CARBAMAZEPINE-INDUCED RELEASE OF SEROTONIN FROM RAT HIPPOCAMPUS IN-VITRO

Purpose: Carbamazepine is one of several antiepileptic drugs (AEDs) th at release the inhibitory neurotransmitter serotonin as part of their pharmacodynamic action on brain neurons. We undertook this study to in vestigate the cellular processes by which carbamazepine (CBZ) releases serotonin from brain tissue. Methods: Tissue slices were prepared fro m hippocampi of Sprague-Dawley rats. These hippocampal slices were pre incubated in vitro in a buffer so that neurons within the slice would take up tritium-labeled serotonin. Subsequently the slices were superf used with buffer containing CBZ or other chemicals (or both) that incr ease the overflow of serotonin radioactivity. Results: Carbamazepine p roduced a concentration-dependent (50, 125, 250, or 500 mu M) increase in basal overflow of serotonin radioactivity from superfused rat hipp ocampal slices in vitro. In contrast, these concentrations did not alt er potassium-stimulated release, suggesting that the CBZ-induced relea se does not depend on depolarization or exocytosis. Blockade of the ne uronal membrane serotonin transporter by fluoxetine (1 mu M) or citalo pram (2 mu M) did not alter overflow of serotonin radioactivity produc ed by 250 mu M CBZ. p-chloramphetamine (10 mu M) produced a substantia l increase in overflow of serotonin radioactivity, and this effect app ears to be antagonized by 250 mu M CBZ. Uptake of [H-3]-labeled seroto nin into hippocampal synaptosomes was inhibited by CBZ with a median i nhibitory concentration (IC50) of 511 +/- 33 mu M and a Hill coefficie nt of 0.87 +/- 0.11, suggesting competitive inhibition of uptake by CB Z.Conclusions: We conclude that CBZ (a) releases serotonin from hippoc ampal slices independent of exocytosis and by a mechanism not involvin g the neuronal membrane serotonin transporter, and (b) at high enough concentration, blocks the neuronal serotonin transporter.