Modulatory effects of various neuropsychopharmaca on intracellular pH of hippocampal CA3-neurons in vitro (guinea pig)

The intracellular pH (pHi) of neurons is tightly regulated e.g. by membrane bound acid-exchangers and loaders. Since we recently found some antiepileptics reducing neuronal steady state pHi in hippocampus slices, we were curious about whether or not other neuropsychopharmaca (NPP) may exert similar effects. We screened a total of 16 drugs currently used as neuroleptics, antidepressants and further antiepileptics. Neuronal pHi was measured fluorometrically using BCECF-AM loaded hippocampal slices under bicarbonate-buffered conditions. The antipsychotics haloperidol, clozapine, ziprasidone, and the antidepressants amitriptyline, doxepin, trimipramine, citalopram, mirtazapine, as well as the anticonvulsive drug tiagabine reversibly reduced the steady state pHi of CA3 neurons by up to 0.35 pH-units in concentrations of 5–50µM, calculated to be in the upper therapeutic range. In contrast, venlafaxine, the anticonvulsants carbamazepine, clonazepam, gabapentin, lamotrigine, zonisamide, and the mood stabilizer lithium had no effect on neuronal pHi. We provide first evidence that many NPP are able to lower neuronal steady state pHi of hippocampal neurons in acute in vitro experiments.It appears reasonable to suggest that these acidifications will influence neuronal cell functions, such as excitability and intra- as well as intercellular signaling. Therefore, the pHi activity of NPP should be taken into consideration when therapeutic or even toxic effects of these drugs are discussed.