Alpha2-adrenergic drug effects on brain monoamines, locomotion, and body temperature are largely abolished in mice lacking the alpha2A-adrenoceptor subtype.
alpha(2)-ARs regulate brain monoaminergic function by inhibiting neuronal firing and release of monoamine neurotransmitters, noradrenaline (NA), serotonin (5-HT) and dopamine (DA). Both alpha(2A)- and alpha(2C)-AR inhibit monoamine release in vitro in brain slices, but the in vivo roles of individual alpha(2)-AR subtypes in modulating monoamine metabolism have not been characterised. Metabolism of brain monoamine neurotransmitters, locomotor activity and body temperature were investigated in mice with targeted inactivation of the gene encoding alpha(2A)-AR (alpha(2A)-knockout, alpha(2A)-KO) and wild-type (WT) mice after treatment with the alpha(2)-AR agonist dexmedetomidine and the antagonist atipamezole. Dexmedetomidine caused profound hypothermia (up to 14.7 degrees C mean reduction in rectal temperature) and locomotor inhibition in WT mice, and inhibited the turnover of NA, 5-HT and DA, but increased NA turnover in alpha(2A)-KO mice. alpha(2)-AR agonist-induced hypothermia and locomotor inhibition were attenuated, but not totally abolished, in alpha(2A)-KO mice. These results suggest that alpha(2A)-ARs are principally responsible for the alpha(2)-AR mediated inhibition of brain monoamine metabolism, but other alpha(2)-ARs, possibly alpha(2C)-ARs, are also involved, especially in the striatum. However, secondary effects of the physiological alterations caused by drug administration, especially hypothermia, may have contributed to the observed neurochemical changes in WT mice.
Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520 Turku, Finland.
Janne
J
Lähdesmäki
Jukka
J
Sallinen
Ewen
E
MacDonald
Jouni
J
Sirviö
Mika
M
Scheinin
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001831:Body Temperature / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D020927:Dexmedetomidine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000235:genetics
C547769:Adra2a protein, mouse; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D015306:Biogenic Monoamines; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D020927:Dexmedetomidine