REDUCTIONS OF FE-56 HEAVY-PARTICLE IRRADIATION-INDUCED DEFICITS IN STRIATAL MUSCARINIC RECEPTOR SENSITIVITY BY SELECTIVE CROSS-ACTIVATION/INHIBITION OF 2ND-MESSENGER SYSTEMS

Recent experiments have revealed radiation-induced (600 MeV/u Fe-56 energetic particles) losses of sensitivity of rodent neostriatal muscarinic receptors to stimulation by cholinergic agonists that appears as reductions in oxotremorine enhancement of K+-evoked dopamine release. These losses were postulated to be the result of radiation-induced alterations early in phosphoinositide-mediated signal transduction. Additional findings indicated that if the ligand-receptor-G protein interface was bypassed no radiation deficits were seen. In the present study, radiation-induced deficits in K+-evoked dopamine release were examined in perifused striatal tissue obtained from rats exposed to 0, 0.1 or 1.0 Gy of Fe-56 particles (600 MeV/u). Results showed that these deficits could be reduced by co-applying combinations of various pharmacological agents that were known to have differential effects on various second messengers such as 1,4,5-inositol-trisphosphate (IP3) Combinations included oxotremorine-carbachol, and either oxotremorine or carbachol with arginine vasopressin or arachidonic acid. These results are discussed in terms of putative radiation-induced changes in receptor-containing membranes which alter receptor-G protein coupling/uncoupling.