The 5-HT1A receptor knockout mouse and anxiety

The 5-HT1A receptor has been implicated in the modulation of anxiety processes, mainly via pharmacological experiments. The recent production, in three independent research groups, of 5-HT1A 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-HT1A R KO made in the Swiss-Webster background displays disturbances in the GABA(A)-benzodiazepine (BZ) receptor system in the brain, including downregulation of GABAA alpha (1) and alpha (2) subunits in the amygdala. In contrast, the GABA(A)-BZ receptor system seems to function normally in the 5-HT1A 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-HT1A 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. (C) 2001 Lippincott Williams & Wilkins.