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The 5-HT 1A receptor knockout mouse and anxiety

Olivier, B.a,b; Pattij, T.a; Wood, S.J.c; Oosting, R.d; Sarnyai, Z.e,f; Toth, M.c


The 5-HT 1A receptor has been implicated in the modulation of anxiety processes, mainly via pharmacological experiments. The recent production, in three independent research groups, of 5-HT 1A receptor knockout (R KO) mice in three different genetic backgrounds (C57BL/6J, 129/Sv, Swiss–Webster) led to the intriguing finding that all mice, independent from the genetic background strain from which the null mutants were made, showed an ‘anxious’ phenotype compared to corresponding wild-type mice. The present paper reviews the behavioral findings in these three KO lines and focuses on new findings in the 129/Sv-KO mice. These mice were more anxious or stress-prone only under specific conditions (high stress) and not as broadly as suggested from the initial studies. The 5-HT 1A R KO made in the Swiss–Webster background displays disturbances in the GABA A –benzodiazepine (BZ) receptor system in the brain, including downregulation of GABA A α 1 and α 2 subunits in the amygdala. In contrast, the GABA A -BZ receptor system seems to function normally in the 5-HT 1A R KO in the 129/Sv background suggesting that changes in the GABA A -BZ receptor system may not be a prerequisite for anxiety but rather could have a modifying effect on this phenotype. It can be concluded that the constitutive absence of the 5-HT 1A receptor gene and receptor leads to a more ‘anxious’ mouse, dependent on the stress level but independent from the strain. Depending on the genetic background, this null mutation may be associated with changes in GABA A -ergic neurotransmission. It is as yet unclear which mechanisms are involved in this intriguing differentiation.

a Department of Psychopharmacology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands; b Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA; c Joan and Sanford I. Weil College of Cornell University, Department of Pharmacology, New York, USA; d Department of Pharmaceutical Proteomics, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands; e PsychoGenics Inc., Hawthorne, New York, USA; f Department of Neuroendocrinology, The Rockefeller University, New York, USA

Correspondence to Berend Olivier, Department of Psychopharmacology, Faculty of Pharmacy, Utrecht University, Sorbonnelaan 16, 3584CA Utrecht, The Netherlands. E-mail:

Received 7 May 2001

Revised 19 July 2001

Accepted 19 July 2001

© 2001 Lippincott Williams & Wilkins, Inc.