Hypothesis-Driven Medication Discovery for the Treatment of Psychostimulant Addiction

Abstract

Psychostimulant abuse is a serious social and health problem, for which no effective treatments currently exist. A number of review articles have described predominantly ‘clinic’-based pharmacotherapies for the treatment of psychostimulant addiction, but none have yet been shown to be definitively effective for use in humans. In the present article, we review various ‘hypothesis’- or ‘mechanism’-based pharmacological agents that have been studied at the preclinical level and evaluate their potential use in the treatment of psychostimulant addiction in humans. These compounds target brain neurotransmitter or neuromodulator systems, including dopamine (DA), γ-aminobutyric acid (GABA), endocannabinoid, glutamate, opioid and serotonin, which have been shown to be critically involved in drug reward and addiction. For drugs in each category, we first briefly review the role of each neurotransmitter system in psychostimulant actions, and then discuss the mechanistic rationale for each drug’s potential anti-addiction efficacy, major findings with each drug in animal models of psychostimulant addiction, abuse liability and potential problems, and future research directions. We conclude that hypothesis-based medication development strategies could significantly promote medication discovery for the effective treatment of psychostimulant addiction.

Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

“…Unlike PG01037 and NGB2904, the D2-preferential antagonist L-741626 and other D2-like receptor antagonists (Platt et al, 2002(Platt et al, , 2003 have been found to reduce cocaine self-administration in monkeys, which might suggest a more promising role for D2 than D3 receptor antagonists in reducing active cocaine use. D2 antagonists have not, however, been developed successfully for cocaine addiction treatment for a number of reasons (Xi and Gardner, 2008), including the observation that many of these drugs, such as L-741626, produce extrapyramidal side effects and reduce food-maintained operant behavior at doses similar to or slightly higher than those needed to reduce cocaine self-administration (present study; Platt et al, 2002Platt et al, , 2003.…”

CTDP-32476: A Promising Agonist Therapy for Treatment of Cocaine Addiction

“…Although several pharmacological agents have been tested as treatments for cocaine addiction, none has proven effective Gorelick et al, 2004;Vocci and Ling, 2005;Xi and Gardner, 2008). Cocaine is a monoamine transport (MAT) blocker that inhibits the neuronal reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (Wise, 1996).…”

Design, Preparation, and Characterization of High-Activity Mutants of Human Butyrylcholinesterase Specific for Detoxification of Cocaine

“…There is no U.S. Food and Drug Administration-approved medication specific for cocaine abuse treatment. The disastrous medical and social consequences of cocaine abuse have made a high priority the development of an anticocaine medication (Karila et al, 2008;Xi and Gardner, 2008). It would be an ideal anticocaine medication to accelerate cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway [i.e., cocaine hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma] (Landry et al, 1993;Kamendulis et al, 1996;Carrera et al, 2004;Meijler et al, 2005;Gorelick, 2008).…”