Dopamine/serotonin releasers as medications for stimulant addictions

Prog Brain Res. 2008;172:385-406. doi: 10.1016/S0079-6123(08)00919-9.


The use of 'agonist therapy' for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g. monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability due to activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs might be to add in serotonin (5-HT)-releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This chapter addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, we briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, we discuss data demonstrating that 5-HT release can dampen DA-mediated stimulant effects, and the 'anti-stimulant' role of 5-HT(2C) receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, we discuss recently published data with PAL-287, a novel non-amphetamine DA/5-HT-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions as well as for obesity, attention deficit disorder and depression.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Addictive / drug therapy*
  • Central Nervous System Stimulants / chemistry
  • Central Nervous System Stimulants / metabolism
  • Cocaine / chemistry
  • Cocaine / metabolism*
  • Dopamine / metabolism*
  • Dopamine Agents / metabolism
  • Dopamine Agents / therapeutic use
  • Dopamine Uptake Inhibitors / therapeutic use*
  • Fenfluramine / metabolism
  • Fenfluramine / therapeutic use
  • Humans
  • Methamphetamine / chemistry
  • Methamphetamine / metabolism*
  • Molecular Structure
  • Neurons / metabolism
  • Phentermine / metabolism
  • Phentermine / therapeutic use
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism*
  • Serotonin Uptake Inhibitors / metabolism
  • Serotonin Uptake Inhibitors / therapeutic use
  • Substance-Related Disorders / drug therapy*


  • Central Nervous System Stimulants
  • Dopamine Agents
  • Dopamine Uptake Inhibitors
  • Receptors, Serotonin
  • Serotonin Uptake Inhibitors
  • Fenfluramine
  • Serotonin
  • Methamphetamine
  • Phentermine
  • Cocaine
  • Dopamine