Dual dopamine-5-HT releasers: potential treatment agents for cocaine addiction.
Biogenic amine transporters (BATs) are integral membrane proteins that translocate biogenic amine neurotransmitters [norepinephrine, dopamine (DA) and 5-hydroxytryptamine (5-HT)] across cell membranes. BATs are the principal sites of action for many psychotropic drugs, including abused stimulants such as cocaine and methamphetamine. Preclinical and human data demonstrate that withdrawal from long-term cocaine administration produces a dual deficit of synaptic DA and 5-HT in the brain, indicating the advantage of developing medications that normalize impairments in both neurotransmitter systems. In this article, we review data supporting the notion that stimulant effects normally produced by increased levels of extracellular DA can be antagonized by concurrent increases in levels of extracellular 5-HT. Accordingly, nonselective BAT substrates that can release both DA and 5-HT, such as the novel compound PAL287, have low abuse potential while maintaining the ability to suppress drug-seeking behavior. The collective findings indicate that such drugs will provide neurochemical normalization therapy for cocaine addiction and might also be useful for treating depression, obsessive-compulsive disorder, attention deficit disorder and obesity.
Rothman
Richard B
RB
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, PO Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. rrothman@mail.nih.gov
Blough
Bruce E
BE
Baumann
Michael H
MH
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D012701:Serotonin / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism / Q000502:physiology*; D050492:Vesicular Biogenic Amine Transport Proteins / Q000145:classification / Q000378:metabolism / Q000502:physiology*
C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D050492:Vesicular Biogenic Amine Transport Proteins; D012701:Serotonin; D004298:Dopamine