Modulatory effects of neuropsychopharmaca on intracellular pH of hippocampal neurones in vitro.

background and purposeThe intracellular pH (pHi) of neurones is tightly regulated by, for example, membrane-bound acid-exchangers and loaders. Nevertheless, excessive bioelectric activity lowers steady-state pHi. In turn, even a moderate acidification can inhibit neuronal activity, a process believed to be part of a negative feedback loop controlling neuronal excitation. As moclobemide, an antidepressant, and also some antiepileptic drugs can reduce neuronal pHi in hippocampus slices in vitro, we screened a panel of currently used neuropsychopharmaca for comparable effects. EXPERIMENTAL APPROACH: BCECF-AM loaded hippocampal slices were superfused with 16 different neuroleptics, antidepressants and antiepileptics under bicarbonate-buffered conditions. Changes in steady-state pHi of CA3 neurones were measured fluorometrically. KEY

resultsThe 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 by up to 0.35 pH-units in concentrations of 5-50 microM. In contrast, venlafaxine, the anticonvulsants carbamazepine, clonazepam, gabapentin, lamotrigine, zonisamide, and the mood stabilizer lithium had no effect on neuronal pHi. CONCLUSION AND IMPLICATIONS: These data substantiate the view that clinically relevant concentrations of neuroleptics and antidepressants can mediate changes in neuronal pHi, which may contribute to their pharmacological mode of action. Effects on pHi should be taken into account when therapeutic or even harmful effects of these drugs are evaluated.