Autoradiographical and behavioural effects of a chronic infusion of antisense to the alpha2D-adrenoceptor in the rat.
1. The aims of this study were, firstly to use receptor autoradiography to investigate the effect of antisense oligonucleotides to the alpha2D-adrenoceptor on receptor binding and, secondly to measure behavioural and physiological parameters to determine whether the chronic antisense infusion had any effect on alpha2-adrenoceptor function in vivo. 2. A 3 day infusion of antisense to the alpha2D-adrenoceptor significantly reduced specific [3H]-RX821002 binding in the septum (20 - 30%) and anterior hypothalamic area (20 - 30%). beta-Adrenoceptor expression was unaffected in those brain areas examined, indicating the antisense knockdown was specific to the alpha2-adrenoceptors. 3. On the second day of the infusion, the hypothermic response to UK 14,304 was significantly attenuated in the antisense-treated group compared with both vehicle and mismatch controls. The effect was fully reversible and a similar decrease in body temperature was observed in all the treatment groups 4 days after the end of infusion. 4. During the second day of the infusion, the effects of UK 14,304 on behaviour were reduced in the antisense-treated rats, but were not significantly lower than those of the vehicle and mismatch, UK 14, 304 controls. These trends were not observed 4 days after the end of the infusion. 5. In conclusion, antisense has been shown to selectively knockdown alpha2-adrenoceptor expression in specific brain areas. The consequence of this knockdown is a significant attenuation of UK 14,304-induced hypothermia and a reduction in its sedative actions. These changes were fully reversed 4 days after the end of the infusion.
Robinson
E S
ES
Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK.
Nutt
D J
DJ
Hall
L
L
Jackson
H C
HC
Hudson
A L
AL
D000818:Animals; D001345:Autoradiography; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000068438:Brimonidine Tartrate; D019329:Idazoxan / Q000031:analogs & derivatives / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D011680:Pupil / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D016372:RNA, Antisense / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics* / Q000378:metabolism
D011810:Quinoxalines; D016372:RNA, Antisense; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; C058525:2-methoxyidazoxan; D019329:Idazoxan