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Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats

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An Erratum to this article was published on 30 July 2008

Abstract

Background

Brain-derived neurotrophic factor (BDNF) is involved in the survival and function of midbrain DA neurons. BDNF action is mediated by the TrkB receptor–tyrosine kinase, and both BDNF and TrkB transcripts are widely expressed in the rat mesolimbic pathway, including the nucleus accumbens (NAc) and the ventral tegmentum area (VTA).

Objective

BDNF was previously shown to be involved in cocaine reward and relapse, as assessed in rat models. The goal of this study is to explore the role of BDNF and TrkB in the rat nucleus accumbens (NAc) in cocaine-induced psychomotor sensitization and in conditioned-place preference acquisition, expression, and reinstatement.

Materials and methods

In vivo genetic manipulations of BDNF and TrkB were performed using a lentiviral gene delivery approach to over-express these genes in the NAc and siRNA-based technology to locally knockdown gene expression. Behavioral experiments consisted of locomotor activity monitoring or cocaine-induced conditioned-place preference (CPP).

Results

BDNF and/or its receptor TrkB in the NAc enhance drug-induced locomotor activity and induce sensitization in rats. Furthermore, LV-BDNF- and LV-TrkB-treated rats display enhanced cocaine-induced CPP, delayed CPP-extinction upon repeated measurements, and increased CPP reinstatement. In contrast, expression of TrkT1 (truncated form of TrkB, acting as a dominant negative) inhibits these behavioral changes. This inhibition is also observed when rats are fed doxycycline (to block lentivirus-mediated gene expression) or when injected with siRNAs-expressing lentiviruses against TrkB. In addition, we investigate the establishment, maintenance, extinction, and reinstatement of cocaine-induced CPP. We show that BDNF and TrkB-induced CPP takes place during the learning period (conditioning), whereas extinction leads to the loss of CPP. Extinction is delayed when rats are injected LV-BDNF or LV-TrkB, and in turn, priming injections of 2 mg/kg of cocaine reinstates it.

Conclusions

These results demonstrate the crucial function of BDNF—through its receptor TrkB—in the enhancement of locomotor activity, sensitization, conditioned-place preference, CPP-reinstatement, and rewarding effects of cocaine in the mesolimbic dopaminergic pathway.

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Abbreviations

BDNF:

brain-derived neurotrophic factor

DA:

dopamine

GFP:

green fluorescent protein

HEK293T:

human embryonic kidney 293T cells

NAc:

nucleus accumbens

NGF:

nerve growth factor

qRT-PCR:

quantitative real-time polymerase chain reaction

shRNA:

short hairpin RNA

siRNA:

small interference RNA

TH:

tyrosine hydroxylase

Trk:

receptor–tyrosine kinase

uPA:

urokinase-type plasminogen activator

VTA:

ventral tegmental area

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Acknowledgements

Supported, by Swiss National Foundation grants 3100-059350 and 3100AO-100686 (JLD). The authors are grateful to Mrs. C. Deforel-Poncet and Dominique Schlicht for their skilful assistance and to Dr. Eero Castren (University of Helsinki, Finland) for providing TrkB and TrkT1 constructs, useful discussions, and comments on our data. Authors are also grateful to Dr. Alexander Kusnecov (Rutgers University, USA) for critical comments and suggestions of the manuscript and for Y. Mineur and C. Brabant, Department of Psychiatry, Yale University School of Medicine, for useful help in statistical analysis.

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  1. Amine Bahi

    Present address: Department of Psychiatry, Yale University School of Medicine, 301 Cedar Street, New Haven, CT, 06508, USA

Authors and Affiliations

  1. Division of Biochemistry, Department of Medicine, University of Fribourg, Rue du Musée 5, CH-1700, Fribourg, Switzerland

    Frederic Boyer & Jean-Luc Dreyer

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  1. Amine Bahi
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Correspondence to Jean-Luc Dreyer.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-008-1255-z

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supplementary Figure S1

BDNF and TrkB expression at the sites of stereotaxic injections. a low magnification (5× and 33×) of the injected areas. Left panels: LV-BDNF-treated brain; right panels: LV-TrkB-treated brain. Strong lentiviral-induced expression is observed in the NAc. Arrows show the injected areas. b High magnification (100×) of the sites on injections in the NAc core and shell region and in the caudate putamen of rat brains from animals injected LV-BDNF (left panels, revealed with HRP-conjugated secondary antibody, see “Materials and methods” section) or animals injected LV-TrkB (right panels, revealed with Texas-red-conjugated secondary antibody). Sections from brains of doxycycline-fed animals display no expression of lentiviral-induced BDNF or TrkB. No expression of lentiviral-induced BDNF or TrkB is observed in caudate putamen under each regimen. (GIF 675 KB)

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Bahi, A., Boyer, F. & Dreyer, JL. Role of accumbens BDNF and TrkB in cocaine-induced psychomotor sensitization, conditioned-place preference, and reinstatement in rats. Psychopharmacology 199, 169–182 (2008). https://doi.org/10.1007/s00213-008-1164-1

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