STUDIES OF ALUMINUM NEUROBEHAVIORAL TOXICITY IN THE INTACT MAMMAL

1. Aluminum (Al) has been implicated in neurotoxic syndromes in severa l conditions, including Alzheimer's disease (AD). The developmental st age of the mammalian brain most susceptible to Al was determined in ra bbits systemically exposed to Al during the prenatal, postnatal, or se cond month or for 1 month as adults or as aged subjects. Eyeblink refl ex classical conditioning showed an Al-induced learning deficit only i n the adult and aged rabbits. 2. 4-Aminopyridine, which was reported t o improve learning in AD subjects, attenuated this Al-induced learning deficit. 3. Conditioned eyeblink acquisition is slower in AD subjects than controls, supporting the Al-loaded rabbit as a model of some AD effects. 4. To determine if the Al-loaded rabbit modeled the AD cholin ergic deficit, acetylcholine (Ach) overflow was measured in rabbit hip pocampus using microdialysis. Aluminum pretreatment reduced basal and potassium-stimulated Ach overflow compared to controls. 5. Acetylcholi ne overflow increased as control rabbits acquired the conditioned eyeb link reflex, then subsequently decreased, although conditioned eyeblin k performance continued. In contrast, Al-loaded rabbits showed a delay in conditioned eyeblink acquisition and greatly attenuated Ach overfl ow. The Al-induced attenuation of Ach overflow may contribute to the A l-induced learning deficit. 6. Brain Al entry was studied using microd ialysis of blood, brain, and lateral ventricle. Aluminum rapidly enter ed the brain and lateral ventricle. Frontal cortical Al was greater th an lateral ventricular Al, suggesting that Al primarily enters the bra in through the cerebral microvasculature. 7. The brain/blood Al ratio was always significantly less than 1. This ratio was influenced by the Al form administered, brain site and animal species. Thus, there appe ars to be an active process moving Al out of brain extracellular fluid (ECF). 8. Brain and blood dialysate Ach concentrations were not diffe rent after cyanide addition to the dialysate, supporting the conclusio n that an active process moves Al out of brain ECF.