The dopamine transporter expression level differentially affects responses to cocaine and amphetamine

Although both cocaine and amphetamine mainly target the dopamine transporter (DAT) and cause psychomotor effects, they have very different mechanisms of actions. The authors examined whether responses to cocaine and amphetamine were affected differentially by changes in DAT expression levels using transgenic mice with different DAT expression levels. In the constitutive DAT knockdown mice, reduced DAT expression enhanced cocaine's locomotor stimulatory effects and at the same time diminished amphetamine's locomotor stimulatory effects. Similar effects were observed in the inducible DAT knockdown mice, ruling out the contribution of developmental compensations in DAT knockdown mice. Extracellular dopamine levels in response to psychostimulants were assessed by in vivo microdialysis. Whereas amphetamine-induced increase in extracellular dopamine was drastically diminished in constitutive DAT knockdown mice, cocaine-induced increase in extracellular dopamine had a faster onset in knockdown mice compared with wild-type controls. Postsynaptically, D1 agonist-stimulated c-fos expression was significantly attenuated in constitutive DAT knockdown mice compared with wild-type controls. The authors propose that responses to cocaine and amphetamine depend on psychostimulant drug type, drug dose, as well as DAT expression level. DAT expression level affects presynaptic responses to psychostimulants directly and postsynaptic responses to psychostimulants indirectly via changes in receptor signaling. These data imply that individual differences in DAT expression (either genetically or pharmacologically induced) may affect susceptibility to addiction of different types of psychostimulants.