IN-VIVO OR IN-VITRO ADMINISTRATION OF THE NITRONE SPIN-TRAPPING COMPOUND, N-TERT-BUTYL-ALPHA-PHENYLNITRONE, (PBN) REDUCES AGE-RELATED DEFICITS IN STRIATAL MUSCARINIC RECEPTOR SENSITIVITY

Previous research has indicated that age-related reductions in muscarinic (m) (e.g. oxotremorine, Ore) agonist enhancement of striatal K+-evoked dopamine release (K+-ERDA) and decreased IP3 release upon m receptor (mAChR) agonist stimulation are partially the result of deficits in signal transduction (ST). The present experiments were carried out to test the hypothesis that these age-related ST deficits occur as a result of free radical-induced alterations in membranes containing receptor-G protein complexes. To test this hypothesis, the effects of in vivo and in vitro administration of the nitrone trapping agent, n-tert-butyl-alpha-phenylnitrone (PEN), on the Ore-enhancement of K+-ERDA were examined. Results showed that: both in vivo (10 mg/kg/2 X day PEN i.p./14 days) in vitro (incubation of striatal slices 0-100 mu M PBN/30 min) applications of PEN were effective in ameliorating age-related deficits in Ore-enhanced K+-ERDA. The results of the in vivo administration of PEN indicate that the loss of mAChR sensitivity in aging may be the result of oxidative stress that can be restored by this nitrone trapping agent. These findings show that reductions of endogenous or exogenous free radicals may alter one important biomarker of aging, i.e. the loss of sensitivity in mAChR systems. However, these results, when considered along with those obtained with in vitro administration indicate that in addition, PEN may have acute effects (e.g. perhaps membrane structural alterations) which can also improve mAChR responsiveness.