A review of the effects of dopaminergic agents on humans, animals, and drug-seeking behavior, and its implications for medication development

Abstract

Medication development for cocaine abuse has focused on potential mechanisms of action related to the abuse of cocaine. The hypothesis that mesolimbic dopamine (DA) is the key neurochemical mediator of cocaine's addictive and reinforcing effects is well supported by a wide variety of data from animal studies. On the other hand, medications that increase DA or block its action in humans can produce effects that appear incompatible with this hypothesis. This article reviews these incompatibilities between animal and human data with a focus on the DAergic actions of drugs, including DA reuptake inhibitors, direct DA agonists, DA increasers, and DA antagonists. Possible reasons for these discrepancies are discussed, and the potential role of high-affinity DA uptake inhibitors, such as GBR12909, for pharmacotherapies for treating cocaine addiction in humans is likely to come from understanding its mechanisms of action, it is clear that further research on the effects of cocaine in humans and animals will be critical to the medication development effort.

Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys

“…These results support efforts to develop similar pharmacotherapeutic strategies to treat cocaine dependence (Grabowski et al, 2004;Howell and Wilcox, 2001;Mello and Negus, 1996). Several preclinical studies with DAT inhibitors provide evidence that substitute agonists may be used to reduce cocaine use (Lindsey et al, 2004;Mello and Negus, 1996;Rothman and Glowa, 1995). However, a possible limitation to the use of selective DAT inhibitors as medications for cocaine abuse is their potential for abuse.…”

Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

“…Notably, SB-277011A shows none of the side effects commonly associated with D 1 or D 2 antagonism (Rothman and Glowa 1995;Platt et al 2002). For example, SB-277011A (up to 90 mg/kg, PO) has no effect on spontaneous or stimulant-induced locomotion, does not alter memory, and is non-cataleptogenic (Reavill et al 2000;Vorel et al 2002).…”

“…These three classes of triggers also reinstate extinguished drug-seeking in animals (Shalev et al 2002). The involvement of mesolimbic dopamine (DA) in cocaine addiction and relapse (Wise 1996;Stewart 2000;Nestler 2001;Shalev et al 2002;Volkow et al 2002) has implicated DA receptors as targets for the development of anti-cocaine medication (Rothman and Glowa 1995;Platt et al 2002). Among the five DA receptor subtypes identified (Greengard 2001), the D 3 receptor has attracted special attention because it is highly localized in the nucleus accumbens (NAcc) and adjacent mesolimbic loci (Bouthenet et al 1991;Landwehrmeyer et al 1993;Diaz et al 1995).…”

Levo-tetrahydropalmatine inhibits cocaine's rewarding effects: Experiments with self-administration and brain-stimulation reward in rats

“…In light of the important role of the mesolimbic dopamine (DA) system in drug abuse (Wise, 2005), much attention has focused on various DA receptor antagonists as potential treatments (Rothman and Glowa, 1995;Platt et al, 2002). However, clinical trials with D 1 or D 2 receptor antagonists for cocaine addiction have failed due to either ineffectiveness, surmountability by increased drug intake, and/or unfavorable side-effects such as dysphoria, extrapyramidal movements or inhibition of natural reward (Sherer et al, 1989;Nann-Vernotica et al, 2001;Haney et al, 2001;Newton et al, 2001; see reviews by Platt et al, 2002;Gorelick et al, 2004).…”