Behavioral and morphological responses to cocaine require kalirin7

Biol Psychiatry. 2010 Aug 1;68(3):249-55. doi: 10.1016/j.biopsych.2010.03.024. Epub 2010 May 10.


Background: Long-lasting increases in dendritic spine density and gene expression in the nucleus accumbens and in the ambulatory response to cocaine occur following chronic cocaine treatment. Despite numerous reports of these findings, the molecular mechanisms leading to these morphological, biochemical, and behavioral changes remain unclear.

Methods: We used mice genetically lacking Kalirin7 (Kal7(KO)), a Rho guanine nucleotide exchange factor that regulates dendritic spine formation and function. Both wild-type (Wt) and Kal7(KO) mice were given high-dose cocaine (20 mg/kg) for 4 or 8 consecutive days. Locomotor sensitization and conditioned place preference elicited by cocaine were evaluated. The nucleus accumbens core was diolistically labeled and spine density and morphology were quantified using confocal microscopy.

Results: Cocaine increased Kalirin7 messenger RNA and protein expression in the nucleus accumbens of Wt mice. The Kal7(KO) animals showed greater locomotor sensitization to cocaine than Wt mice. In contrast, Kal7(KO) mice exhibited decreased place preference for cocaine, despite displaying a normal place preference for food. While Wt mice showed a robust increase in dendritic spine density after 4 and 8 days of cocaine treatment, dendritic spine density failed to increase in cocaine-exposed Kal7(KO) mice. Wild-type mice treated with cocaine for 8 days exhibited larger dendritic spines than cocaine-treated Kal7(KO) mice.

Conclusions: Kalirin7 is an essential determinant of dendritic spine formation following cocaine treatment. The absence of this single isoform of one of the many Rho guanine nucleotide exchange factors expressed in the nucleus accumbens results in enhanced locomotor sensitization and diminished place preference in response to cocaine.

Publication types

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

MeSH terms

  • Animals
  • Association Learning / drug effects
  • Behavior, Animal / drug effects*
  • Central Nervous System Depressants / pharmacology*
  • Cocaine / pharmacology*
  • Conditioning, Classical / drug effects
  • Dendritic Spines / drug effects*
  • Dendritic Spines / metabolism
  • Guanine Nucleotide Exchange Factors / drug effects
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • RNA, Messenger / analysis


  • Central Nervous System Depressants
  • Guanine Nucleotide Exchange Factors
  • KALRN protein, mouse
  • RNA, Messenger
  • Cocaine