The alpha2-adrenoceptor antagonist atipamezole reduces the development and expression of d-amphetamine-induced behavioural sensitization.
The possible effect of atipamezole, a potent and specific alpha(2)-adrenoceptor antagonist, on the development and expression of d-amphetamine-induced behavioural sensitization was evaluated in mice. Male (C57Bl/6J) mice were given daily doses of d-amphetamine (2 mg/kg). In addition, groups of mice received injections of atipamezole (0.3 or 1 mg/kg) 20 min before d-amphetamine or vehicle administration. Idazoxan (1 mg/kg) was used in some experiments to extend the results to other alpha(2)-adrenoceptor antagonists. Challenge doses of d-amphetamine were administered to the mice on days 7-9 to evaluate the effects of alpha(2)-adrenoceptor antagonists on the d-amphetamine sensitization, evidenced by increased locomotor activation. Mice treated repeatedly with d-amphetamine developed strong locomotor sensitization that was reduced by pretreatment with alpha(2)-adrenoceptor antagonists. Acute atipamezole at both doses attenuated the expression of d-amphetamine-induced sensitization. Atipamezole at 1 mg/kg alone had no effect on locomotor activity, but the lower dose (0.3 mg/kg) increased locomotor activity after repeated administration. These results indicate that alpha(2)-adrenoceptor antagonists modulate the actions of d-amphetamine in a manner not explicable by their enhancing actions on noradrenaline and dopamine release, and may thus provide a novel approach to the treatment of motor complications caused by dopaminergic agents, such as dyskinesias, and perhaps also drug dependence.
Juhila
Juuso
J
Department of Pharmacology and Clinical Pharmacology, University of Turku, 20520 Turku, Finland.
Haapalinna
Antti
A
Sirviö
Jouni
J
Sallinen
Jukka
J
Honkanen
Aapo
A
Korpi
Esa R
ER
Scheinin
Mika
M
D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects
D058669:Adrenergic alpha-2 Receptor Antagonists; D007093:Imidazoles; C050701:atipamezole; D003913:Dextroamphetamine; D004298:Dopamine; D019329:Idazoxan