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

Anxiety is a common psychiatric illness often treated by benzodiazepines (B Zs). BZs, such as Valium, bind to the alpha subunit of the pentameric GABA( A) receptor and increase inhibition in the CNS. There is considerable evide nce for abnormal GABA(A) receptor function in anxiety, and a significant pr oportion of anxiety patients has a reduced sensitivity to BZs. Here, we sho w that serotonin(1A) (5-HT1A) 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 mu tant mice. These changes were reflected by abnormal alpha subunit expressio n 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 GABA(A) receptor com position and level, which in turn result in BZ-insensitivity and anxiety. T his model mechanistically links together the 5-HT and GABA systems, which b oth have been implicated in anxiety. A related mechanism may underlie reduc ed BZ sensitivity in certain forms of anxiety.