Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs

Ann N Y Acad Sci. 2006 Aug;1074:245-60. doi: 10.1196/annals.1369.064.


The abuse of illicit stimulants is a worldwide crisis, yet few medicines are available for treating stimulant addiction. We have advocated the idea of "agonist therapy" for cocaine dependence. This strategy involves administration of stimulant-like medications (e.g., monoamine releasers) to alleviate cocaine withdrawal symptoms and prevent relapse. A chief limitation of this strategy is that many candidate medicines possess high abuse liability due to activation of mesolimbic dopamine (DA) neurons in reward pathways. Evidence suggests that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is a critical variable when developing medications with reduced stimulant side effects. In this article, we review recent studies from our laboratory that examined neurochemical and behavioral effects of a series of monoamine releasers which displayed different potencies at DA and 5-HT transporters. The data show that increasing 5-HT release can attenuate stimulant effects mediated by DA release, such as motor stimulation and drug self-administration. Our findings support the work of others and indicate that elevated synaptic 5-HT can dampen certain behavioral effects of DA-releasing agents. Moreover, the relationship between DA and 5-HT releasing potency is an important determinant in developing new agonist medications with reduced stimulant properties.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Amphetamine / administration & dosage*
  • Animals
  • Behavior, Addictive / chemically induced
  • Behavior, Addictive / etiology
  • Cocaine-Related Disorders / prevention & control*
  • Dopamine / metabolism*
  • Dopamine Agents / administration & dosage*
  • Haplorhini
  • Male
  • Microdialysis / methods
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • Substance-Related Disorders
  • Synaptosomes / metabolism
  • Time Factors


  • Dopamine Agents
  • Serotonin
  • Amphetamine
  • Dopamine