Genetic inactivation of the Serotonin(1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety. Academic Article uri icon

Overview

abstract

  • Anxiety is a common psychiatric illness often treated by benzodiazepines (BZs). BZs, such as Valium, bind to the alpha subunit of the pentameric GABA(A) receptor and increase inhibition in the CNS. There is considerable evidence for abnormal GABA(A) receptor function in anxiety, and a significant proportion of anxiety patients has a reduced sensitivity to BZs. Here, we show that serotonin(1A) (5-HT(1A)) receptor knock-out mice display BZ-resistant anxiety. Consistent with this finding, binding of both BZ and non-BZ GABA(A) receptor ligands were reduced and GABAergic inhibition was impaired in mutant mice. These changes were reflected by abnormal alpha subunit expression in the amygdala and hippocampus, two important limbic regions involved in fear and anxiety. These data suggest a pathological pathway, initiated by a 5-HT(1A) receptor deficit, leading to abnormalities in GABA(A) receptor composition and level, which in turn result in BZ-insensitivity and anxiety. This model mechanistically links together the 5-HT and GABA systems, which both have been implicated in anxiety. A related mechanism may underlie reduced BZ sensitivity in certain forms of anxiety.

publication date

  • April 15, 2000

Research

keywords

  • Amygdala
  • Anti-Anxiety Agents
  • Anxiety
  • Benzodiazepines
  • Hippocampus
  • Receptors, GABA-A
  • Receptors, Serotonin

Identity

PubMed Central ID

  • PMC6772213

Scopus Document Identifier

  • 0034655423

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.20-08-02758.2000

PubMed ID

  • 10751426

Additional Document Info

volume

  • 20

issue

  • 8