Predisposed to anxiety : involvement of 5-HT1A and GABAA receptors

Abstract

Anxiety disorders are prevalent occurring disorders and are characterized by behavioural and autonomic symptoms. Neurotransmitter systems that are involved include the GABAA ergic and the serotonergic systems. To further investigate the role of 5-HT1A receptors in anxiety disorders, three research groups created 5-HT1A receptor knockout mice (1AKO), all using different genetic backgrounds (129S, SW, B6). Despite similar findings, reporting increased anxiety in all 1AKO mice, differences between 1AKO mice on the three background strains were also observed. The first part of this thesis engages in differences between genetic strains, used to create 1AKO mice, by measuring autonomic parameters and pharmacological sensitivity. In the second part, 1AKO mice of all three genetic backgrounds were compared to their wildtypes and to each other. Finally, the role of 5-HT1A receptors during postnatal neurodevelopment and the effects on anxiety at adult age were investigated by development of a pharmacological 5-HT1A receptor knockout mouse. Differences in autonomic parameters (body temperature and heart rate) as well as in activity levels were observed between the three genetic background strains in circadian rhythm experiments and in stress-induced responses. 129S mice showed highest autonomic stress response and least activity and were therefore indicated as the most anxious strain. Pharmacological differences in sensitivity to the effects of anxiolytic drugs were also observed between the genetic backgrounds, but not one strain was consistently most sensitive. Despite the strain differences shown by us and from literature, choosing one most appropriate strain for a receptor knockout mouse cannot be done exclusively by knowledge of the genetic background. Comparison of 1AKO mice on different genetic backgrounds showed that behavioural changes were present principally on the SW background. Autonomic parameter measurements showed no differences between wildtype and 1AKO mice in any strain. These results led to the conclusion that 5-HT1A receptors might be involved in processes underlying anxiety-related behaviour, but only to a modest extent. Furthermore, the influence of genetic background on the 1AKO phenotype was emphasized by these experiments. Differences between wildtype and 1AKO mice in pharmacological sensitivity were primarily observed in the SW strain, 1AKO mice showed reduced sensitivity towards the anxiolytic-like effects of benzodiazepines. The findings in 1AKO mice on different genetic backgrounds led to the idea that changes in GABAA receptor sensitivity in the SW strain were, at least partly, responsible for the anxious phenotype that was observed. By chronically blocking 5-HT1A receptors during postnatal development, effects on anxiety at adult age were assessed in the final chapter of the thesis. Anxiety levels that resemble those of 1AKO mice were observed already after 7 days of treatment with a 5-HT1A receptor antagonist and increased anxiety levels continued until adult age. Furthermore, these pharmacological 1AKO mice also showed reduced benzodiazepine sensitivity, indicating a neuro-developmental influence of 5-HT1A receptors on GABAA receptor functioning. Hence, disturbed 5-HT1A receptor functioning during postnatal development most likely initiates increased levels of anxiety in adult 1AKO mice, possibly by changes in the GABAA receptor subunit development.