Development of heroin addiction: a consequence of heroin or of its metabolites?

The objective of the present project is to investigate if and how heroin metabolites contribute to the development and appearance of heroin addiction. Heroin abuse is a significant medical problem due to its damaging consequences, both social and individu al, and it is difficult to treat. Heroin reaches the brain in significant concentrations very rapidly after intake, which is supposed to be the reason why drug addicts prefer heroin over other opioids like morphine. However, heroin has a very short half l ife; its concentration is reduced by half already after less than five minutes. Also, heroin has a low affinity for receptors in the brain known to mediate the effects of opioids. Therefore, it is surprising that a substance with a relative little effect in the brain and which disappears so quickly can have a so strong effect on behaviour like drug addiction. There is a sequence of substances appearing after heroin intake which can be responsible for its effects and the development of heroin dependence. H eroin is transformed to 6-monoacetylmorphine, which is converted to morphine. This is further metabolised to morphine-3- and morphine-6-glucuronide. Morphine is a well known active opioid with strong addictive properties. The pharmacological activity and addiction potential of the other metabolites are not well established, but there is some evidence that they also may have effects which could contribute to heroin effects and addiction. We will study the addictive potential of these heroin metabolites in animal tests, as well as their possible contribution to the development of addiction after heroin intake. By using neurochemical tools (in vivo microdialysis) we will also examine dopaminergic neural systems responsible for the pharmacological activity of the metabolites, and which can mediate their potential effects on heroin addiction.