Neuroscientists have devised inventive procedures to investigate drugs of abuse. One procedure, the self administration model, is a useful technique to examine mechanisms and treatment of drug self administration. The present proposal will investigate issues related to amphetamine self-administration in rats. Alpha-lobeline is a tobacco alkaloid derived from an Indian tobacco plant. Lobeline (LOB) has a similar neuropharmacological profile as amphetamine: both are potent inhibitors of the vesicular monoamine transporter (VMAT2). However, rather than evoking dopamine efflux like that of amphetamine, lobeline results in the release DOPAC, a metabolite of dopamine which is not reinforcing. Targeting VMAT2 may be a promising approach in the treatment of amphetamine abuse, as mice that lack VMAT2 do not exhibit the effects of amphetamine reinforcement as measured through conditioned place preference. The present experiments will examine whether pretreatment of LOB will attenuate amphetamine self-administration in rats. Since LOB has a high affinity for nicotine receptors, structural analogs of LOB which are devoid of nicotinic receptor interaction, but which inhibit dopamine uptake, have been synthesized and are available for study. The present research will determine whether these analogs potently inhibit dopamine uptake at VMAT2 by using a dopamine uptake assay. The LOB analogs ability to decrease amphetamine self-administration, in comparison to LOB, will also be investigated. It is hypothesized that pretreatment of LOB and LOB analogs will reduce the cytosolic pool of dopamine available for release by subsequent administration of amphetamine, and thereby reduce amphetamine self-administration.
