Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens

Psychopharmacology (Berl). 2009 Apr;203(3):641-50. doi: 10.1007/s00213-008-1411-5. Epub 2008 Dec 4.


Introduction: Alterations in protein kinase (PKA) protein levels have been implicated in the regulation of responses to and development of cocaine addiction. However, the contribution of differences in PKA intracellular cascade to the known sex differences in responses to cocaine is not well understood. This study examined whether there are intrinsic or cocaine-induced alterations in PKA-mediated responses, such as phosphorylation of cyclic AMP response element binding protein, in male and female rats.

Materials and methods: To this end, protein levels of PKA and phosphorylated CREB (pCREB) in the caudate putamen (CPu) and nucleus accumbens (NAc) of male and female rats were measured basally or after acute (one 30-mg/kg intraperitoneal injection) or chronic (twice-daily 15-mg/kg injections for 14 days) cocaine administration. Behavioral responses to both cocaine administration paradigms were also studied.

Results: Similar to previous findings, ambulatory, rearing, and stereotypic activities were higher in female rats after acute cocaine administration. Sex differences in cocaine-induced responses were also observed after chronic cocaine administration: While males developed a robust sensitization in ambulatory activities to cocaine, females developed tolerance in cocaine-induced rearing and stereotypic activities. In the basal group, females had significantly higher PKA protein levels in the NAc. Regardless of the cocaine administration paradigm, PKA protein levels in the NAc were higher overall in females than in males. Furthermore, after cocaine administration, while pCREB protein levels in male rats were induced for a longer amount of time than in female rats, the magnitude of change on pCREB levels were higher in female than male rats. However, in the CPu, no sex differences in PKA or pCREB protein levels were observed either in the basal group or after acute or chronic cocaine administration.

Discussion: Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Cocaine / adverse effects*
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Female
  • Male
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / enzymology
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Inbred F344
  • Sex Characteristics*


  • Cyclic AMP Response Element-Binding Protein
  • Cyclic AMP-Dependent Protein Kinases
  • Cocaine