Silencing dopamine D3-receptors in the nucleus accumbens shell in vivo induces changes in cocaine-induced hyperlocomotion

Amine Bahi, Frederic Boyer, Gaelle Bussard, Jean Luc Dreyer

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

Abstract

The dopamine D3 receptor (D3R) is an important pharmacotherapeutic target for its potential role in psychiatric disorders and drug dependence. To further explore its function in rats, a regulatable lentivirus, Lenti-D3, holding the rat D3R cDNA, has been constructed as well as three nonregulatable lentiviruses, Lenti-D3-siRNA1, Lenti-D3-siRNA2 and Lenti-D3-siRNA3, expressing small hairpin RNAs, aimed at silencing D 3R expression and specifically targeted against different regions of the D3R mRNA. In vitro, Lenti-D3 expressed D3R and could efficiently be blocked with Lenti-D3-Sils. These viruses were stereotaxically injected into the shell part of the nucleus accumbens (NAcc) and effects of passive cocaine delivery on locomotor activity were assessed. Manipulations of D3R levels induced changes in the locomotor stimulant effects of cocaine as compared to control treatment. Suppression of dopamine (DA) D 3R in the NAcc by means of local knockdown (with Lenti-D3-Sils) increased locomotor stimulant effects, whereas its overexpression with Lenti-D3 drastically reduced them. The latter effects could be reversed when animals were fed doxycycline, which prevented lentiviral-mediated DA D3R overexpression in the NAcc. Gene expression assessed by quantitative RT-PCR confirmed very efficient gene knockdown in vivo in animals treated with Lenti-D3-Sils (> 93% silencing of D3R gene). Thus D3R expression significantly contributes to behavioural changes associated with chronic cocaine delivery.

Original languageEnglish
Pages (from-to)3415-3426
Number of pages12
JournalEuropean Journal of Neuroscience
Volume21
Issue number12
DOIs
Publication statusPublished - Jun 2005
Externally publishedYes

Keywords

  • Addiction
  • Cocaine
  • Dopamine D3 receptor
  • Drugs of abuse
  • Lentivirus
  • Plasticity
  • in vivo gene transfer
  • siRNA

ASJC Scopus subject areas

  • General Neuroscience

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