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.
BACKGROUND
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.


OBJECTIVE
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.


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.
Belin
D
D
CRI U862, INSERM, 146 rue Léo Saignat, 33077 Bordeaux Cedex, France.
Deroche-Gamonet
V
V
Jaber
M
M
D000818:Animals; D017660:Autoreceptors; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism
D017660:Autoreceptors; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine