ALUMINUM DECREASES MUSCARINIC, ADRENERGIC, AND METABOTROPIC RECEPTOR-STIMULATED PHOSPHOINOSITIDE HYDROLYSIS IN HIPPOCAMPAL AND CORTICAL SLICES FROM RAT-BRAIN

Effects of aluminum chloride (AlCl3) (0.1 to 1000 muM) on inositol pho sphate (IP) accumulation stimulated by carbachol (CARB), norepinephrin e (NE) or quisqualate (QUIS) were examined in rat hippocampal and cort ical slices. In the absence of agonist, only 1000 muM AlCl3 significan tly reduced basal accumulation of IPs. For CARB-stimulated IP accumula tion, 100 muM and greater AlCl3 significantly inhibited IP accumulatio n. In cortical slices, 1000 muM AlCl3 reduced CARB-stimulated IP accum ulation by 55% and in hippocampal slices 1000 muM AlCl3 inhibited IP a ccumulation by 40%. Similar effects of AlCl3 were observed for NE-stim ulated IP accumulation. In cortical slices, the concentration-response for AlCl3 effects on agonist-stimulated IP accumulation was significa ntly different from that in hippocampal slices. For QUIS-stimulated ac cumulation of IPs, 1000 muM AlCl3 Significantly inhibited IP accumulat ion in hippocampal slices. However, in cortical slices a biphasic effe ct of AlCl3 was observed. 500 and 1000 muM AlCl3 significantly inhibit ed IP accumulation, whereas 10 and 50 muM AlCl3 significantly enhanced QUIS-stimulated IP accumulation. In both hippocampal and cortical sli ces, 500 muM AlCl3 significantly inhibited CARB-, NE- or QUIS-stimulat ed IP accumulation at all agonist concentrations (0.1 to 10000 muM) te sted, indicating a post-receptor effect on agonist-mediated IP accumul ation. Stimulation of G-proteins with NaF (5-30 mM) resulted in accumu lation of IPs in hippocampal and cortical slices in the absence of add ed agonists. NaF (5-30 mM) plus 1 mM CARB produced increased accumulat ion of IPs over CARB or NaF alone. AlCl3 inhibited CARB- and NaF-stimu lated IP accumulation, suggesting that AlCl3 decreases IP accumulation by inhibiting G-protein or phospholipase C (PLC) activity. To determi ne the influence of the form of aluminum salt on IP accumulation, the effects of equimolar concentrations of AlCl3, aluminum citrate (Al(Cit )), and aluminum lactate (Al(Lac)) on CARB-stimulated IP accumulation were determined. AlCl3 and Al(Lac) produced similar inhibition of IP a ccumulation, whereas Al(Cit) did not inhibit receptor-stimulated IP ac cumulation. These results suggest that: (1) AlCl3 disrupts IP accumula tion mediated by different pharmacological classes of receptors; (2) d ifferences in sensitivity to AlCl3 exist in the hippocampus and cortex ; (3) AlCl3 and AlF4- influence IP accumulation through separate mecha nisms and AlF4- is not responsible for effects of AlCl3 on receptor-st imulated IP accumulation; (4) AlCl3 appears to exert its action on IP accumulation 'downstream' of the receptor and receptor-G-protein inter action; and (5) Effects of aluminum on IP accumulation are dependent u pon the aluminum salts used.