In vivo amphetamine action is contingent on αCaMKII

Neuropsychopharmacology. 2014 Oct;39(11):2681-93. doi: 10.1038/npp.2014.124. Epub 2014 May 29.


Addiction to psychostimulants (ie, amphetamines and cocaine) imposes a major socioeconomic burden. Prevention and treatment represent unmet medical needs, which may be addressed, if the mechanisms underlying psychostimulant action are understood. Cocaine acts as a blocker at the transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), but amphetamines are substrates that do not only block the uptake of monoamines but also induce substrate efflux by promoting reverse transport. Reverse transport has been a focus of research for decades but its mechanistic basis still remains enigmatic. Recently, transporter-interacting proteins were found to regulate amphetamine-triggered reverse transport: calmodulin kinase IIα (αCaMKII) is a prominent example, because it binds the carboxyl terminus of DAT, phosphorylates its amino terminus, and supports amphetamine-induced substrate efflux in vitro. Here, we investigated whether, in vivo, the action of amphetamine was contingent on the presence of αCaMKII by recording the behavioral and neurochemical effects of amphetamine. Measurement of dopamine efflux in the dorsal striatum by microdialysis revealed that amphetamine induced less dopamine efflux in mice lacking αCaMKII. Consistent with this observation, the acute locomotor responses to amphetamine were also significantly blunted in αCaMKII-deficient mice. In addition, while the rewarding properties of amphetamine were preserved in αCaMKII-deficient mice, their behavioral sensitization to amphetamine was markedly reduced. Our findings demonstrate that amphetamine requires the presence of αCaMKII to elicit a full-fledged effect on DAT in vivo: αCaMKII does not only support acute amphetamine-induced dopamine efflux but is also important in shaping the chronic response to amphetamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Central Nervous System Stimulants / pharmacology*
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dextroamphetamine / pharmacology*
  • Disks Large Homolog 4 Protein
  • Dopamine / metabolism
  • Guanylate Kinases / metabolism
  • Hyperkinesis / chemically induced
  • Hyperkinesis / metabolism
  • Locomotion / drug effects
  • Locomotion / physiology
  • Male
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Dopamine / metabolism
  • Reward
  • Space Perception / drug effects
  • Space Perception / physiology


  • Central Nervous System Stimulants
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Receptors, Dopamine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2a protein, mouse
  • Guanylate Kinases
  • Dextroamphetamine
  • Dopamine