Congrès annuel SFT - Paris, 23-24 octobre 2006
"Toxicologie de la pharmacodépendance aux médicaments et aux drogues" Current non-clinical models for assessment of drug dependency Pascal CHAMPEROUX Non-clinical models of drug dependency can be classified in two categories designed to assess the two main kinds of dependency found in Man, respectively. The mechanisms underlying these two kinds of drug dependency are complex and different but are often closely related, since some addictive drugs are able to produce both kinds of dependency. The first kind of drug dependency refers to the concept of positive reinforcement and a state of psychic dependence. In this case, drug self administration behaviour is a form of pleasure-seeking which can establish habituation, that is compulsive drug-taking. This first form of dependency is related to common central dopaminergic mechanisms involved in “rewards pathways” which lead to an increase in dopamine release in specific CNS areas such as the nucleus accumbens or the ventral tegmental area. The main models used for assessment of such positive reinforcing properties are conditioned place avoidance, drug discrimination and self administration models, which will be presented by R. Porsolt.
The second kind of drug dependency refers to the concept of negative reinforcement and a state of physical dependence. In this case, the main motivation of a subject for repeated self administration is to prevent withdrawal symptoms on cessation of drug intake. From a neurobiolological point of view, the underlying mechanisms are various but frequently are a consequence of a neuroadaptation through up or down regulation mechanisms of receptors involved in the primary pharmacological response. Drug tolerance, which corresponds to a progressive reduction in the pharmacological response following repeated administration, is a consequence of this neuroadaptation and is considered to be a strong indicator of a possible physical dependence. Evaluation of symptoms related to spontaneous withdrawal may be used for detection of such a dependency. However, treatment protocols based on tolerance induction are preferable to reveal signs of withdrawal. Models of precipitated withdrawal based on use of selective antagonists enable a more sensitive and mechanistic evaluation of a possible physical dependence. However, selective antagonists might not be available for testing new classes of drugs with new mechanisms of action. Moreover, characterisation of a withdrawal syndrome may need a long period of treatment, up to several weeks for some classes of molecules such as the benzodiazepines. There is a need for shorter procedures in particular applicable to the earliest stages of drug development. The assessment of EEG threshold to an anaesthetic agent like hexobarbital could be an interesting model. |
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