Pharmacological adaptations and muscarinic receptor plasticity in hypothalamus of senescent rats treated chronically with cholinergic drugs.

Abstract

Receptor plasticity is an important compensatory process by which the central nervous system adapts to pathological insult or long-term exposure to drugs. Senescent animals may show an age-related impairment of muscarinic receptor up- or down-regulation after chronic exposure to cholinergic drugs. The purpose of this study was to assess biochemical and pharmacological endpoints of muscarinic receptor plasticity in young, adult and senescent animals. Male, Fischer 344 rats (ages 3, 9, and 27 months) were administered methylatropine or oxotremorine intracerebroventricularly (IVT) for 3 weeks and tested for their functional response to a muscarinic agonist. The density of hypothalamic, muscarinic receptors was also estimated from analysis of 3H-QNB binding isotherms. In young rats, parallel changes in muscarinic receptors and response were noted, but chronic administration of cholinergic drugs to senescent animals had no effect. Thus, 3H-QNB binding in hypothalamus of young and adult rats was increased (31% and 17%) after chronic IVT methylatropine and decreased (20% and 15%) after IVT oxotremorine. Also, young rats treated with IVT methylatropine were supersensitive to the hypothermic effects of a muscarinic agonist (oxotremorine), while young and adult animals administered chronic IVT oxotremorine exhibited marked tolerance. In contrast, identically treated senescent rats showed no changes in 3H-QNB binding or oxotremorine-induced hypothermia. These results demonstrate the impaired ability of senescent rats to up- or down-regulate brain muscarinic receptors and to exhibit functional adaptations seen in young animals treated chronically with cholinergic drugs.