Appetite Suppressants as Agonist Substitution Therapies for Stimulant Dependence

Abstract

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 [3H]DA, [3H]NE, and [3H]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.

Development of a Rationally Designed, Low Abuse Potential, Biogenic Amine Releaser That Suppresses Cocaine Self-Administration

“…We, and others, have advocated the use of monoamine releasers such as amphetamine as "agonist" therapies for stimulant dependence (Rothman et al, 2002a;Grabowski et al, 2004). Preclinical studies strongly support this approach (Wojnicki et al, 1999).…”

“…Agonist substitution therapy illustrates this approach. Often described as neurochemical normalization therapy (Rothman et al, 2002a), agonist substitution therapy has generated effective treatments for nicotine dependence (Henningfield, 1995) and opioid dependence (Kreek, 1996).…”

Discriminating Depression, Physical and Social Anhedonia by Neurotransmitter Related Challenge Tests

“…This would mean that an uptake inhibitor like citalopram can not lead to a large increase of 5-HT in the synaptic cleft so that the low response of socially anhedonic persons could be explained by low production of 5-HT. The combination of low DA and low 5-HT responses resembles the pattern described for withdrawal induced anhedonia (Rothman et al, 2002) or the type of anhedonia described as negative symptoms in schizophrenia with a predominance of social withdrawal (Wolf, 2006;Kuha et al, 2011;Juckel et al, 2003). It is conceived as a fairly enduring trait (Cohen et al, 2011) with probably a hereditary component (Docherty & Sponheim, 2008).…”

Therapeutic Potential of Monoamine Transporter Substrates

“…Along with other researchers, we have advocated the use of amphetamine-type monoamine releasers as agonist therapies for cocaine dependence [54,78]. Similar to cocaine, these compounds target monoamine transporters to elevate synaptic levels of NE, DA and 5-HT [8,25].…”

“…Preclinical studies have shown that amphetamine-type appetite suppressants decrease cocaine and methamphetamine self-administration in various animal species [49][50][51][52][53]. Thus, we believed that clinically available appetite suppressants, such as phentermine, diethylpropion, and phendimetrazine, might be logical candi- dates for the pharmacotherapy of stimulant dependence [54]. We have performed experiments to examine the molecular mechanisms associated with anorectic drugs.…”