Sex differences in novelty- and psychostimulant-induced behaviors of C57BL/6 mice

Psychopharmacology (Berl). 2013 Feb;225(3):707-18. doi: 10.1007/s00213-012-2860-4. Epub 2012 Sep 14.


Rationale: Women are more sensitive than men to psychostimulants and progress from initial use to drug addiction more quickly. The mouse has been an under-utilized model to study sex differences in psychostimulant action. Mice could serve as an ideal genetically tractable model for mechanistic studies into sex and hormone effects on psychostimulant behavior.

Objectives: The objective of this study was to characterize psychostimulant effects in male and female mice with a combination of automated data collection and behavioral observation.

Methods: Male and female C57BL/6 mice (Charles River) were given a single dose or sequential ascending binge doses of D-amphetamine (AMPH) or cocaine (COC). Behavior was assessed in open field chambers using both automated photobeam interruptions and behavioral observations. Brain psychostimulant concentrations were determined at the time of maximum behavioral stimulation.

Results: Psychostimulants induced behavioral activation in mice including both increased locomotion as detected with an automated system and a sequence of behaviors progressing from stereotyped sniffing at low doses to patterned locomotion and rearing at high doses. Females exhibited more patterned locomotion and a shift towards higher behavior scores after either psychostimulant despite having lower AMPH and equivalent COC brain levels as males.

Conclusions: Female C57BL/6 mice exhibit enhanced psychostimulant-induced behavior compared to males, similar to reports in rats. The combination of automated behavioral measures and behavioral observation was essential for verifying the existence of these differences. These results indicate the importance of testing both sexes when characterizing genetically manipulated mice to control for potential sex-specific effects.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Animal / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Central Nervous System Stimulants / blood
  • Central Nervous System Stimulants / pharmacokinetics
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / blood
  • Cocaine / pharmacokinetics
  • Cocaine / pharmacology*
  • Dextroamphetamine / blood
  • Dextroamphetamine / pharmacokinetics
  • Dextroamphetamine / pharmacology*
  • Dose-Response Relationship, Drug
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Sex Characteristics*
  • Stereotyped Behavior / drug effects


  • Central Nervous System Stimulants
  • Cocaine
  • Dextroamphetamine