Mental Health and Psychiatry Services, VA Boston Healthcare System, Boston, MA 02130, USA.
Pharmacol Biochem Behav. 2011 Aug;99(2):217-28. doi: 10.1016/j.pbb.2011.01.009. Epub 2011 Jan 20.
In anxiety disorders, such as posttraumatic stress disorders and phobias, classical conditioning pairs natural (unconditioned) fear-eliciting stimuli with contextual or discrete cues resulting in enduring fear responses to multiple stimuli. Extinction is an active learning process that results in a reduction of conditioned fear responses after conditioned stimuli are no longer paired with unconditioned stimuli. Fear extinction often produces incomplete effects and this highlights the relative permanence of bonds between conditioned stimuli and conditioned fear responses. The animal research literature is rich in its demonstration of cognitive enhancing agents that alter fear extinction. This review specifically examines the fear extinguishing effects of cognitive enhancers that act on gamma-aminobutyric acid (GABA), glutamatergic, cholinergic, adrenergic, dopaminergic, and cannabinoid signaling pathways. It also examines the effects of compounds that alter epigenetic and neurotrophic mechanisms in fear extinction. Of these cognitive enhancers, glutamatergic N-methyl d-aspartate (NMDA) receptor agonists, such as D-cycloserine, have enhanced fear extinction in a context-, dose- and time-dependent manner. Agents that function as glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonists, alpha2-adrenergic receptor antagonists (such as yohimbine), neurotrophic factors (brain derived neurotrophic factor or BDNF) and histone deacetylase inhibitors (valproate and sodium butyrate) also improve fear extinction in animals. However, some have anxiogenic effects and their contextual and temporal effects need to be more reliably demonstrated. Various cognitive enhancers produce changes in cortico-amygdala synaptic plasticity through multiple mechanisms and these neural changes enhance fear extinction. We need to better define the changes in neural plasticity produced by these agents in order to develop more effective compounds. In the clinical setting, such use of effective cognitive enhancers with cue exposure therapy, using compounds derived from animal model studies, provides great hope for the future treatment of anxiety disorders.
在焦虑障碍中，如创伤后应激障碍和恐惧症，经典条件作用将自然（非条件）引起恐惧的刺激与上下文或离散线索配对，导致对多种刺激产生持久的恐惧反应。消退是一种主动的学习过程，导致条件刺激不再与非条件刺激配对后，条件恐惧反应减少。恐惧消退常常产生不完全的效果，这突出了条件刺激和条件恐惧反应之间的相对永久性。动物研究文献丰富，证明了改变恐惧消退的认知增强剂。本综述特别考察了作用于γ-氨基丁酸（GABA）、谷氨酸能、胆碱能、肾上腺素能、多巴胺能和大麻素信号通路的认知增强剂对恐惧消退的影响。它还考察了改变恐惧消退中表观遗传和神经营养机制的化合物的作用。在这些认知增强剂中，谷氨酸 N-甲基-D-天冬氨酸（NMDA）受体激动剂，如 D-环丝氨酸，以上下文、剂量和时间依赖的方式增强了恐惧消退。作为谷氨酸能α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体激动剂的药物（如育亨宾）、神经生长因子（脑源性神经营养因子或 BDNF）和组蛋白去乙酰化酶抑制剂（丙戊酸和丁酸钠）也改善了动物的恐惧消退。然而，有些具有焦虑作用，其上下文和时间作用需要更可靠地证明。各种认知增强剂通过多种机制改变皮质-杏仁核突触可塑性，这些神经变化增强了恐惧消退。我们需要更好地定义这些药物产生的神经可塑性变化，以便开发更有效的化合物。在临床环境中，使用有效的认知增强剂与线索暴露疗法结合使用，使用来自动物模型研究的化合物，为未来焦虑障碍的治疗提供了很大的希望。
