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.

A 1.1-Mb Segmental Deletion on the X Chromosome Causes Meiotic Failure in Male Mice

“…A double mutant of Nxf2 and Nxf3 lacks compound effects [22]. GPRASP1 has been implicated in regulating dopamine and cannabinoid receptor signaling, and Gprasp1 null-mutant mice exhibit impaired striatum-dependent responses [31,32]. The Nxf segment also contains a cluster of genes belonging to the Prame (preferentially expressed antigen in melanoma) family of genes that are expressed in testis and several types of cancers (cancer-testis genes): Pramel, Pramel3 (five nearly identical copies), and Prame; two genes (Tceal6 and Bhlhb9) encode transcription factors; Gm6215 (three nearly identical copies) and 3632454L22Rik are long intergenic noncoding RNA (lincRNA) genes; and Mir1970 is a micro-RNA gene.…”

Overexpression of Reelin Prevents the Manifestation of Behavioral Phenotypes Related to Schizophrenia and Bipolar Disorder

“…The procedure for cocaine self-administration used in this work was previously described in detail (Boeuf et al , 2009). Briefly, mice were anaesthetized and implanted with an intravenous catheter in the jugular vein.…”

G Protein-Coupled Receptor-Associated Sorting Protein 1 Regulates the Postendocytic Sorting of Seven-Transmembrane-Spanning G Protein-Coupled Receptors

“…More recently, dysbindin -a cytoplasmic protein encoded by DTNBP1 [38] -was implicated in the postendocytic sorting of the dopamine D 2 receptor and DOR to the degradative pathway and was shown to co immunoprecipitate with both Hrs proteins and another sorting protein, the GPCR-associated sorting protein 1 (GASP-1) [39] . The GPCR-Associated Sorting Proteins GASP-1 was discovered by Whistler et al [7] in 2002 in a yeast two-hybrid screen with the carboxyl terminus of the DOR and has since been reported to specifically target several diverse 7TM-GPCRs to the lysosomal/degradative pathway [7,29,[40][41][42][43][44][45] ( table 1 ). Although 9 additional family members of GASP-1 (GASP-2 to GASP-10) have been suggested [47] , there is no functional evidence to date that any of these other GASP family members are involved in the sorting of 7TM-GPCRs.…”

“…In addition, disruption of GASP-1 has been shown to alter behavioral responses to cocaine. For example, GASP-1 knockout mice show a reduced locomotor sensitization to cocaine and reduced acquisition of cocaine self-administration [41,45] .…”