Dataset Information

The CaMKII-dependent phosphorylation of GABA_B receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

ABSTRACT:

Background

Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABA_B heteroreceptor (GABA_B R) is determined by its stability, and hence residence time, on the plasma membrane.

Aims

Here, we show that GABA_B R in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression.

Materials & methods

By immunofluorescent labeling, flow cytometry analysis, Co-immunoprecipitation and open field test, we measured the role of Ca²⁺ /calmodulin-dependent protein kinase II (CaMKII) to the control of GABA_B R membrane anchoring and cocaine induced-behavioral sensitization.

Results

Repeated cocaine treatment in rats (15 mg/kg) significantly decreases membrane levels of GABA_B1 R and GABA_B2 R in the NAc after day 3, 5 and 7. The membrane fluorescence and protein levels of GABA_B R was also decreased in NAc GAD₆₇ ⁺ neurons post cocaine (1 μM) treatment after 5 min. Moreover, the majority of internalized GABA_B1 Rs exhibited perinuclear localization, a decrease in GABA_B1 R-pHluroin signals was observed in cocaine-treated NAc neurons. By contrast, membrane expression of phosphorylated CaMKII (pCaMKII) post cocaine treatment was significantly increased after day 1, 3, 5 and 7. Baclofen blocked the cocaine induced behavioral sensitization via inhibition of cocaine enhanced-pCaMKII-GABA_B1 R interaction.

Conclusion

These findings reveal a new mechanism by which pCaMKII-GABA_B R signaling can promote psychostimulant-induced behavioral sensitization.

SUBMITTER: Lu MF

PROVIDER: S-EPMC10068462 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The CaMKII-dependent phosphorylation of GABA<sub>B</sub> receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Lu Ming F MF Fu Qiang Q Qiu Tian Y TY Yang Jian H JH Peng Qing H QH Hu Zhen Z ZZ

CNS neuroscience & therapeutics 20230208 5

<h4>Background</h4>Previous studies have established that the regulation of prolonged, distal neuronal inhibition by the GABA<sub>B</sub> heteroreceptor (GABA<sub>B</sub> R) is determined by its stability, and hence residence time, on the plasma membrane.<h4>Aims</h4>Here, we show that GABA<sub>B</sub> R in the nucleus accumbens (NAc) of rats affects the development of cocaine-induced behavioral sensitization by mediating its perinucleus internalization and membrane expression.<h4>Materials & me ...[more]

PMID: 36756679

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Project description:Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is known to be methylated by protein arginine N-methyltransferases (PRMTs). Evidence shows that PRMT1 contributes to >90% of cellular PRMT activity, which regulates histone H4 arginine 3 asymmetric dimethylation (H4R3me2a). Though histone arginine methylation represents a chemical modification that is relatively stable compared with other histone alterations, it is less well studied in the setting of addiction. Here, we demonstrate that repeated noncontingent cocaine injections increase PRMT1 activity in the nucleus accumbens (NAc) of C57BL/6 mice. We, subsequently, identify a selective inhibitor of PRMT1, SKLB-639, and show that systemic injections of the drug decrease cocaine-induced conditioned place preference to levels observed with genetic knockdown of PRMT1. NAc-specific downregulation of PRMT1 leads to hypomethylation of H4R3me2a, and hypoacetylation of histone H3 lysine 9 and 14. We also found that H4R3me2a is upregulated in NAc after repeated cocaine administration, and that H4R3me2a upregulation in turn controls the expression of Cdk5 and CaMKII. Additionally, the suppression of PRMT1 in NAc with lentiviral-short hairpin PMRT1 decreases levels of CaMKII and Cdk5 in the cocaine-treated group, demonstrating that PRMT1 affects the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injections is relatively long-lived, as increased expression was observed for up to 7 d after the last cocaine injection. These results show the role of PRMT1 in the behavioral effects of cocaine.Significance statementThis work demonstrated that repeated cocaine injections led to an increase of protein arginine N-methyltransferase (PRMT1) in nucleus accumbens (NAc). We then identified a selective inhibitor of PRMT1 (SKLB-639), which inhibited cocaine-induced conditioned place preference (CPP). Additionally, genetic downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction.

Dataset Information

The CaMKII-dependent phosphorylation of GABA_B receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Background

Aims

Materials & methods

Results

Conclusion

Publications

The CaMKII-dependent phosphorylation of GABA<sub>B</sub> receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The CaMKII-dependent phosphorylation of GABAB receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Background

Aims

Materials & methods

Results

Conclusion

Publications

The CaMKII-dependent phosphorylation of GABA<sub>B</sub> receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The CaMKII-dependent phosphorylation of GABA_B receptors in the nucleus accumbens was involved in cocaine-induced behavioral sensitization in rats.