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.