Activation-induced regulation of GABA(A) receptors: Is there a link with the molecular basis of benzodiazepine tolerance?

作者：Clara Gravielle Maria

来源：Pharmacological Research, 2016, 109: 92-100.

DOI：10.1016/j.phrs.2015.12.030

• Benzodiazepine
• Tolerance
• GABA
• GABA(A) receptor
• Uncoupling

Benzodiazepines have been used clinically for more than 50 years to treat disorders such as insomnia, anxiety, and epilepsy, as well as to aid muscle relaxation and anesthesia. The therapeutic index for benzodiazepines if very high and the toxicity is low. However, their usefulness is limited by the development of either or both tolerance to most of their pharmacological actions and dependence. Tolerance develops at different rates depending on the pharmacological action, suggesting the existence of distinct mechanisms for each behavioral parameter. Alternatively, multiple mechanisms could coexist depending on the subtype of GABA(A) receptor expressed and the brain region involved. Because most of the pharmacological actions of benzodiazepines are mediated through GABA(A) receptor binding, adaptive alterations in the number, structure, and/or functions of these receptors may play an important role in the development of tolerance. This review is focused on the regulation of GABA(A) receptors induced by long-term benzodiazepine exposure and its relationship with the development of tolerance. Understanding the mechanisms behind benzodiazepine tolerance is critical for designing drugs that could maintain their efficacy during long-term treatments.

• 出版日期2016-7