Journal
TRENDS IN PHARMACOLOGICAL SCIENCES
Volume 27, Issue 12, Pages 612-618Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tips.2006.10.006
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Funding
- Intramural NIH HHS Funding Source: Medline
- NIDA NIH HHS [R01 DA 12970] Funding Source: Medline
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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.
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