Nicotine protects cultured cortical neurons against glutamate-induced cytotoxicity via α₇-neuronal receptors and neuronal CNS receptors

We examined the effects of nicotine on glutamate-induced cytotoxicity using primary cultures of rat cortical neurons. The cell viability decreased significantly when cultures were exposed to glutamate for 10 min and then incubated with glutamate-free medium for 1 h. The exposure of cultures to nicotine (10 μM) for 8-24 h prior to glutamate application ameliorated the glutamate-induced cytotoxicity, with no significant effect of nicotine alone on the cell viability. Neuroprotection by nicotine was dependent on the incubation period. α-bungarotoxin (α-BTX) and methyllycaconitine (MLA), both of which are α₇-neuronal receptor antagonists, and dihydro-β- erythroidine (DHβE), a neuronal central nervous system (CNS) receptor antagonist, each significantly antagonized the protection by nicotine against glutamate-induced cytotoxicity. Ionomycin, a calcium ionophore, and S- nitrosocysteine (SNOC), a nitric oxide (NO) donor, also induced cytotoxicity in a manner similar to glutamate. Nicotine protected cultures against ionomycin-induced cytotoxicity, but not against SNOC-induced cytotoxicity. These results suggest that nicotine protects cultured cortical neurons against glutamate-induced cytotoxicity via α₇-neuronal receptors and neuronal CNS receptors by reducing NO-formation triggered by Ca²⁺ influx.