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2C-Adrenoceptor Expression
in Mice: Influence on Locomotor, Hypothermic, and Neurochemical Effects
of Dexmedetomidine, a Subtype-Nonselective
2-Adrenoceptor Agonist
Department of Pharmacology and Clinical Pharmacology, University of
Turku, FIN-20520 Turku, Finland (J.S., M.K., B.S., M.S.),
Orion
Corporation, Orion-Pharma, FIN-20101 Turku, Finland (A.H., T.V., T.L.),
Department of Pharmacology and Toxicology (E.M.) and
Department of
Neurology (M.P.-H.), University of Kuopio, FIN-70211 Kuopio, Finland,
Department of Anatomy, Tampere University Medical School, FIN-33101
Tampere, Finland (M.P.-H.),
Department of Molecular and Cellular
Physiology (R.E.L., B.K.K.),
Howard Hughes Medical Institute (G.S.B.,
B.K.K.),
Department of Pediatrics (G.S.B.), and
Division of
Cardiovascular Medicine (B.K.K.), Stanford University, Stanford,
California 94305
2-Adrenergic receptors (2-ARs) regulate
many physiological functions and are targets for clinically important
antihypertensive and anesthetic agents. Three human and mouse genes
encoding 2-AR subtypes (2A,
2B, and 2C) have been cloned. We
investigated the involvement of the 2C-AR in
2-adrenergic pharmacology by applying molecular genetic
techniques to alter the expression of 2C-AR in mice. The
effects of dexmedetomidine, a subtype-nonselective 2-AR
agonist, on monoamine turnover in brain and on locomotor activity were
similar in mice with targeted inactivation of the 2C-AR
gene and in their controls, but the hypothermic effect of the
2-AR agonist was significantly attenuated by the
receptor gene inactivation. Correspondingly, another strain of
transgenic mice with 3-fold overexpression of 2C-AR in
striatum and other brain regions expressing 2C-AR showed
normal reductions in brain monoamine metabolism and locomotor activity
after dexmedetomidine, but their hypothermic response to the
2-AR agonist was significantly accentuated. The
hypothermic effect of 2-AR agonists thus seems to be
mediated in part by 2C-AR. Some small but statistically significant differences between the strains were also noted in brain
dopamine metabolism. Lack of 2C-AR expression was linked with reduced levels of homovanillic acid in brain, and mice with increased 2C-AR expression had elevated concentrations
of the dopamine metabolite compared with their controls.
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