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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

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Abstract

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.

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Abbreviations

DA:

dopamine

DAT:

dopamine transporter

D2:

autoreceptor D2

TH:

tyrosine hydroxylase

VTA:

ventral tegmental area

SNc:

substantia nigra pars compacta

Nacc:

nucleus accumbens

mRNA:

ribonucleic acid messenger

CS:

conditioned stimuli

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Acknowledgements

This work was supported by INSERM, MILDT-INSERM and Région Aquitaine. MJ is supported by the CNRS, FRM, MILDT-INSERM and Région Poitou-Charentes. DB is supported by Foundation Fyssen. The authors would like to thank Drs. Joff Lee and Adam Mar for their precious help on the realization of this manuscript.

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Author notes

  1. D. Belin

    Present address: Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK

Authors and Affiliations

  1. CRI U862, INSERM, 146 rue Léo Saignat, 33077, Bordeaux Cedex, France

    D. Belin & V. Deroche-Gamonet

  2. CNRS 6187, Université de Poitiers, 40 av. du recteur Pineau, 86022, Poitiers Cedex, France

    M. Jaber

  3. Institut François Magendie, Université Victor Segalen-Bordeaux 2, 146 rue Léo Saignat, 33077, Bordeaux Cedex, France

    V. Deroche-Gamonet

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Correspondence to V. Deroche-Gamonet.

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Belin, D., Deroche-Gamonet, V. & Jaber, M. 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 193, 567–578 (2007). https://doi.org/10.1007/s00213-007-0790-3

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