Dopamine Transporter--Structure/function Studies Of Transporter And Promoters

National Institute On Drug Abuse

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Abstract

The dopamine transporter (DAT) has been a principal brain receptor site that has been correlated with the rewarding and euphoric properties of cocaine. MNB scientists cloned the DAT cDNA and gene, and found that deletion of both DAT and SERT are required to eliminate cocaine conditioned place preferences in mice. DAT is required for the actions of each of the current dopamine-selective toxins that produce the best models of Parkinsons disease. Analyses of the relationships between DAT expression and a number of pharmacological endpoints continued through this year, with emphasis on relationships with serotonin systems defined through the serotonin receptor subtypes. During this year, we reported detailed studies of effects of DAT deletion by itself or in combination with deletion of other sites on methamphetamine-induced locomotor activity and sensitization, methamphetamine-induced hyperthermia and lethal toxicity, Expression of pharmacologically-defined substates of DRD2 receptors. Effects of VMAT2 deletion on DAT expression were also reported. Work continued on double and ttriple knockout mice with alterations of DAT, 5HT1A and 5HT1B receptors. These insights should continue to help in identification of relationships between DAT gene expression and regulation, human individual differences in DAT levels of expression and a number of interesting features of stimulant pharmacology.