The mechanisms of action of three psychotropic drugs, carbamazepine, lithium, and buspirone, have been studied. We previously demonstrated that carbamazepine (CBZ) at concentrations above the therapeutic range is toxic to cultured cerebellar granule cells (CGC). We now show that treatment of cultured CGC with CBZ for 3 days resulted in fragmentation of DNA characteristic of apoptosis. N-methyl-D-aspartate (NMDA) blocked carbamazepine-induced DNA fragmentation and neurotoxicity. Aurintricarboxylic acid (ATA), a poly anionic dye, also markedly suppressed DNA fragmentation and the cell death. Moreover, NMDA and ATA prevented CBZ-induced chromatin condensation. Pretreatment of cells with cycloheximide, a protein synthesis inhibitor, prevented CBZ-induced neurotoxicity. CBZ-induced neuro-toxicity was similar to that induced by phenytoin, another anticonvulsant. CBZ and phenytoin added to aged CGC protected against aging-induced apoptosis. Both neuro-toxic and neuroprotective effects of CBZ may be due to its ability to inhibit NMDA receptor-mediated Ca2+ influx. CGC express a novel type of NMDA receptor with atypical sensitivity to glycine. This putative receptor was developmentally regulated and appeared to confer CBZ sensitivity. Additionally, we have studied the mechanisms of action of lithium. We found that lithium was neurotrophic to CGC and protected against neurotoxicity induced by CBZ and phenytoin. Lithium also induced transcription factor binding to AP-1 sites in CGC and in vivo. This action could be relevant to its clinical effect. We have also studied the in vivo actions of another psychotropic drug, buspirone. After chronic buspirone treatment of rats, the 5-HT1A receptor mRNA levels were significantly decreased in the CA1 and CA2 of the hippocampus, but were markedly increased in the dentate gyrus (DG, CA3, and CA4). Buspirone treatment markedly increased 5-HT2A receptor mRNA levels in the DG CA2, CA3, and CA4. This was accompanied by a significant increase in the level of 5-HT2A receptor binding sites in all sub-hippocampal regions.
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