Elsevier

Neuroscience

Volume 87, Issue 2, 20 July 1998, Pages 479-487
Neuroscience

Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors

https://doi.org/10.1016/S0306-4522(98)00167-5Get rights and content

Abstract

Behavioural assessments were made of mutant mice lacking histamine H1 receptors to reveal the function of H1 receptors in the behaviour of mice. Exploratory behaviour of mice in a new environment was examined to discover whether the absence of H1 receptors in mice affects actions relating to their emotions. The H1 receptor-deficient mice showed a significant decrease in ambulation in an open field and on an activity wheel. Cognitive functions and anxiety were examined using passive avoidance response test and the elevated plus-maze test, respectively. The passive avoidance test did not show any change in latency. The elevated plus-maze test revealed that the transfer latency of the mutant mice was significantly prolonged, indicating that H1 receptors are partly associated with the control of anxiety. Aggressive behaviour was examined by a resident-intruder aggression test. When confronted with an intruder, the mutant mice attacked the intruder significantly slower and less frequently than did wild-type mice after a six-month isolation period. A formalin test and a forced swimming test were used to evaluate the nociceptive response and depressive or despairing state, respectively, of both groups. The mutant mice showed a significant decrease of nociceptive response in the late phase without affecting the early phase. There was no significant difference in the forced swimming test between the two groups. The brain content of monoamines and their metabolites was measured in the H1 receptor null and wild-type mice. The turnover rate of 5-hydroxytryptamine defined by the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine was significantly increased in the cerebral cortex and hippocampus of H1 receptor null mice.

These results support the previous pharmacological findings that histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception and aggressive behaviour through H1 receptors.

Section snippets

Animals

The mutant mice lacking the H1 receptor subtype were generated by homologous recombination as previously described.[14]Male mutant mice (−/−) and wild-type mice (+/+) weighing 30–35 g were used. These mice were bred in our laboratory. Approximately 10 mice were housed as a group in one cage. All experiments were performed on mice at the age of three- to five-months-old. The total number of mice used in the study was 129 (+/+ mice) and 144 (−/− mice). For each behavioural task, naı̈ve mice were

Locomotor activity and motor co-ordination

The locomotion in an open field was measured in the daytime as shown in Fig. 1A. The locomotor activity of the mutant mice decreased in an open field. The decrease in locomotion was statistically significant when compared to the wild-type mice (ANOVA for nested design of time-series repeated measurement data, P<0.05). Actually, the mutant mice almost did not move at all after about 40 min in a new circumstance. The locomotor activity on the activity wheel was also measured during 24 h for five

Discussion

Decades of research have resulted in a coherent picture of the involvement of histamine in neuronal communication. In addition, the design of an increasing number of pharmacological tools to selectively modify histaminergic transmission and their utilization in electrophysiological, neurochemical, behavioural, and neuroendocrinological studies has led to a progressively more precise hypothesis about the function of the histaminergic neuron system in the CNS. An alternative approach to determine

Conclusions

Gene targeting in embryonic stem cells can produce mice with alterations to specific endogenous genes. The field has developed rapidly over the past several years, so that large numbers of mice with different gene deficiencies have been generated to study the functional roles of the gene. Here we have attempted to reveal the functional role for histamine H1 receptor-mediated neurotransmission using a new technology of gene targeting. The data obtained by this study are partly compatible with

Acknowledgements

This work was supported by grants-in-aid from the Ministry of Education, Science and Culture, the Uehara Memorial Foundation, the Sasagawa Memorial Foundation, and the Shimazu Science Foundation. We appreciate technical assistance of A. Miyake, and N. Miyama in behavioural studies. We also thank Dr I. Sato (Miyagi Cancer Center) for his suggestion of statistical evaluation.

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