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Modelling drug abuse potential with positron emission tomography of the dopaminergic system

By J. van der Aart

Abstract

BACKGROUND: Recreational and medicinal drugs need to be evaluated with regard to addictive properties. Reinforcing effects contribute to a drug’s abuse liability and predict subsequent use. The neurotransmitter dopamine plays an important role in modulating reinforcing effects in the reward circuitry of the brain. Most drugs of abuse increase extrasynaptic dopamine by stimulating release from synaptic vesicles, by blocking reuptake by binding to the dopamine transporter or by indirectly increasing dopamine via interactions with other neurotransmitter systems. This increase in dopamine is necessary, but not sufficient to produce reinforcing effects such as a feeling of ‘high’. Molecular imaging techniques such as positron emission tomography (PET) allow the tracking of drugs in vivo and moreover, can provide an indirect measure of drug-induced dopaminergic responses. OBJECTIVE: The present paper (1) investigates pharmacokinetics and potency to increase dopamine of commonly used psychoactive drugs, (2) relates the neurochemical effects with subjective emotional effects, (3) explores the contribution of personality factors to abuse liability, and (4) ultimately assesses the utility of PET in predicting reinforcing effects of drugs of abuse and hence their abuse potential. We focus on the abuse potential of 5 classes of drugs: psychostimulants, nicotine, hallucinogens, cannabis and alcohol. The rationale for the review of these compounds is twofold. First, there is a rich scientific database of dopaminergic effects of (medicinal) psychostimulants. Second, many of these drugs are widely available in many countries, and are consequently abused by millions. METHOD: Publications cited include preclinical studies of drug self-administration and clinical PET studies of healthy and drug addicted humans. No non-English-language publications were identified. We first briefly outline the theories of the establishment of addiction in humans and the role of dopamine in the brain’s reward areas. In this framework, reinforcing effects are associated with PET results to come to a molecular imaging model of abuse liability. This model is integrated with theories of drug kinetics, target of action, chronic drug abuse effects and the contribution of personality factors, to eventually come to a neurobiological model of drug abuse liability. CONCLUSION: It is concluded that a strong and particularly fast neurobiological response of the dopaminergic system to drugs may constitute a risk factor in the development of addiction. A robust association is reported between dopamine levels and positive subjective effects. Moreover, impulsive personality factors predispose individuals to drug misuse through differences in baseline dopaminergic tone. Therefore, PET can provide valuable information to study the mechanisms of human emotion underlying drug effects

Topics: Geneeskunde, PET, dopamine, drugs, abuse potential, reinforcing
Year: 2009
OAI identifier: oai:dspace.library.uu.nl:1874/33694
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