Hypothesis-driven medication discovery for the treatment of psychostimulant addiction.
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), gamma-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.
National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA. zxi@intra.nida.nih.gov
Zheng-Xiong
ZX
Xi
Eliot L
EL
Gardner
D000818:Animals; D001921:Brain / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D000697:Central Nervous System Stimulants; D019970:Cocaine-Related Disorders / Q000175:diagnosis / Q000523:psychology / Q000534:rehabilitation; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000009:adverse effects / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects / Q000627:therapeutic use; D018755:GABA Agonists / Q000009:adverse effects / Q000627:therapeutic use; D058805:GABA Uptake Inhibitors; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists; D019966:Substance-Related Disorders / Q000175:diagnosis / Q000523:psychology / Q000534:rehabilitation*; D016896:Treatment Outcome; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D063385:Cannabinoid Receptor Modulators; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018690:Excitatory Amino Acid Agonists; D018755:GABA Agonists; D058805:GABA Uptake Inhibitors; D009292:Narcotic Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D050493:Vesicular Monoamine Transport Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine