ORGANIC CATION TRANSPORTER 3: A NOVEL MOLECULAR TARGET TO TREAT AMPHETAMINE ABUSE

Medications to help treat addiction exist for many major drugs of abuse, but not for psychostimulants, such asamphetamine, and its congeners. They are also lacking for increasingly used synthetic drugs designed to mimicthe actions of known psychostimulants. Both known and new psychoactive substances continue to pose a majorand increasing public health threat. To develop effective treatments, the mechanisms by which these stimulantsproduce their abuse-related effects need to be fully understood. Many stimulants interact with the dopamine (DA)transporter (DAT), which is thought to mediate their abuse-related effects. However, strategies targeting DAT haveyielded little to no benefit in the treatment of psychostimulant addiction, raising the possibility that these stimulantshave significant actions elsewhere to modulate dopaminergic neurotransmission. Consistent with this, a rapidlygrowing literature supports a prominent role for organic cation transporter 3 (OCT3) in regulating dopaminergicneurotransmission. Our preliminary data support this idea, showing that an OCT3 inhibitor, decynium-22 (D22),inhibits amphetamine-evoked hyperlocomotion and DA release in vivo, effects that were lost in constitutive OCT3knockout (KO, -/-) mice. Furthermore, amphetamine-induced substrate efflux could be inhibited by D22 in a mannerindependent of cocaine-sensitive transporters. These data raise the exciting possibility that OCT3 is a criticalplayer in the actions of amphetamine, which may help to explain why DAT-based therapeutics have not beensuccessful in treating amphetamine abuse. Our intention is to submit an R01 to build on these exciting findings,but before doing so, additional preliminary data are needed. First, we need to determine if potential compensationin constitutive OCT3-/- mice accounts for the lack of difference in their locomotor and DA releasing responses toamphetamine compared with wild-type (OCT3+/+) mice. To do this, OCT3 floxed mice have recently beengenerated at the University of Texas Health Science Center at San Antonio (UTHSCSA). We will cross these micewith a commercially available Cre line to generate a tamoxifen inducible global OCT3 KO. In this way, we cantemporally control OCT3 KO, and in future studies, use different Cre lines to create brain region specific inducibleKOs. We will use these mice to test the hypothesis that amphetamine-induced DA release, locomotion, andstereotypy will be attenuated in inducible OCT3 KO mice compared with control mice. Moreover, if OCT3 is to bea useful target in the treatment of amphetamine abuse, we need to demonstrate that OCT3 is important in mediatingthe rewarding and reinforcing effects of amphetamine. To this end, we will use conditioned place preference (CPP),and self-administration in mice to test the hypotheses that the rewarding and reinforcing effects of amphetamineare less in inducible OCT3 KO mice than control mice, and that D22 will attenuate development of CPP toamphetamine and amphetamine self-administration in control mice, but not in the inducible OCT3 KO. Theseproposed studies will provide data essential for an R01 submission, and will begin to fill crucial knowledge gapsabout the role of OCT3 in abuse-related effects of amphetamine.