Quantitative changes in Gαolf protein levels, but not D1 receptor, alter specifically acute responses to psychostimulants

Jean Christophe Corvol, Emmanuel Valjent, Vincent Pascoli, Aurélie Robin, Alexandre Stipanovich, Robert R. Luedtke, Leonardo Belluscio, Jean Antoine Girault, Denis Hervé

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54 Scopus citations

Abstract

Striatal dopamine D1 receptors (D1R) are coupled to adenylyl cyclase through Gαolf. Although this pathway is involved in important brain functions, the consequences of quantitative alterations of its components are not known. We explored the biochemical and behavioral responses to cocaine and D-amphetamine (D-amph) in mice with heterozygous mutations of genes encoding D1R and Gαolf (Drd1a+/- and Gnal+/-), which express decreased levels of the corresponding proteins in the striatum. Dopamine-stimulated cAMP production in vitro and phosphorylation of AMPA receptor GluR1 subunit in response to D-amph in vivo were decreased in Gnal+/-, but not Drd1a+/- mice. Acute locomotor responses to D1 agonist SKF81259, D-amph and cocaine were altered in Gnal+/- mice, and not in Drd1a+/- mice. This haploinsufficiency showed that Gαolf but not D1R protein levels are limiting for D1R-mediated biochemical and behavioral responses. Gnal+/- mice developed pronounced locomotor sensitization and conditioned locomotor responses after repeated injections of D-amph (2 mg/kg) or cocaine (20 mg/kg). They also developed normal D-amph-conditioned place preference. The D1R/cAMP pathway remained blunted in repeatedly treated Gnal+/- mice. In contrast, D-amph-induced ERK activation was normal in the striatum of these mice, possibly accounting for the normal development of long-lasting behavioral responses to psychostimulants. Our results clearly dissociate biochemical mechanisms involved in acute and delayed behavioral effects of psychostimulants. They identify striatal levels of Gαolf as a key factor for acute responses to psychostimulants and suggest that quantitative alterations of its expression may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine function.

Original languageEnglish
Pages (from-to)1109-1121
Number of pages13
JournalNeuropsychopharmacology
Volume32
Issue number5
DOIs
StatePublished - 24 May 2007

Keywords

  • Addiction
  • Dopamine D1a receptor
  • Drd1a
  • G protein
  • Gnal
  • Psychostimulants

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    Corvol, J. C., Valjent, E., Pascoli, V., Robin, A., Stipanovich, A., Luedtke, R. R., Belluscio, L., Girault, J. A., & Hervé, D. (2007). Quantitative changes in Gαolf protein levels, but not D1 receptor, alter specifically acute responses to psychostimulants. Neuropsychopharmacology, 32(5), 1109-1121. https://doi.org/10.1038/sj.npp.1301230