PKA-mediated responses in females' estrous cycle affect cocaine-induced responses in dopamine-mediated intracellular cascades.
An extensive body of literature provides evidence for both sexual dimorphism and menstrual cycle effects in drug abuse patterns and behavioral responses. However, the cellular mechanisms underlying sexually dimorphic responses to and hormonal effects on cocaine use remain unclear. We hypothesized that endogenous hormonal fluctuations during the estrous cycle of rats modulate cocaine's effects on dopamine- and PKA-mediated intracellular responses. To test this hypothesis, intact female rats at different stages of their cycle received a single injection of saline or cocaine (20 mg/kg) and were sacrificed after 15 or 60 min. The nucleus accumbens (NAc) and caudate putamen (CPu) were dissected and analyzed via Western blot for total and phosphorylated (p-thr34) dopamine- and 3'-5'-cyclic AMP-regulated phosphoprotein with molecular weight 32 kDa (DARPP-32), PP1, PP2B (CNA1 and CNB1 subunits), PKA, CREB, cFOS, and Delta-FosB. Our results show that saline-treated rats had estrous cycle-related differences in protein levels of pCREB, DARPP-32, p-thr34-DARPP-32, PP1, and CNA1. Saline-treated female rats in the estrus stage had higher levels of pCREB in the NAc, but cocaine-treatment lowered pCREB levels. The estrous cycle also significantly affected the magnitude of change for p-thr34-DARPP-32 protein levels in both the NAc and CPu. Sixty minutes of cocaine administration increased p-thr34-DARPP-32 levels in the NAc of rats during estrus and proestrus and in the CPu of rats in diestrus. Furthermore, cocaine-induced changes in PP1 protein levels in the NAc were also affected by the stage of the cycle; 60 min of cocaine administration increased PP1 levels in the NAc of rats during diestrus, whereas PP-1 levels decreased in rats during estrus. Taken together, these novel findings suggest that hormonal fluctuations during the estrous cycle may contribute to the previously reported sex differences in the PKA pathway and in behavioral responses to cocaine.
Doctoral Subprogram in Biopsychology and Behavioral Neuroscience, City University of New York, New York, NY 10065, USA.
J
J
Weiner
W Lun
WL
Sun
L
L
Zhou
C M
CM
Kreiter
S
S
Jenab
V
V
Quiñones-Jenab
D000818:Animals; D015153:Blotting, Western; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D030762:Estrous Cycle / Q000502:physiology*; D005260:Female; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D016760:Proto-Oncogene Proteins c-fos; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine; D004298:Dopamine