Cocaine-induced sensitization is associated with altered dynamics of transcriptional responses of the dopamine transporter, tyrosine hydroxylase, and dopamine D2 receptors in C57Bl/6J mice

Psychopharmacology (Berl). 2007 Sep;193(4):567-78. doi: 10.1007/s00213-007-0790-3. Epub 2007 May 17.


Rationale: Behavioural sensitization is a long lasting phenomenon that has been proposed to be involved in drug addiction. Although the expression of cocaine-induced sensitization has been associated with the activity of the mesencephalic dopaminergic neurons, little is known about the transcriptional adaptations of these neurons to a new challenge with cocaine long after cessation of repeated exposure to the drug.

Objectives: We studied the time course of the mRNA levels of three main regulatory elements of dopaminergic transmission after a challenge with cocaine (15 mg/kg) that followed 21 days of withdrawal from a cocaine pretreatment (20 mg/kg, ip, every 2 days for 21 days) in C57Bl/6J mice.

Materials and methods: Mice were placed 45 min in activity chambers and were killed 45 min, 2 h or 24 h after the challenge injection. Dopamine transporter (DAT), D2 auto-receptor (D2) and tyrosine hydroxylase (TH) mRNA levels were assessed by in situ hybridization in the ventral tegmental area and the substantia nigra compacta.

Results: As compared to vehicle challenge, cocaine challenge in vehicle pretreated mice induced a rapid increase (+208%) in DAT mRNA (45 min) followed by a delayed decrease (-70%) (24 h), while TH and D2 mRNA were both increased (+45%) 24 h after the challenge. In cocaine pretreated mice, cocaine-induced short-term increase and long-term decrease in DAT mRNA levels were amplified (+328%) and reduced (-40%), respectively.

Conclusions: Repeated exposure to cocaine alters the transcriptional response of DA neurons to a new cocaine challenge long after cessation of repeated exposure to the drug. They point to the DAT mRNA as a major responsive element to a new presentation of cocaine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoreceptors
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • RNA, Messenger / drug effects*
  • RNA, Messenger / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Substantia Nigra / metabolism
  • Transcription, Genetic / drug effects*
  • Tyrosine 3-Monooxygenase / drug effects
  • Tyrosine 3-Monooxygenase / metabolism
  • Ventral Tegmental Area / metabolism


  • Autoreceptors
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Tyrosine 3-Monooxygenase
  • Cocaine