[Mechanism of receptor regulation during repeated administration of drugs]

The effects of drugs is mainly explained by their action on specific receptors located on target cells. However, the receptors are can be regulated by changes into the levels of the physiological neurotransmitter and/or by drugs. A chronic treatment by an agonist induces a desensitization leading to a decrease in cellular response. The desensitization is "homologous" when it only involves the activated pathway and "heterologous" when a decrease in the response to other factors (transmitters, drugs) appears. At the molecular level, desensitization is explained by covalent modification of the receptors by phosphorylation catalyzed by a variety of protein kinases. A long term stimulation elicits an internalization of the receptor followed by degradation: this mechanism is called "down regulation". In contrast, treatment with antagonists can induce hypersensitization (i.e. increase in the cellular response) with up regulation. The consequences of these notions are discussed in term of both clinical pharmacology and pharmacovigilance.