Antisense Knockdown of the Shaker-like Kv1.1 Gene Abolishes the Central Stimulatory Effects of Amphetamines in Mice and Rats

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 transporters and/or intravesicular alkalinization is assumed to have a role in AMPH-induced exocytosis. However, the action mechanism of this compound has not yet been completely clarified. Recent evidence on the action of AMPHs indicates potassium channel-blocking properties in peripheral tissues. We investigated the possible involvement of a Shaker-like Kv1.1 channel subtype in the central effects of AMPH, using an antisense oligodeoxyribonucleotide (aODN) that specifically and reversibly inhibits the expression of these channels in the brain. The effect of aODN pretreatments was studied by evaluating the modification of behavioral effects induced in mice through the intracerebroventricular administration of AMPH, COC, or other compounds. The aODN in mice almost completely blocked the stimulatory effects of AMPH and other releasers but was ineffective in reducing the central activity of COC. In aODN-pretreated rats a strong reduction of the AMPH, but not of the COC-stimulated DA efflux from nucleus accumbens was observed. Our results suggest that the stimulant effects of AMPH and chemically related compounds, but not COC, require the presence of functionally active Kv1.1 channels in the brain.

Dopamine and Aging: Intersecting Facets

“…Mouse Kv1.1 mediates amphetamine-induced hyperactivity and hypophagia [141] and Kv1.6 modulates DA release [142]. K ?…”

Modifier Selection by Transgenes: The Case of Growth Hormone Transgenesis and Hyperactive Circling Mice

“…channel blocker improves learning, including object recognition (Stackman et al 2002). Mouse Kv1.1 contributes to amphetamine-induced hyperactivity and hypophagia (Ghelardini et al 2003;Prisino et al 2006) and Kv1.6 modulates DA release (Raimondi et al 2007). SRIF reduces epileptic seizures via induction of K ?…”

The serotonin 5-HT2Creceptor and the non-addictive nature of classic hallucinogens

“…Moreover, cocaine's inhibitory effects on MSN activity are specific to the NAc shell, with cocaine actually increasing MSN firing in the NAc core (Kourrich and Thomas, 2009; Kourrich et al, 2013; Mu et al, 2010). Finally, overexpression of a hyperpolarizing, inwardly-rectifying potassium channel (Kir2.1) in NAc MSN enhances psychomotor effects of cocaine (Dong et al, 2006), whereas knockdown of the Kv1.1 channel blocks behavioral effects of another psychostimulant, amphetamine (Ghelardini et al, 2003). Thus, there is a strong argument that some psychostimulant effects are mediated by alterations in intrinsic plasticity in NAc shell MSN, driven by Kv1.x currents that decrease excitability (Kourrich et al, 2015), and CH-mediated 5-HT 2C receptor activation may offset these effects (Figure 2).…”