Gonadal hormones differentially modulate cocaine-induced conditioned place preference in male and female rats

Neuroscience. 2003;120(2):523-33. doi: 10.1016/s0306-4522(03)00317-8.


There is accumulating evidence that suggests there are sex differences in behavioral and subjective responses to cocaine. However, it is not known whether differences in cocaine reward contribute to sex differences in these responses or whether gonadal hormones affect the rewarding properties of cocaine. In the present study, conditioned place preference (CPP), a measure of non-contingent reward, was used to determine the effects of endogenous gonadal hormones and of estrogen and progesterone replacement on cocaine reward. Neurochemical measurements were also taken to identify monoaminergic substrates which underlie the behavioral phenotype. Although both intact and gonadectomized male and female rats showed a significant CPP for cocaine, ovariectomy attenuated the magnitude of CPP. These alterations coincided with a decrease in serum levels of corticosterone. In ovariectomized rats, pretreatment with progesterone inhibited cocaine CPP while estrogen plus progesterone potentiated the magnitude of CPP. Additionally, gonadectomy and ovarian hormone replacement in female rats affected serotonin/dopamine levels and turnover ratios in the ventral tegmental area and nucleus accumbens shell. While no effects of castration were observed, ovariectomy decreased levels of dopamine and serotonin in the ventral tegmental area. In females, progesterone replacement increased levels of serotonin and dopamine in the ventral tegmental area, while estrogen plus progesterone replacement increased dopamine levels in the nucleus accumbens. Collectively, these results indicate that ovarian hormones may influence cocaine reward by altering monoaminergic systems, which, in turn, may contribute to the current sex disparities in overall cocaine use.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Anesthetics, Local / pharmacology
  • Animals
  • Behavior, Animal
  • Biogenic Monoamines / metabolism
  • Cesarean Section / methods
  • Chromatography, High Pressure Liquid / instrumentation
  • Chromatography, High Pressure Liquid / methods
  • Cocaine / pharmacology*
  • Conditioning, Psychological / drug effects*
  • Conditioning, Psychological / physiology
  • Corticosterone / blood
  • Drug Interactions
  • Estrogens / pharmacology*
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Female
  • Hormone Replacement Therapy / methods
  • Male
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Progesterone / pharmacology*
  • Radioimmunoassay / methods
  • Rats
  • Rats, Inbred F344
  • Reaction Time
  • Reward
  • Sex Characteristics*
  • Time Factors
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism


  • Anesthetics, Local
  • Biogenic Monoamines
  • Estrogens
  • Progesterone
  • Cocaine
  • Corticosterone