Stimulation of postsynaptic alpha1b- and alpha2-adrenergic receptors amplifies dopamine-mediated locomotor activity in both rats and mice.
Recent experiments have shown that mice lacking the alpha1b-adrenergic receptor (alpha1b-AR KO) are less responsive to the locomotor hyperactivity induced by psychostimulants, such as D-amphetamine or cocaine, than their wild-type littermates (WT). These findings suggested that psychostimulants induce locomotor hyperactivity not only because they increase dopamine (DA) transmission, but also because they release norepinephrine (NE). To test whether NE release could increase DA-mediated locomotor hyperactivity, rats were treated with GBR 12783 (10 mg/kg), a specific inhibitor of the DA transporter, and NE release was enhanced with dexefaroxan (0.63-10 mg/kg), a potent and specific antagonist at alpha2-adrenergic receptors. Dexefaroxan increased the GBR 12783-mediated locomotor response by almost 8-fold. The role of alpha1b-ARs in this effect was then verified in alpha1b-AR KO mice: whereas dexefaroxan (1 mg/kg) doubled locomotor hyperactivity induced by GBR 12783 (14 mg/kg) in WT mice, it decreased it by 43% in alpha1b-AR KO mice. Finally, to test whether this latter inhibition was related to the occupation of alpha2-adrenergic autoreceptors or of alpha2-ARs not located on noradrenergic neurons, effects of dexefaroxan on locomotor hyperactivity induced by D-amphetamine (0.75 mg/kg) were monitored in rats depleted in ascending noradrenergic neurons. In these animals dexefaroxan inhibited by 25-70% D-amphetamine-induced locomotor hyperactivity. These data indicate not only that the stimulation of alpha1b-ARs increases DA-mediated locomotor response, but also suggest a significant implication of postsynaptic alpha2-ARs. Involvement of these adrenergic receptor mechanisms may be exploited in the therapy of Parkinson's disease.
Villégier
Anne-Sophie
AS
Inserm U. 114, Collège de France, 75231 Paris, France.
Drouin
Candice
C
Bizot
Jean-Charles
JC
Marien
Marc
M
Glowinski
Jacques
J
Colpaërt
Francis
F
Tassin
Jean-Pol
JP
D018663:Adrenergic Agents / Q000633:toxicity; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001578:Benzopyrans / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000503:physiopathology; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016627:Oxidopamine / Q000633:toxicity; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D013997:Time Factors
C547717:Adra1b protein, mouse; D018663:Adrenergic Agents; D001578:Benzopyrans; D018491:Dopamine Agonists; D007093:Imidazoles; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; C039737:1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine; D016627:Oxidopamine; D000661:Amphetamine; C451723:dexefaroxan; D004298:Dopamine