EXPLORING A ROLE FOR ORGANIC TRANSPORTER 3 IN THE MECHANISM OF ACTION OF DRUGS OF ABUSE

Co-abuse of cocaine and alcohol is one of the most common, and dangerous drug pairings, as evidenced bytheir concurrent use being a major cause for emergency hospitalization. Thus, this drug combination is notonly a serious health threat to the individual user, but a major public health burden. Currently, there are noeffective treatments for addiction to cocaine and ethanol, underscoring the vital need to understand themechanistic basis of this highly addictive drug pairing in order to discover new targets for therapeuticintervention. It is well-known that cocaine and ethanol each increase extracellular levels of dopamine (DA),serotonin (5-HT), and norepinephrine (NE), biogenic amine neurotransmitters that are strongly linked to therewarding properties of drugs. Cocaine does this by inhibiting the high-affinity, low-capacity transporters forthese neurotransmitters, DAT, SERT, and NET, respectively. However, the mechanisms by which ethanoldoes so are unclear. It is known that ethanol inhibits uptake of DA, 5-HT, and NE, however our published data,together with literature evidence, show this inhibition to be DAT-, SERT-, and NET-independent. Organiccation transporter 3 (OCT3) is a low-affinity, high-capacity transporter for DA, 5-HT, and NE, and is emergingas an important player in regulation of biogenic amine homeostasis. Interestingly, recent reports show thatcorticosterone, a blocker of OCT3, enhances cocaine-induced DA signaling and potentiates reinstatement ofcocaine seeking via an OCT3-dependent mechanism. Moreover, we found that OCT3 expression is increasedin mice lacking SERT (-/-), and that ethanol, and corticosterone, both inhibit 5-HT clearance in SERT-/- mice toa much greater extent than in their wild-type counterpart. Together, these findings raise the possibility thatethanol may interact with OCT3 to inhibit uptake of biogenic amines, thereby increasing the addictiveproperties of cocaine, and propagating the concurrent use of these drugs. To this end, the studies proposed inthis exploratory R21 will test the overarching hypothesis that one mechanism by which ethanol increasesextracellular DA, 5-HT and NE is by inhibition of their uptake via OCT3, and that this inhibition enhances theincrease in biogenic amines produced by cocaine, which blocks their uptake via DAT, SERT and NET.Importantly, we will determine the OCT3-dependency of ethanol?s ability to enhance the rewarding propertiesof cocaine. We will use pharmacological and genetic approaches, combined with in vivo neurochemistry, andbehavioral assays relevant for reward. Regardless of the outcome of these exploratory studies, results will fillfundamental knowledge gaps about the mechanism(s) through which ethanol inhibits uptake of biogenicamines and enhances rewarding effects of cocaine. Results from these studies will improve our understandingof mechanisms that make the abuse potential of concurrent alcohol and cocaine use so high. Importantly,these studies will form an essential platform on which to base larger scale studies probing novel moleculartargets, putatively OCT3, for medications to treat abuse of alcohol and cocaine.