Dopamine/serotonin releasers as medications for stimulant addictions.
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.
Rothman
Richard B
RB
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, MD, USA. rrothman@mail.nih.gov
Blough
Bruce E
BE
Baumann
Michael H
MH
D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000378:metabolism; D003042:Cocaine / Q000737:chemistry / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism / Q000627:therapeutic use; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use*; D005277:Fenfluramine / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008694:Methamphetamine / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D009474:Neurons / Q000378:metabolism; D010645:Phentermine / Q000378:metabolism / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D019966:Substance-Related Disorders / Q000188:drug therapy*
D000697:Central Nervous System Stimulants; D003042:Cocaine; D004298:Dopamine; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D005277:Fenfluramine; D008694:Methamphetamine; D010645:Phentermine; D011985:Receptors, Serotonin; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors