Psychopharmacology

, 199:169

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

Original Investigation

DOI: 10.1007/s00213-008-1164-1

Cite this article as:
Bahi, A., Boyer, F. & Dreyer, JL. Psychopharmacology (2008) 199: 169. doi:10.1007/s00213-008-1164-1

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.

Keywords

siRNA RNA interference BDNF TrkB Cocaine Addiction Lentivirus CPP 

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

Supplementary material

213_2008_1164_Fig1_ESM.gif (675 kb)
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)

213_2008_1164_Fig1_ESM.tif (1.1 mb)
High resolution image file (TIF 1.05 MB)

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Division of Biochemistry, Department of MedicineUniversity of FribourgFribourgSwitzerland
  2. 2.Department of PsychiatryYale University School of MedicineNew HavenUSA

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