Miczek Klaus A, Fish Eric W, De Bold Joseph F, De Almeida Rosa M M
Department of Psychology, Tufts University, Medford, MA 02155, USA.
Psychopharmacology (Berl). 2002 Oct;163(3-4):434-58. doi: 10.1007/s00213-002-1139-6. Epub 2002 Aug 6.
Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments.
To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options.
(1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and gamma-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT(1B) receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but not the striatal dopamine system. Dopaminergic manipulations, particularly targeting the D(2) receptor family, can influence aggressive behavior in animals and human patients, suggesting that mesocorticolimbic dopamine may have important enabling or permissive functions. (4) GABA is critical in the neurochemical control of aggressive behavior as evidenced by studies that directly modify GABAergic neurotransmission and neurochemical studies that correlate GABA measurements with aggressive behavioral responses in several animal species. The GABA(A) receptor complex is a mechanism through which certain benzodiazepines and alcohol enhance and inhibit aggressive behaviors. Social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression.
导致伤害的攻击性爆发对公共卫生和刑事司法系统而言是一个重大问题，但目前尚无足够的治疗方案。在开发动物模型的社会政策、机构监管和科学策略层面存在的障碍，持续阻碍着用于紧急和长期治疗的特定抗攻击药物的研发。
为了更贴近临床实际情况，临床前攻击行为研究已开始聚焦于超过物种典型模式的升级攻击行为的神经生物学决定因素。本综述的目的是研究新型药理学和分子工具，这些工具能够比以往更有选择性地针对不同类型攻击行为的神经机制，并概述潜在的药物治疗选择。
（1）临床前对强烈攻击行为的行为特征和决定因素的关注，有望与人类攻击行为中拟议的冲动 - 反应 - 敌意 - 情感亚型和控制 - 主动 - 工具性 - 掠夺性亚型之间的临床区分最为相关。多种人类和动物攻击行为的神经回路关键涉及血清素、多巴胺和γ-氨基丁酸（GABA）以及特定的受体亚型。（2）参与攻击行为所引发的额叶皮质血清素的动态变化表明，血清素能药物的作用在很大程度上取决于药物治疗时受体的功能状态。在目前已确定的众多5 - HT受体中，5 - HT（1B）受体为减少冲动攻击行为提供了一个有前景的靶点，特别是如果该作用能够局限于中枢神经系统的部位。（3）攻击性对抗对攻击者以及攻击行为的受害者而言都是显著的应激源，同时伴随着中脑皮质边缘多巴胺系统而非纹状体多巴胺系统的激活。多巴胺能操作，尤其是针对D（2）受体家族的操作，能够影响动物和人类患者的攻击行为，这表明中脑皮质边缘多巴胺可能具有重要的促成或允许功能。（4）GABA在攻击行为的神经化学控制中至关重要，这一点在直接改变GABA能神经传递的研究以及将GABA测量与多种动物物种的攻击行为反应相关联的神经化学研究中得到了证明。GABA（A）受体复合物是某些苯二氮䓬类药物和酒精增强和抑制攻击行为的一种机制。社会和药理学体验决定性地决定了GABA能正性调节剂对攻击行为的影响。
