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The Journal of Neuroscience, April 15, 2000, 20(8):2758-2765

Genetic Inactivation of the Serotonin_1A Receptor in Mice Results in Downregulation of Major GABA_A Receptor  Subunits, Reduction of GABA_A Receptor Binding, and Benzodiazepine-Resistant Anxiety

Etienne Sibille¹, Constantine Pavlides², Dietmar Benke³, and Miklos Toth¹

¹ Department of Pharmacology, Weill Medical School of Cornell University, New York, New York 10021, ² Laboratory of Neurophysiology, Rockefeller University, New York, New York 10021, and ³ Institute of Pharmacology, University of Zurich, CH-8057 Zurich, Switzerland

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

Key words: 5-HT_1A receptor; GABA_A receptor; subunit; knock-out; benzodiazepine; anxiety; sedation; anxiolytic

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2082758-08$05.00/0

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