Date of Graduation
School of Pharmacy
Rae R Matsumoto
Cocaine is a powerful psychostimulant that is highly abused by 1.9 million people in the United States. It accounts for more emergency department visits than any other illicit drug. Even with the high rate of cocaine abuse, no FDA approved pharmacological treatments exist. Many attempts at finding a pharmacotherapy for cocaine abuse and addiction have been made, but proven unsuccessful. Cocaine is known to bind sigma receptors at physiologically relevant concentrations, deeming them potential targets for cocaine pharmacotherapies and helping to elucidate the actions of cocaine. Two subtypes of sigma receptors have been described, sigma-1 and sigma-2. Minimal information is known about the function of sigma-2 receptors in relationship to cocaine-induced effects. This is attributed to the inability to clone the subtype and the absence of highly selective ligands. In the present study four novel compounds (CM699, CM398, CM777 and CM775) were found through radioligand binding assays, in rat brain homogenates and liver P2 membrane (with the exception of opioid receptors in CHO cells), to possess substantially high affinities for sigma-2 receptors versus sigma-1 and non-sigma receptor sites. Behavioral studies, performed in male, Swiss-Webster mice, showed that pretreatment of CM398, CM777 and CM775 to a convulsive or stimulatory locomotor dose of cocaine led to significant attenuation of cocaine-induced convulsions and hyperactivity. Additionally, administration of pretreatment doses of CM699 to non-convulsive doses of cocaine led to the occurrence or exacerbation of cocaine-induced convulsions. The availability of these sigma-2 receptor preferring compounds provide pharmacological tools to elucidate the relationship between sigma-2 receptors and cocaine effects. Furthermore, these ligands present promising putative pharmacological treatments for cocaine abuse and addiction.
Noorbakhsh, Bahar, "Pharmacological Characterization of Sigma-2 Preferring Compounds: Implications in Cocaine-induced Behaviors" (2012). Graduate Theses, Dissertations, and Problem Reports. 4905.