D-amphetamine and L-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the alpha2C-adrenergic receptor subtype.
Three human and mouse genes encoding alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) have been cloned. The alpha2C-adrenoceptor is the most abundant alpha2-adrenoceptor subtype in the striatum and modulates metabolism of both dopamine and serotonin. To investigate the possible involvement of the alpha2C-adrenoceptor subtype in behaviours regulated by dopamine and serotonin, two strains of genetically-engineered mice were examined. One had a targeted inactivation of the alpha2C-adrenoceptor gene, and the other had tissue-specific over-expression of alpha2C-adrenoceptors. The locomotor activity of the mice was evaluated after stimulation with D-amphetamine, and the behavioural serotonin syndrome and head twitches were investigated after L-5-hydroxytryptophan treatment. In addition, the effects of D-amphetamine and L-5-hydroxytryptophan were studied after pretreatment with dexmedetomidine, a subtype-nonselective alpha2-adrenoceptor agonist. The lack of alpha2C-adrenoceptor expression increased and the over-expression of alpha2C-adrenoceptors decreased the response to D-amphetamine stimulation. The effect of alpha2C-adrenoceptor gene inactivation was more prominent in D-amphetamine-treated males than in females. Dexmedetomidine inhibited D-amphetamine-induced hyperlocomotion and the L-5-hydroxytryptophan-induced serotonin syndrome, but the inhibition was attenuated in mice lacking alpha2C-adrenoceptors. However, the head twitches induced by L-5-hydroxytryptophan were effectively inhibited by dexmedetomidine in all studied mice, which suggests that alpha2A-adrenoceptors mediate the inhibition of the head twitch response. The results lend further support to the proposed existence of functionally distinct alpha2-adrenoceptor subtypes that can serve as new and specific therapeutic targets in various neuropsychiatric diseases.
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.
J
J
Sallinen
A
A
Haapalinna
T
T
Viitamaa
B K
BK
Kobilka
M
M
Scheinin
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D003433:Crosses, Genetic; D003913:Dextroamphetamine / Q000494:pharmacology*; D005260:Female; D018390:Gene Targeting; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020926:Medetomidine; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012727:Sex Characteristics; D019956:Stereotypic Movement Disorder / Q000235:genetics / Q000503:physiopathology; D013577:Syndrome
C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D012701:Serotonin; D006916:5-Hydroxytryptophan; D020926:Medetomidine; D003913:Dextroamphetamine