alpha(2A)-Adrenoceptors regulate d-amphetamine-induced hyperactivity and behavioural sensitization in mice.
Stimulants, such as d-amphetamine, enhance the release of dopamine in the central nervous system (CNS) and induce locomotor activation in mice. When amphetamine is administered repeatedly, the locomotor activation is progressively increased. This behavioural sensitization may be associated with the development of drug craving, addiction and dependence. Also noradrenergic mechanisms participate in the mediation of the effects of psychostimulants. In this study we show that mice lacking the alpha(2)-adrenoceptor subtype A (alpha(2A)-AR knock-out (KO) on C57Bl/6J background) are supersensitive to the acute locomotor effects of d-amphetamine (5 mg/kg) in a novel environment compared to wild-type (WT) control mice. When both genotypes were treated repeatedly with d-amphetamine (2 mg/kg) they developed locomotor hyperactivation (sensitization), but its amplitude was lower in alpha(2A)-AR KO mice. Development of hyperactivation was reduced in both genotypes by pretreatment with the selective alpha(2)-adrenoceptor antagonist, atipamezole (1 mg/kg). Acute atipamezole also attenuated the expression of d-amphetamine-induced behavioural sensitization especially in WT mice. Interestingly, alpha(2A)-AR KO mice failed to exhibit persistent sensitization after 2 weeks of abstinence from repeated d-amphetamine. Rewarding properties of d-amphetamine, measured by conditioned place preference, were similar in both genotypes. These findings indicate that d-amphetamine-induced acute and sensitized locomotor effects are controlled by alpha(2)-adrenoceptors. Drugs antagonizing the alpha(2A)-adrenoceptor subtype may provide a novel approach for reducing drug sensitization and motor complications caused by dopaminergic agents.
Department of Pharmacology and Clinical Pharmacology, University of Turku, FI-20520 Turku, Finland. juuso.juhila@helsinki.fi
Juuso
J
Juhila
Aapo
A
Honkanen
Jukka
J
Sallinen
Antti
A
Haapalinna
Esa R
ER
Korpi
Mika
M
Scheinin
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003213:Conditioning, Psychological; D003913:Dextroamphetamine / Q000494:pharmacology*; D005838:Genotype; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*
C547769:Adra2a protein, mouse; D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; C050701:atipamezole; D003913:Dextroamphetamine