Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats
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Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.
Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.
Materials and methods
Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.
Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.
These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.
KeywordsCocaine Dopamine and cAMP-regulated phosphoprotein of 32 kDa, DARPP-32 Glutamate receptor 1, GluR1 Protein kinase A, PKA Self-administration Sex differences
We would like to acknowledge the Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Scholar program (PI, Carolyn Mazure), the Specialized Centers of Research (SCOR) on Sex and Gender Factors Affecting Women’s Health (PI, Rajita Sinha), and the NIH Office of Research on Women’s Health. The research described in the manuscript was supported by National Institutes on Health grants AR049469 (JRT and MRP), K01 DA 114038 (Carolyn Mazure, PI), K02 DA00436 (MRP), and R01 DA11717 (JRT).
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