Behavioral Effects of Calcium Channel Blockers: Acute Exposures and Neuroprotection Against Methylmercury Neurotoxicity
Abstract
The maintenance of intracellular calcium homeostasis is among the most important homeostatic functions of the nervous system as it allows the calcium ion to function as a chemical messenger. Often damage to the central nervous system (CNS) disrupts intracellular calcium homeostasis, causing increased intracellular concentrations of calcium ions, which result in cellular dysfunction and/or death and manifests as changes in the organism’s behavior. Calcium channel blockers (CCBs) have been touted as “cognitive enhancers” but result in divergent effects on behavior that seem to depend upon the presence or absence of nervous system insult. When administered in the absence of CNS injury CCBs often have deleterious effects, are beneficial or no effect at all on behavior. However, in the presence of a variety of CNS injuries resulting in increased intracellular calcium, CCBs reliably offer protection. Here, CCBs were administered acutely to healthy, adult mice to determine their effects in the absence of CNS injury. Following that, one dihydropyridine CCB (nimodipine) was administered chronically to mice with and without chronic co-exposure to 15 ppm Methylmercury (MeHg), a toxicant known to elevate intracellular calcium concentration and cause cognitive and motor impairments. When administered acutely to healthy animals CCBs either had no effect or reduced responding and accuracy on an incremental repeated acquisition (IRA) procedure, depending on dose. When administered chronically to MeHg exposed animals, nimodipine prevented the declines in performance and responding on IRA. Importantly, nimodipine had no effect on any of these endpoints when administered to the non-MeHg control animals, suggesting a MeHg-dependent effect of nimodipine. The series of experiments presented here support the hypothesis that CCBs are exclusively beneficial when CNS injury is present. Additionally, the beneficial effects of nimodipine + MeHg exposure support the hypothesis that MeHg-induced changes in calcium homeostasis mediate the behavioral toxicity seen with MeHg exposure.