TRANSGENIC MODELS OF DOPAMINE, OPIOIDS AND DRUG ABUSE

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Psychostimulant drugs bind to specific sites on the dopamine transporter and block dopamine reuptake. This increases the amount of dopamine available for binding to post-synaptic receptors and affecting molecular and cellular events. The intermediate lobe of the pituitary has all the necessary elements for investigating interactions between drugs of abuse and the dopaminergic system. These include a well characterized dopaminergic innervation, a dopamine reuptake mechanism, a high density of dopamine receptors and a constitutively expressed target gene, the proopiomelanocortin (POMC), which is suppressed by dopamine. We will use transgenic mice with massive intermediate lobe tumors, tissue slices and a melanotroph cell line to: a) study the regulation of POMC gene expression and peptide release by dopamine ligands and selected drugs iii vitro, and b) investigate the effects of dopamine ligands and drugs of abuse on POMC gene expression and peptide release in transgenic mice bearing intermediate lobe tumors. These studies will provide cellular and animal models with clearly defined and measurable endpoints to evaluate perturbation of dopaminergic neurotransmission by psychostimulant drugs.