2001 ), were obtained from an in house colony at the University of Texas Health Science Center at San Antonio (UTHSCSA). Wild-type mice (OCT3+/+), or OCT3 knockout (KO, OCT3−/−) mice, bred on a C57BL/6 background (originally developed by Zwart et al. Our findings encourage further investigation of OCT3 in the actions of amphetamine and as a potential target for the development of novel therapeutics to treat amphetamine addiction. Here we report the novel finding that a substantial component of amphetamine-evoked substrate release (i.e., DA and 1-methyl-4-phenylpyridinium (MPP +)) is OCT3-dependent and cocaine (a blocker of DAT, NET, and SERT) insensitive. To our knowledge, no studies have investigated this possibility. However, it is conceivable that amphetamine, once gaining access to the intracellular compartment via its transport through DAT (or other mechanism(s)), may promote neurotransmitter efflux via OCT3. A previous study reported that amphetamine is not a substrate for OCT3 and, therefore, concluded that amphetamine is unlikely to inhibit monoamine uptake via OCT3. Once inside the nerve terminal, amphetamine acts to increase cytosolic concentrations of DA via its activity at the vesicular monoamine transporter 2 (VMAT2), leading to reverse transport (or efflux) of DA into the extracellular space via DAT. It is well documented that amphetamine is a substrate for DAT, and therefore, a competitive inhibitor of DA uptake. However, whether OCT3 contributes to the actions of amphetamine is unclear. Taken together, these findings raise the possibility that OCT3 may be important for the actions of amphetamine-type psychostimulants that cause release of monoamines. OCT3 is distributed widely in brain, and is richly expressed in brain regions important in the rewarding effects of amphetamine, including striatum and nucleus accumbens. Moreover, gene variants of OCT3 have been linked to methamphetamine abuse. It is also a bidirectional transporter, and there is evidence that OCT3 may play an important role in neurotransmitter efflux. OCT3 is a low-affinity (“uptake-2”) transporter with a high capacity to non-selectively transport monoamines. However, a rapidly growing literature supports a prominent role for organic cation transporter 3 (OCT3) in the regulation of monoaminergic neurotransmission. These transporters are thought to be the main players regulating clearance of these monoamines from extracellular fluid. It is well known that amphetamine, as well as many other stimulants, interact with high-affinity transporters for monoamine neurotransmitters, the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters (DAT, NET, and SERT, respectively). To develop effective treatments, the mechanisms by which these stimulants produce their abuse-related effects need to be fully understood.
Currently there are no medications to treat psychostimulant addiction, including addiction to amphetamine. Our findings support OCT3 as a new player in the actions of amphetamine and encourage investigation of this transporter as a potential new target for the treatment of psychostimulant abuse.Īmphetamine-type drugs are among the most commonly abused in the world, afflicting an estimated 56 million people, creating a major public health burden, and underscoring a vital need to find effective treatments. Then, applying a combination of in vivo, ex vivo, and in vitro approaches, we revealed that a substantial component of amphetamine’s actions is OCT3-dependent and cocaine insensitive. We found that OCT3 is expressed in dopamine neurons.
Organic cation transporter 3 (OCT3) has recently been found to play an important role in regulating monoamine signaling. It is well known that amphetamine exerts its actions by targeting high-affinity transporters for monoamines, in particular the cocaine-sensitive dopamine transporter. To develop effective treatments, the mechanisms by which amphetamine produces its abuse-related effects need to be fully understood. Amphetamine abuse is a major public health concern for which there is currently no effective treatment.
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