Study on social isolation-induced functional changes in noradrenergic system in the brain

长期的社会隔离增强了小鼠和大鼠的自发运动活动，并诱发了攻击行为。然而，这种行为改变的潜在机制尚不清楚。我们初步报道了一种抗抑郁药物地西帕明（DMI）增强了分离小鼠的攻击行为（Matsumoto et al., Pharmacol.Biochem.Behav.）。， 39, 167, 1991)。在这项研究中，我们研究了社会隔离引起的中枢去肾上腺素能系统的功能变化。实验前将雄性小鼠分离6-7周。当测试攻击性时，两只分离的老鼠被放在一个中性的笼子里。测量了在20分钟内观察到的咬伤和/或摔跤的总持续时间。具有阻断去甲肾上腺素（NA）在大脑中的吸收能力的抗抑郁药在低剂量下增强了攻击行为。这些药物的作用被a2肾上腺素受体拮抗剂育亨宾阻断，但不被α 1肾上腺素受体拮抗剂吡唑嗪阻断，提示α 2肾上腺素受体参与抗抑郁药增强攻击行为。此外，β -肾上腺素受体拮抗剂普萘洛尔和β -肾上腺素受体拮抗剂ICIII8551剂量依赖性阻断DMI的作用而不影响基础攻击行为，而β -肾上腺素受体拮抗剂美托洛尔未能影响地西帕明的作用。盐酸克仑特罗是一种选择性β - 2激动剂，可增强离体小鼠的攻击行为。综上所述，这些结果表明NA刺激α 2-和β 2-肾上腺素受体在增强攻击行为中起重要作用。然后，我们测试了神经毒素DSP-4对离体小鼠攻击行为的影响。已知这种毒素可选择性地退化源自蓝斑的去肾上腺素能末梢。DSP-4治疗不影响基础攻击行为，但减弱了攻击行为的DMI增强。因此，这些结果表明蓝斑去甲酰基酶的活性可能是由

Long-term social isolation enhances spontaneous motor activity, and induces aggressive behavior in mice and rats. However, underlying mechanisms of such behavioral changes remain unclear. We preliminary reported that an antidepressant drug desipramine (DMI) enhanced aggressive behavior in isolated mice (Matsumoto et al., Pharmacol.Biochem.Behav., 39, 167, 1991). In this study, we investigated functional changes in central noradrenergic system caused by social isolation. Male ddY mice were isolated for 6-7 weeks before experiments. When testing aggressive, two isolated mice were placed in a neutral cage. The total duration of biting attacks and/or wrestling observed during a 20-min period was measured. Antidepressants with ability to block noradrenaline (NA) uptake in the brain enhanced aggressive behavior at lower doses. The effects of these drugs were blockd by an a2 adrenoceptor antagonist yohimbine, but not alpha1 adrenoceptor antagonist prazosin, suggesting an involvement of alpha2 adrenoceptors in antidepressant enhancement of aggressive behavior. Moreover, a beta-adrenoceptor atntagonist propranolol and a beta2-adrenoceptor antagonist ICIII8551 dose-dependently blockd the effect of DMI without affecting the basal aggressive behavior, while a beta1-adrenoceptor antagonist metprolol failed to affect the effect of desipramine. Clenbuterol, a selective beta2-agonist, enhanced aggressive behavior in isolated mice. Taken together, these results indicated that alpha2- and beta2-adrenoceptor stimulation by NA plays important roles in enhancement of aggressive behavior. Then, we tested effect of a neurotoxin DSP-4 on the aggressive behavior in isolated mice. This toxin is known to selectively degnerate noradrenergic terminals originating from locus coeruleus. DSP-4 treatment did not affect the basal aggressive behavior, but it attenuated the DMI enhancement of aggressive behavior. Thus, these results show the possibility that the activity of locus coeruleus noradrener