Adolescent exposure to cocaine, amphetamine, and methylphenidate cross-sensitizes adults to methamphetamine with drug- and sex-specific effects

Behav Brain Res. 2015 Mar 15;281:116-24. doi: 10.1016/j.bbr.2014.12.002. Epub 2014 Dec 8.


The increasing availability, over-prescription, and misuse and abuse of ADHD psychostimulant medications in adolescent populations necessitates studies investigating the long-term effects of these drugs persisting into adulthood. Male and female C57Bl/6J mice were exposed to amphetamine (AMPH) (1.0 and 10 mg/kg), methylphenidate (MPD) (1.0 and 10 mg/kg), or cocaine (COC) (5.0 mg/kg) from postnatal day 22 to 31, which represents an early adolescent period. After an extended period of drug abstinence, adult mice were challenged with a subacute methamphetamine (METH) dose (0.5 mg/kg), to test the long-term effects of adolescent drug exposures on behavioral cross-sensitization using an open field chamber. There were no sex- or dose-specific effects on motor activity in adolescent, saline-treated controls. However, AMPH, MPD, and COC adolescent exposures induced cross-sensitization to a subacute METH dose in adulthood, which is a hallmark of addiction and a marker of long-lasting plastic changes in the brain. Of additional clinical importance, AMPH-exposed male mice demonstrated increased cross-sensitization to METH in contrast to the female-specific response observed in MPD-treated animals. There were no sex-specific effects after adolescent COC exposures. This study demonstrates differential drug, dose, and sex-specific alterations induced by early adolescent psychostimulant exposure, which leads to behavioral alterations that persist into adulthood.

Keywords: Addiction; Adolescence; Cross-sensitization; Mice; Psychostimulants; Sex-specific effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / psychology
  • Amphetamine / pharmacology*
  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology*
  • Dose-Response Relationship, Drug*
  • Female
  • Injections, Intraperitoneal
  • Locomotion / drug effects
  • Male
  • Methamphetamine / pharmacology*
  • Methylphenidate / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Sex Factors
  • Time Factors


  • Central Nervous System Stimulants
  • Methylphenidate
  • Methamphetamine
  • Amphetamine
  • Cocaine