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5-HT1A receptor knockout (KO) mice have been described as more anxious in various anxiety paradigms. Because anxiety is often associated with autonomic changes like elevated body temperature and tachycardia, radiotelemetry was used to study these parameters in wild type (WT) and KO mice in stress-/anxiety-related paradigms. Basal body temperature (BT), heart rate (HR), and their diurnal rhythmicity did not differ between well-adapted WT and KO mice. In a simple stress-test, the Stress-induced Hyperthermia (SIH), injection-stress resulted in an exaggerated stress-response in KO mice. Furthermore, the 5-HT1A receptor agonist flesinoxan dose-dependently antagonized SIH and stress-induced tachycardia in WT, but not in KO, mice. In both genotypes, diazepam blocked SIH, but not stress-induced tachycardia. Finally, KO mice displayed an exaggerated stress response in HR and BT to novelty stress; this was supported by behavioral indications of enhanced anxiety. The present findings show that 5-HT1A receptor KO mice display a more “anxious-like” phenotype not only at a behavioral, but also at autonomic levels. [Copyright &y& Elsevier]

Previous studies in 5-HT1A receptor knockout (1AKO) mice on a mixed Swiss Webster×129/Sv (SW×129/Sv) and a pure 129/Sv genetic background suggest a differential γ-aminobutyric acid (GABAA)–benzodiazepine receptor complex sensitivity in both strains, independent from the anxious phenotype. To further investigate these discrepancies, various GABAA–benzodiazepine receptor ligands were tested in different behavioral paradigms in 1AKO and wild type (WT) mice on a 129/Sv background. 1AKO and WT mice responded comparably to alprazolam, flumazenil, alcohol and pentylenetetrazol as measured in the stress-induced hyperthermia paradigm. In addition, sedative–anesthetic effects of pentobarbital measured via the righting reflex were similar and a selected dose of diazepam exerted similar anxiolytic effects in both genotypes in the elevated plus maze. In conclusion, 1AKO mice on a 129/Sv background have undisturbed GABAA–benzodiazepine receptor sensitivity in contrast to those described on a mixed Swiss Webster×129/Sv background. The anxious phenotype of 1AKO mice seems to occur independent of the GABAA–benzodiazepine receptor complex functioning. [Copyright &y& Elsevier]

Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT1A and 5-HT1B receptor. The present study focuses on putative adaptive changes in the 5-HT1A receptor system in mice that lack 5-HT1B receptors (5-HT1B KO). 5-HT1A receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT1A receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT1A receptor activation by flesinoxan (0.1–3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT1B KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT1A receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT1B KO mice showed no shift in 5-HT1A receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT1A receptor function in 5-HT1B KO mice as measured telemetrically on body temperature and heart rate responses. [Copyright &y& Elsevier]