Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice

Eur J Neurosci. 2009 Sep;30(5):860-8. doi: 10.1111/j.1460-9568.2009.06865.x. Epub 2009 Aug 27.


G protein-coupled receptor (GPCR) associated sorting protein 1 (GASP-1) interacts with GPCRs and is implicated in their postendocytic sorting. Recently, GASP-1 has been shown to regulate dopamine (D(2)) and cannabinoid (CB1) receptor signalling, suggesting that preventing GASP-1 interaction with GPCRs might provide a means to limit the decrease in receptor signalling upon sustained agonist treatment. In order to test this hypothesis, we have generated and behaviourally characterized GASP-1 knockout (KO) mice and have examined the consequences of the absence of GASP-1 on chronic cocaine treatments. GASP-1 KO and wild-type (WT) mice were tested for sensitization to the locomotor effects of cocaine. Additional mice were trained to acquire intravenous self-administration of cocaine on a fixed ratio 1 schedule of reinforcement, and the motivational value of cocaine was then assessed using a progressive ratio schedule of reinforcement. The dopamine and muscarinic receptor densities were quantitatively evaluated in the striatum of WT and KO mice tested for sensitization and self-administration. Acute and sensitized cocaine-locomotor effects were attenuated in KO mice. A decrease in the percentage of animals that acquired cocaine self-administration was also observed in GASP-1-deficient mice, which was associated with pronounced down-regulation of dopamine and muscarinic receptors in the striatum. These data indicate that GASP-1 participates in acute and chronic behavioural responses induced by cocaine and are in agreement with a role of GASP-1 in postendocytic sorting of GPCRs. However, in contrast to previous studies, our data suggest that upon sustained receptor stimulation GASP-1 stimulates recycling rather than receptor degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Corpus Striatum / metabolism
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology
  • Exploratory Behavior / drug effects*
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Radioligand Assay
  • Receptors, Dopamine / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / physiology*
  • Receptors, Muscarinic / metabolism
  • Self Administration
  • Stereotyped Behavior / drug effects*
  • Stereotyped Behavior / physiology


  • Dopamine Uptake Inhibitors
  • Gprasp2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Dopamine
  • Receptors, G-Protein-Coupled
  • Receptors, Muscarinic
  • Cocaine