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.
Sallinen
J
J
Department of Pnarmacology and Clinical Pharmacology, University of Turku, Finland.
Link
R E
RE
Haapalinna
A
A
Viitamaa
T
T
Kulatunga
M
M
Sjöholm
B
B
Macdonald
E
E
Pelto-Huikko
M
M
Leino
T
T
Barsh
G S
GS
Kobilka
B K
BK
Scheinin
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D015306:Biogenic Monoamines / Q000032:analysis*; D001831:Body Temperature / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D019329:Idazoxan / Q000031:analogs & derivatives / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D020926:Medetomidine; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects*; D012333:RNA, Messenger / Q000032:analysis; D018341:Receptors, Adrenergic, alpha-2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D015306:Biogenic Monoamines; D007093:Imidazoles; D012333:RNA, Messenger; D018341:Receptors, Adrenergic, alpha-2; C058525:2-methoxyidazoxan; D020926:Medetomidine; D019329:Idazoxan