Attenuated behavioural responses to acute and chronic cocaine in GASP-1-deficient mice.
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.
Boeuf
Julien
J
Institut de Recherche de l'ESBS, Centre National de la Recherche Scientifique, Université de Strasbourg, Illkirch, France.
Trigo
José Manuel
JM
Moreau
Pierre-Henri
PH
Lecourtier
Lucas
L
Vogel
Elise
E
Cassel
Jean-Cristophe
JC
Mathis
Chantal
C
Klosen
Paul
P
Maldonado
Rafael
R
Simonin
Frédéric
F
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
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