Antisense knockdown of theshaker-like KvI.I gene abolishes the central stimulatory effects of amphetamines in mice andrats

Abstract

Amphetamine (AMPH) is an indirect sympathomimetic compound classified as a substrate-type releaser that distinguishes it from other stimulants that act as uptake 1 blockers, such as cocaine (COC). In mammals, AMPH elicits central stimulation, hypermotility, anorexia, analgesia and analeptic activity, mainly through the increase of extracellular brain dopamine (DA). The inversion of vesicular transportersand/or intravesicular alkalinization is assumed to have a role in AMPH-induced exocytosis. However, the action mechanism of thiscompound has not yet been completely clarified. Recent evidence on the action of AMPHs indicates potassium channel-blockingproperties in peripheraltissues. We investigated the possible involvement of aShaker-likeKvi.i channelsubtype in the centraleffects ofAMPH, using an antisense oligodeoxyribonucleotide (aODN) that specifically and reversibly inhibits the expression of these channels inthe brain. The effect of aODN pretreatments was studied by evaluating the modification of behavioral effects induced in mice throughthe intracerebroventricular administration of AMPH, COC, or other compounds. The aODN in mice almost completely blocked thestimulatory effects of AMPH and other releasers but was ineffective in reducing the central activity of COC. In aODN-pretreated rats astrong reduction of the AMPH, but not of the COC-stimulated DA efflux from nucleus accumbens was observed. Our results suggestthat the stimulant effects of AMPH and chemically related compounds, but not COC, require the presence of functionally active Kvl.lchannels in the brain. © 2003 Nature Publishing Group.