Genetic Inactivation of the Serotonin1A Receptor in Mice Results in Downregulation of Major GABAA Receptor a Subunits, Reduction of GABAA Receptor Binding, and Benzodiazepine-Resistant Anxiety

Anxiety is a common psychiatric illness often treated by benzodiazepines (BZs). BZs, such as Valium, bind to the a subunit of the pentameric GABAA receptor and increase inhibition in the CNS. There is considerable evidence for abnormal GABAA receptor function in anxiety, and a significant proportion of anxiety patients has a reduced sensitivity to BZs. Here, we show that serotonin1A (5-HT1A) receptor knock-out mice display BZ-resistant anxiety. Consistent with this finding, binding of both BZ and non-BZ GABAA receptor ligands were reduced and GABAergic inhibition was impaired in mutant mice. These changes were reflected by abnormal a 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-HT1A receptor deficit, leading to abnormalities in GABAA 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.