Dopamine receptor supersensitivity: Development, mechanisms, presentation, and clinical applicability

The process of receptor supersensitivity (RSS) has a long history and is an epiphenomenon of neuronal denervation. Dopamine (DA) RSS (DARSS) similarly occurs after DA-denervation, and this process is invoked in neuropsychiatric and neurodegenerative disorders. From studies largely over the past 25 years, much has been learned regarding DARSS. For example, overt D₁ DARSS occurs after perinatal destruction of nigrostriatal DA fibers. However, following perinatal destruction of DA innervation, the mostprominent behavioral effects of a D₁ agonist are observed after a series of D₁ agonist treatments- a process known aspriming of D₁DA receptors. Moreover, perinatal lesioning of DA fibers produces prominent serotonin (5-HT) RSS, and in fact 5-HT RSS appears to modulate D₁ DA RSS. In rodents, receptor supersensitization by these means appears to be irreversible. In contrast to the observedD ₁ DARSS, D₂ DARSS apparently does not occur after perinatal DA denervation. Also, while repeated D₁ agonist treatment of intact rats has no observable effect, repeated D₂ agonist treatments, during or after the ontogenetic phase, produces prominent life-long D₂ RSS. The process may have an association with substance abuse. Therefore, production of D₁ and D₂ DARSS occurs by different means and under different circumstances, and in association with perhaps different neuronal phenotypes, and with greater incidence in either intact (D₂) or DA-lesioned counterparts (D₁). The physiological consequence of RSS are multiple.