Autoradiographical and behavioural effects of a chronic infusion of antisense to the α 2D ‐adrenoceptor in the rat

The aims of this study were, firstly to use receptor autoradiography to investigate the effect of antisense oligonucleotides to the α 2D ‐adrenoceptor on receptor binding and, secondly to measure behavioural and physiological parameters to determine whether the chronic antisense infusion had any effect on α 2 ‐adrenoceptor function in vivo . A 3 day infusion of antisense to the α 2D ‐adrenoceptor significantly reduced specific [ 3 H]‐RX821002 binding in the septum (20–30%) and anterior hypothalamic area (20–30%). β‐Adrenoceptor expression was unaffected in those brain areas examined, indicating the antisense knockdown was specific to the α 2 ‐adrenoceptors. 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. 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. In conclusion, antisense has been shown to selectively knockdown α 2 ‐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.British Journal of Pharmacology (1999) 128 , 515–522; doi: 10.1038/sj.bjp.0702823