Genes and molecules that can potentiate or attenuate psychostimulant dependence: relevance of data from animal models to human addiction

Ann N Y Acad Sci. 2008 Oct;1141:76-95. doi: 10.1196/annals.1441.024.


Recent evidence suggests that a variety of molecule products play critical roles in the transitions from recreational drug use to drug abuse, and then to drug dependence. Elucidation of the roles of specific molecules in the development of drug dependence can come from preclinical animal models and/or from clinical data. Among animal models, behavioral sensitization, conditioned place preference, drug discrimination, drug self-administration, and extensions of these basic procedures have been widely used to identify molecule products that might be involved in psychostimulant dependence. Repeated exposure to psychostimulants causes cellular adaptations in specific neuronal populations that are likely to contribute to dependence in some humans. In animal models, molecules that include shati, piccolo, tumor necrosis factor-alpha, and glial cell line-derived neurotrophic factor can act as antiaddictive factors. In some of these models, other molecules including matrix metalloproteinase and tissue plasminogen activator can act as proaddictive factors. We review evidence that the balance between levels of anti- and proaddictive factors induced by addictive drugs could play important roles in developing drug dependence. We focus on potential risk molecules in animal models for the development of methamphetamine dependence and their relevance to abusers. We propose that dynamic changes in the balance between levels of antiaddictive and proaddictive factors in the brain provide some of the determinants of susceptibility to drug dependence. Exploration of the roles that candidate molecules play in an appropriate repertoire of animal behavioral models, especially drug self-administration and extensions thereof, should thus help us to understand human stimulant dependence.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptation, Physiological
  • Amphetamine-Related Disorders / genetics*
  • Amphetamine-Related Disorders / physiopathology
  • Animals
  • Central Nervous System Stimulants / adverse effects*
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Discrimination Learning / drug effects
  • Discrimination Learning / physiology
  • Drug Tolerance
  • Genetic Predisposition to Disease
  • Humans
  • Methamphetamine / administration & dosage
  • Methamphetamine / adverse effects*
  • Methamphetamine / pharmacology
  • Methamphetamine / toxicity
  • Mice
  • Models, Animal*
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Rats
  • Self Administration
  • Species Specificity
  • Substance Withdrawal Syndrome / genetics
  • Substance Withdrawal Syndrome / physiopathology
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / physiology
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / physiology


  • Central Nervous System Stimulants
  • Nerve Tissue Proteins
  • Tumor Necrosis Factor-alpha
  • Methamphetamine
  • Tissue Plasminogen Activator