Gibbs Terrell T, Russek Shelley J, Farb David H
Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, United States.
Pharmacol Biochem Behav. 2006 Aug;84(4):555-67. doi: 10.1016/j.pbb.2006.07.031. Epub 2006 Oct 4.
Central nervous system function is critically dependent upon an exquisitely tuned balance between excitatory synaptic transmission, mediated primarily by glutamate, and inhibitory synaptic transmission, mediated primarily by GABA. Modulation of either excitation or inhibition would be expected to result in altered functionality of finely tuned synaptic pathways and global neural systems, leading to altered nervous system function. Administration of positive or negative modulators of ligand-gated ion channels has been used extensively and successfully in CNS therapeutics, particularly for the induction of sedation and treatment of anxiety, seizures, insomnia, and pain. Excessive activation of excitatory glutamate receptors, such as in cerebral ischemia, can result in neuronal damage via excitotoxic mechanisms. The discovery that neuroactive steroids exert rapid, direct effects upon the function of both excitatory and inhibitory neurotransmitter receptors has raised the possibility that endogenous neurosteroids may play a regulatory role in synaptic transmission by modulating the balance between excitatory and inhibitory neurotransmission. The sites to which neuroactive steroids bind may also serve as targets for the discovery of therapeutic neuromodulators.
中枢神经系统的功能严重依赖于兴奋性突触传递（主要由谷氨酸介导）和抑制性突触传递（主要由γ-氨基丁酸介导）之间精确调节的平衡。预计对兴奋或抑制的调节会导致精细调节的突触通路和整体神经系统的功能改变，从而导致神经系统功能改变。配体门控离子通道的正性或负性调节剂已在中枢神经系统治疗中广泛且成功地应用，特别是用于诱导镇静以及治疗焦虑、癫痫、失眠和疼痛。兴奋性谷氨酸受体的过度激活，如在脑缺血时，可通过兴奋毒性机制导致神经元损伤。神经活性甾体对兴奋性和抑制性神经递质受体的功能均有快速、直接的影响，这一发现增加了内源性神经活性甾体可能通过调节兴奋性和抑制性神经传递之间的平衡在突触传递中发挥调节作用的可能性。神经活性甾体结合的位点也可能成为治疗性神经调节剂发现的靶点。
