title: Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice.
abstract: 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.
authors.affiliation: Institut de Recherche de l'ESBS, Centre National de la Recherche Scientifique, Université de Strasbourg, Illkirch, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Boeuf
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Trigo
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Moreau
authors.forename: Lucas
authors.initials: L
authors.lastname: Lecourtier
authors.forename: Elise
authors.initials: E
authors.lastname: Vogel
authors.forename: Jean-Cristophe
authors.initials: JC
authors.lastname: Cassel
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathis
authors.forename: Paul
authors.initials: P
authors.lastname: Klosen
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Frédéric
authors.initials: F
authors.lastname: Simonin
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000378:metabolism; D012646:Self Administration; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology
chemical_list: D018765:Dopamine Uptake Inhibitors; C485065:Gprasp2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011954:Receptors, Dopamine; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; D003042:Cocaine