Basal and cocaine-induced sex differences in the DARPP-32-mediated signaling pathway.
BACKGROUND
Behavioral and dopamine responses to cocaine are sexually dimorphic: Female rats exhibit higher levels of locomotor and reward-associated behaviors after cocaine administration and dopamine release than do males. Activation of the dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32) intracellular cascade mediates responses to cocaine.


OBJECTIVE
To examine the possibility that acute cocaine administration alters the DARPP-32 cascade in a sexually dimorphic pattern.


METHODS
Male and female rats received either saline or cocaine (30 mg/kg). Protein levels of DARPP-32, phosphorylation of DARPP-32 at the Thr34 site (P-Thr34-DARPP-32), protein phosphatase 1 (PP-1), and protein phosphatase 2B (PP-2B) in nucleus accumbens were measured via Western blot analysis.


RESULTS
Females had higher protein levels of DARPP-32, P-Thr34-DARPP-32, calcineurin A (CaN-A; catalytic subunit of PP-2B), and calcineurin B (CaN-B; regulatory subunit of PP-2B) than males 5 min after saline treatment. In females, CaN-A protein levels were also higher at 15 min and PP-1 protein levels were higher 30 min after saline administration than males. In male rats, cocaine significantly increased CaN-A protein levels at 30 min and CaN-B protein levels at 15 min. In females, cocaine administration significantly decreased protein levels of DARPP-32, P-Thr34-DARPP-32, and CaN-A at 45 min but increased PP-1 protein levels at 30 min. Overall, males had higher activation of the DARPP-32 pathway after cocaine administration than did females.


CONCLUSIONS
These novel results show that basal and cocaine-induced sex differences in the DARPP-32/PP-1 cascade may be responsible for the sexual dimorphism in acute cocaine-induced behavioral responses.
Zhou
Luyi
L
Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, 10065, USA.
Nazarian
Arbi
A
Sun
Wei-Lun
WL
Jenab
Shirzad
S
Quinones-Jenab
Vanya
V
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D005260:Female; D007274:Injections, Intraperitoneal; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D013997:Time Factors
D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497930:Ppp1r1b protein, rat; D019703:Calcineurin; D054645:Protein Phosphatase 1; D003042:Cocaine