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Genetic Inactivation of the Serotonin 1A Receptor in Mice Results in Downregulation of Major GABA A Receptor α Subunits, Reduction of GABA A Receptor Binding, and Benzodiazepine-Resistant Anxiety

2000; Society for Neuroscience; Volume: 20; Issue: 8 Linguagem: Inglês

10.1523/jneurosci.20-08-02758.2000

1529-2401

Etienne Sibille, Constantine Pavlides, Dietmar Benke, Miklós Tóth,

Memory and Neural Mechanisms

Anxiety is a common psychiatric illness often treated by benzodiazepines (BZs). BZs, such as Valium, bind to the α 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 α 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.