Potential role of reactive metabolites of addictive drugs at the receptor: A novel hypothesis

The central nervous system (CNS) stimulants to CNS depressants such as morphine, cocaine, methamphetamine and nicotine each have the capacity for inducing chemical dependence with an enormous impact on human behavior. Because of the difficulties in isolation, the role of the reactive metabolites as a modulating factor in the receptor activation and related addiction of these drugs is not studied. The chemical transformations of these compounds to their metabolites at the receptors have been proposed. There is the distinct possibility that irreversible binding of N-hydroxy, N-formyl or related metabolites of morphine, cocaine, methamphetamine, or nicotine with the respective receptors can occur. This unique role of highly reactive molecular species is postulated. In this way, the synaptic glutaminergic and or dopaminergic transmission can be compromised. On repeated exposure of the drug, the receptor reserve may decrease. More drug is needed to activate the residual receptor to maintain the reward in addiction.