1. ¹Department of Preclinical and Clinical Pharmacology, University of Florence Viale Pieraccini, Florence, Italy
2. ²Servizio di Genetica Medica, Ospedale Casa Sollievo della Sofferenza, Foggia, Italy
3. ³Department of Pharmacology, University of La Sapienza, Rome, Italy

Correspondence: R. Pirisino, Dipartimento di Farmacologia Preclinica e Clinica, Viale Pieraccini 6, 50134 Florence, Italy. Tel: +39 055 4271209; Fax: +39 055 4271280; E-mail: renato.pirisino@unifi.it

Received 20 September 2002; Revised 19 November 2002; Accepted 23 December 2002; Published online 9 April 2003.

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.