Evidence for sequence-dependent and reversible nonspecific effects of PS-capped antisense treatment after intracerebral administration

Phosphorothioate (PS)-capped phosphodiester (PE) oligodeoxynucleotides (ODNs) were used to determine whether the dopamine-dependent locomotor-stimulant effect of nicotine is mediated via a4 subunit-containing nicotinic receptors. To this end, rats received direct intraventral tegmental area infusion of a4 antisense via osmotic minipump, and their locomotor response to nicotine (0.2 mg/kg, s.c.) was tested. Eight antisense ODNs were screened, but only one inhibited nicotine-induced locomotion. This inhibition was reversible and selective, insofar as basal (saline) activity was unaffected, and a mismatch ODN was without effect. However, antisense treatment also caused sequence-dependent toxic effects, including neuronal degeneration in the ventral tegmental area, dopaminergic denervation, and weight loss. We conclude that despite previous reports, PS-capped PE-ODNs can cause severe neurotoxicity on chronic infusion into brain tissue. Moreover, sequence dependence and temporal reversibility, two generally accepted criteria of antisense action, may sometimes reflect the occurrence of toxic effects and resultant functional compensation.