Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats.
BACKGROUND
Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.


OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
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.
Lynch
Wendy J
WJ
Division of Molecular Psychiatry and Center for Genes and Behavior, Department of Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508, USA. wlynch@virginia.edu
Kiraly
Drew D
DD
Caldarone
Barbara J
BJ
Picciotto
Marina R
MR
Taylor
Jane R
JR
D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D012646:Self Administration; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome
D003042:Cocaine; D017868:Cyclic AMP-Dependent Protein Kinases; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018091:Receptors, AMPA