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. 2007-05-17; 193(4): 567-578
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1. Psychopharmacology (Berl). 2007 Sep;193(4):567-78. Epub 2007 May 17.
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.
Belin D(1), Deroche-Gamonet V, Jaber M.
(1)CRI U862, INSERM, 146 rue Léo Saignat, 33077 Bordeaux Cedex, France.
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.
PMID: 17505818 [Indexed for MEDLINE]