MECHANISMS OF RECEPTORS REGULATION DURING REPEATED DRUG ADMINISTRATION

The effects of drugs is mainly explained by their action on specific r eceptors located on target cells. However, the receptors are can be re gulated by changes into the levels of the physiological neurotransmitt er and/or by drugs. A chronic treatment by an agonist induces a desens itization leading to a decrease in cellular response. The desensitizat ion is ''homologous'' when if only involves the activated pathway and ''heterologous'' when a decrease in the response to of her factors (tr ansmitters, drugs) appears. At the molecular level, desensitization is explained by covalent modification of the receptors by phosphorylatio n catalyzed by a variety of protein kinases. A long term stimulation e licits an internalization of the receptor followed by degradation : th is mechanism is called ''down regulation''. In contrast, treatment wit h antagonists can induce hypersensitization (ie. increase in the cellu lar response) with up regulation. The consequences of these notions ar e discussed in term of both clinical pharmacology and pharmacovigilanc e.