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Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine‐Type Drugs

Abstract:  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.