show that medical marijuana legalization in the United States may be correlated with a reduction in homicide and assault rates. There are also endogenous cannabinoids that can synthetize in the human body. The biggest difference between endocannabinoids and cannabinoids in cannabis is that endocannabinoids have no addictive and emotional side effects of cannabinoids. Only medical ingredients similar to cannabinoids. Endocannabinoids, endogenous cannabinoid, are mainly anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and have two G protein coupled receptors, known as the cannabinoid type 1 (CB1R) and type 2 receptors (CB2R). CB1R is most abundant in the central nervous system, and couples to G protein type Gi/o that inhibits adenylate cyclase. Moreover, endocannabinoids retrogradely activate presynaptic CB1R and then inhibit voltage-activated Ca2+ channels or stimulate inwardly rectifying K+ channels, which reduce neurotransmitter releases. Preclinical studies reported that the deletion of CB1R increased the occurrence of violent behaviors in rodent. Moreover, numerous experimental studies have shown that the endocannabinoid system is implicated in the control of emotional behavior by functionally altering CB1R.
In the present study, to investigate the role of CB1R to the regulation of the response to acute stress in aggression, we used the animal model of post-weaning social isolation to induce attack behaviors in mice. Socially isolated (SI) mice rather than group housing (GH) mice performed attack behaviors in the resident-intruder test following foot-shocks. After the intraperitoneal injection with the CB1R agonist ACPA (5 mg/kg) or WIN-55,212-2 (0.5 mg/kg), SI mice decreased levels of attack behaviors than vehicle control. Anti-aggressive effect kept to 24 hours. Moreover, the ventral hippocampus regulates the limbic system and projects to hypothalamic nuclei, which is well known brain area in attack behaviors. Intra-ventral hippocampus infusion of CB1R agonist showed lower levels of attack behaviors compared with vehicle control. In contrast, Intra-thalamic infusion which is not involved in aggression brain of CB1R agonists had no effects. Furthermore, we found that the CB1 protein level of SI mice had no difference compared to GH mice. CB1R was co-localized in the glutamatergic neuron or GABAergic neuron in ventral hippocampus of SI mice. We also found that CB1 agonist treatment changed neurotransmitters concentration, it increased 5-HT concentration and decreased dopamine concentration. CB1 agonist treatment also increased ERK and p70S6K phosphorylation. After treated for 24 hours, ERK and p70S6K phosphorylation reverse to basal level. Next, we confirmed CB1 receptor in SI mice again by CB1 knockdown experiment. We used western blotting analysis and Immunofluorescence experiment to confirm knockdown result of CB1. Knockdown of CB1 with small hairpin interfering RNA aggravates attack behaviors in SI mice with acute stress. Knockdown of CB1 with small hairpin interfering RNA did not affect attack behaviors in GH mice with acute stress. Taken together, we found that CB1R agonist treatment reduced attack behaviors under the acute stress-induced, but on the contrary knockdown of CB1R increased attack behaviors under the acute stress-induced.
Amelioration of aggressive behaviors by controlling CB1R may open a new direction for the treatment of psychopathologies that involve outbursts of emotional aggression in neglected children.

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