This project aims to elucidate the mechanisms by which selective serotonin reuptake inhibitors (SSRI's), alter DOM induced stimulus control. SSRI's, as a class, are known to interact with CYP 450 isoforms. In order to study the pharmacodynamic mechanism of potentiation, GC-MS will be used to identify SSRI's that do not alter DOM brain levels. Drug discrimination studies will indicate if SSRI's can both mimic and potentiate the stimulus properties of DOM. The stimulus effects of DOM are believed to be mediated by 5-HT2A and modulated by 5-HT2C serotonergic receptors. The affinity of SSRI's for these receptors will be elucidated by receptor binding studies. SSRI's will be injected into rat cerebral ventricles to determine if a metabolite or the parent SSRI is altering the stimulus properties of DOM. Affinity of DOM for the 5-HT transporter as well as the effect of SSRI's on uptake of DOM in rat brain synaptosomes will be assessed. The inhibition of DOM uptake by the 5-HT transporter in the presence of SSR1's would indicate that the observed potentiation is a result of this inhibition and not a direct effect of SSRI's at the 5-HT2A and 5-HT2C receptors.
