Monoamine transporters and psychostimulant addiction

Psychostimulants are a broadly defined class of drugs that stimulate the central and peripheral nervous systems as their primary pharmacological effect. The abuse liability of psychostimulants is well established and represents a significant public health concern. An extensive literature documents the critical importance of monoamines (dopamine, serotonin and norepinephrine) in the behavioral pharmacology and addictive properties of psychostimulants. In particular, the dopamine transporter plays a primary role in the reinforcing and behavioral-stimulant effects of psychostimulants in animals and humans. Moreover, both serotonin and norepinephrine systems can reliably modulate the neurochemical and behavioral effects of psychostimulants. However, there is a growing body of evidence that highlights complex interactions among additional neurotransmitter systems. Cortical glutamatergic systems provide important regulation of dopamine function, and inhibitory amino acid gamma-aminobutyric acid (GABA) systems can modulate basal dopamine and glutamate release. Repeated exposure to psychostimulants can lead to robust and enduring changes in neurobiological substrates, including monoamines, and corresponding changes in sensitivity to acute drug effects on neurochemistry and behavior. Significant advances in the understanding of neurobiological mechanisms underlying psychostimulant abuse and dependence have guided pharmacological treatment strategies to improve clinical outcome. In particular, functional agonist treatments may be used effectively to stabilize monoamine neurochemistry, influence behavior and lead to long-term abstinence. However, additional clinical studies are required in order to identify safe and efficacious pharmacotherapies.