Dept. Neuroscience, Yale Medical School, 333 Cedar St., New Haven, CT 06510, USA.
Neurobiol Learn Mem. 2020 Dec;176:107327. doi: 10.1016/j.nlm.2020.107327. Epub 2020 Oct 17.
The selective norepinephrine (NE) α2A-adrenoceptor (α2A-AR) agonist, guanfacine (Intuniv™), is FDA-approved for treating Attention Deficit Hyperactivity Disorder (ADHD) based on research in animals, a translational success story. Guanfacine is also widely used off-label in additional mental disorders that involve impaired functioning of the prefrontal cortex (PFC), including stress-related disorders such as substance abuse, schizotypic cognitive deficits, and traumatic brain injury. The PFC subserves high order cognitive and executive functions including working memory, abstract reasoning, insight and judgment, and top-down control of attention, action and emotion. These abilities arise from PFC microcircuits with extensive recurrent excitation through NMDAR synapses. There is powerful modulation of these synapses, where cAMP-PKA opening of nearby potassium (K) channels can rapidly and dynamically alter synaptic strength to coordinate arousal state with cognitive state, e.g. to take PFC "offline" during uncontrollable stress. A variety of evidence shows that guanfacine acts within the PFC via post-synaptic α2A-AR on dendritic spines to inhibit cAMP-PKA-K channel signaling, thus strengthening network connectivity, enhancing PFC neuronal firing, and improving PFC cognitive functions. Although guanfacine's beneficial effects are present in rodent, they are especially evident in primates, where the PFC greatly expands and differentiates. In addition to therapeutic actions in PFC, stress-related disorders may also benefit from additional α2-AR actions, such as weakening plasticity in the amygdala, reducing NE release, and anti-inflammatory actions by deactivating microglia. Altogether, these NE α2-AR actions optimize top-down control by PFC networks, which may explain guanfacine's benefits in a variety of mental disorders.
选择性去甲肾上腺素 (NE) α2A-肾上腺素能受体 (α2A-AR) 激动剂胍法辛 (Intuniv™) 基于动物研究获得美国食品和药物管理局 (FDA) 批准用于治疗注意力缺陷多动障碍 (ADHD)，这是一个成功的转化案例。胍法辛也被广泛用于涉及前额叶皮层 (PFC) 功能障碍的其他精神障碍，包括应激相关障碍，如物质滥用、精神分裂样认知缺陷和创伤性脑损伤。PFC 支持高级认知和执行功能，包括工作记忆、抽象推理、洞察力和判断力，以及对注意力、行动和情绪的自上而下的控制。这些能力源自具有广泛反复兴奋的 PFC 微电路，通过 NMDA 受体突触。这些突触受到强大的调制，其中附近钾 (K) 通道的 cAMP-PKA 开放可以快速而动态地改变突触强度，将唤醒状态与认知状态协调起来，例如在无法控制的压力下使 PFC“离线”。各种证据表明，胍法辛通过树突棘上的突触后 α2A-AR 作用于 PFC 内，抑制 cAMP-PKA-K 通道信号，从而增强网络连接，增强 PFC 神经元放电，并改善 PFC 认知功能。尽管胍法辛在啮齿动物中的有益作用存在，但在灵长类动物中更为明显，灵长类动物的 PFC 大大扩展和分化。除了在 PFC 中的治疗作用外，应激相关障碍也可能受益于额外的 α2-AR 作用，例如减弱杏仁核的可塑性、减少 NE 释放以及通过去激活小胶质细胞发挥抗炎作用。总之，这些 NE α2-AR 作用通过 PFC 网络优化自上而下的控制，这可以解释胍法辛在各种精神障碍中的益处。
