Appetite suppressants as agonist substitution therapies for stimulant dependence

Several lines of evidence support a dual-deficit model of stimulant withdrawal in which decreases in synaptic dopamine (DA) and serotonin (5-HT) contribute to withdrawal symptoms, drug craving, and relapse. According to the dual-deficit model, DA dysfunction during withdrawal underlies anhedonia and psychomotor disturbances, whereas 5-HT dysfunction gives rise to depressed mood, obsessive thoughts, and lack of impulse control. The model suggests that medications capable of normalizing stimulant-induced DA and 5-HT deficits should be effective treatment adjuncts. Furthermore, the model may explain why medications targeting only one neurotransmitter system (i.e., DA) have failed to treat cocaine dependence. Amphetamine-type appetite suppressants are logical choices for neurochemical normalization therapy of stimulant dependence, yet few clinical studies have tested anorectics in this regard. The chief purpose of the present work is to profile the activity of various anorectic agents at DA, 5-HT, and NE transporters, in order to identify possible medications for stimulant dependence. Compounds were tested in vitro for their ability to stimulate release and inhibit uptake of [(3)H]DA, [(3)H]NE, and [(3)H]5-HT. Selected compounds were tested in vivo for their ability to elevate extracellular levels of DA and 5-HT in rat nucleus accumbens. The results show that clinically available appetite suppressants display a wide range of activities at monoamine transporters. However, no single medication possesses equal potency at DA and 5-HT transporters, suggesting that none of the anorectics is ideally suited for treatment of stimulant addictions. Future efforts should focus on developing new medications that possess the desired therapeutic activity but lack the adverse effects associated with older amphetamine-type anorectics.