Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs.
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.
Rothman
Richard B
RB
CPS, IRP, NIDA, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. rrothman@mail.nih.gov
Baumann
Michael H
MH
D000661:Amphetamine / Q000008:administration & dosage*; D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced / Q000209:etiology; D019970:Cocaine-Related Disorders / Q000517:prevention & control*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage*; D000882:Haplorhini; D008297:Male; D017551:Microdialysis / Q000379:methods; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D019966:Substance-Related Disorders; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
D015259:Dopamine Agents; D012701:Serotonin; D000661:Amphetamine; D004298:Dopamine