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 (D2) 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.