The 5‐HT 1A receptor knockout mouse and anxiety

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