Acetylcholine encodes long-lasting presynaptic plasticity at glutamatergic synapses in the dorsal striatum after repeated amphetamine exposure

J Neurosci. 2013 Jun 19;33(25):10405-26. doi: 10.1523/JNEUROSCI.0014-13.2013.


Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted >50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / physiology*
  • Adrenergic Uptake Inhibitors / pharmacology*
  • Amphetamine / pharmacology*
  • Animals
  • Choline O-Acetyltransferase / genetics
  • Choline O-Acetyltransferase / physiology
  • Dependovirus / genetics
  • Electrophysiological Phenomena
  • Excitatory Postsynaptic Potentials / genetics
  • Excitatory Postsynaptic Potentials / physiology
  • Genetic Vectors
  • Glutamic Acid / physiology*
  • Interneurons / physiology
  • Locomotion / physiology
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / physiology
  • Neostriatum / cytology
  • Neostriatum / drug effects
  • Neostriatum / physiology*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Postural Balance / physiology
  • Receptors, Dopamine D1 / physiology
  • Receptors, Dopamine D2 / physiology
  • Receptors, Presynaptic / drug effects
  • Receptors, Presynaptic / physiology*
  • Synapses / drug effects
  • Synapses / physiology*


  • Adrenergic Uptake Inhibitors
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Presynaptic
  • Glutamic Acid
  • Amphetamine
  • Choline O-Acetyltransferase
  • Acetylcholine