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Sallinen, J. et al.

Genetic alteration of alpha 2C-adrenoceptor expression in mice: influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective alpha 2-adrenoceptor agonist.

alpha 2-Adrenergic receptors (alpha 2-ARs) regulate many physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three human and mouse genes encoding alpha 2-AR subtypes (alpha 2A, alpha 2B, and alpha 2C) have been cloned. We investigated the involvement of the alpha 2C- AR in alpha 2-adrenergic pharmacology by applying molecular genetic techniques to alter the expression of alpha 2C- AR in mice. The effects of dexmedetomidine, a subtype-nonselective alpha 2-AR agonist, on monoamine turnover in brain and on locomotor activity were similar in mice with targeted inactivation of the alpha 2C- AR gene and in their controls, but the hypothermic effect of the alpha 2-AR agonist was significantly attenuated by the receptor gene inactivation. Correspondingly, another strain of transgenic mice with 3-fold overexpression of alpha 2C- AR in striatum and other brain regions expressing alpha 2C- AR showed normal reductions in brain monoamine metabolism and locomotor activity after dexmedetomidine, but their hypothermic response to the alpha 2C- AR agonists was significantly accentuated. The hypothermic effect of alpha 2-AR agonists thus seems to be mediated in part by alpha 2C- AR. Some small but statistically significant differences between the strains were also noted in brain dopamine metabolism. Lack of alpha 2C- AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased alpha 2C- AR expression had elevated concentrations of the dopamine metabolite compared with their controls.[1]

References

Genetic alteration of alpha 2C-adrenoceptor expression in mice: influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective alpha 2-adrenoceptor agonist. Sallinen, J., Link, R.E., Haapalinna, A., Viitamaa, T., Kulatunga, M., Sjöholm, B., Macdonald, E., Pelto-Huikko, M., Leino, T., Barsh, G.S., Kobilka, B.K., Scheinin, M. Mol. Pharmacol. (1997) [Pubmed]

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