TY - JOUR T1 - Alterations in calcium antagonist receptors and calcium content in senescent brain and attenuation by nimodipine and nicardipine. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 721 LP - 727 VL - 277 IS - 2 AU - S Yamada AU - S Uchida AU - T Ohkura AU - R Kimura AU - M Yamaguchi AU - M Suzuki AU - M Yamamoto Y1 - 1996/05/01 UR - http://jpet.aspetjournals.org/content/277/2/721.abstract N2 - Characteristics of L- and N-type calcium (Ca++) channel antagonist receptors in brains of senescence-accelerated prone mouse (SAMP8) showing age-related deterioration of learning and memory were examined by using (+)-[3H]PN 200-110 and [125I]omega-conotoxin GVIA as radioligands. There was a tendency toward consistent decrease in Bmax for both radioligands in seven brain regions of SAMP8 compared with the control mouse. The reduction in (+)-[3H]Pn 200-110 binding sites was statistically significant in the hippocampus, midbrain and pons/medulla oblongata, and that in [125I]omega-conotoxin binding sites was significant in the cerebral cortex, corpus striatum and pons/medulla oblongata. On the other hand, there was a marked elevation in Ca++ content in the brain of SAMP8. Chronic p.o. administration (0.3, 1 and 3 mg/kg/day for 3 weeks) of nimodipine and nicardipine to SAMP8 caused a significant increase in the Bmax values of (+)-[3H]PN 200-110 binding in the cerebral cortex and hippocampus. This may reflect up-regulation of brain Ca++ channel antagonist receptors as a result of the prolonged blockade by nimodipine and nicardipine. On the other hand, similar administration of amlodipine and nilvadipine failed to produce an enhancement of Bmax values of (+)-[3H]PN 200-110 binding, whereas both drugs at high doses evoked a significant increase in the apparent dissociation constant. Furthermore, the brain Ca++ content in SAMP8 was markedly reduced by chronic p.o. administration of Ca++ channel antagonists, and the decrease was equivalently observed for all of four 1,4-dihydropyridine antagonists in spite of the difference in the effect on brain receptors. In conclusion, the present study suggests that there is an altered Ca++ homeostasis in the SAMP8 brain that is effectively attenuated by chronic administration of nimodipine and nicardipine. Hence SAMP8 may be a suitable animal model for evaluating the therapeutic effects of Ca++ channel antagonists on neurological disorders associated with the aging brain. ER -