Life Sciences, Vol. 43, pp. 303-307 Pergamon Press Printed in the U.S.A. ANTIDEPRESSANTS AND SEIZURE-INTERACTIONS AT THE GABA-RECEPTOR CHLORIDE-IONOPHORE COMPLEX Ewa Malatynska*, Richard J. Knapp, Masaaki Ikeda, and Henry I. Yamamura University of Arizona, Department of Pharmacology Health Sciences Center Tucson, Arizona 85724 USA (Received in final form May 24, 1988) Summary Convulsive seizures are a potential side effect of antidepressant drug treatment and can be produced by all classes of antidepressants. It is also known that some convulsant and anticonvulsant drug actions are mediated by the GABA-receptor chloride-ionophore complex. Drugs acting at this complex appear to induce convulsions by inhibiting chloride conductance through the associated chloride channel. Using the method of GABA-stimulated 36C1-uptake by rat cerebral cortical vesicles, we show that some antidepressant drugs (imipramine, amitryptyline, and mianserine) can inhibit the GABA-receptor chloride uptake, and that the degree of chloride channel inhibition by these drugs correlates with the frequency of convulsive seizures induced by them. One of the most important side-effects produced by antidepressants are convulsive seizures. Although this phenomenon is uncommon, serious reactions can occur during Ireatment with practically all antidepressants (5) including: desipramine (DMI) (11), amilriptyline (AMI) (7), imipramine (IMI) (6), and mianserine (MIAN) (4). In clinical studies it is sometimes difficult to establish whether convulsive seizures are due to antidepressant treatment ~r to other clinical or pharmacological conditions (4, 9). Animal experiments are also contradictory. Some studies (8, 21, 24) have described antidepressant-induced seizures while others suggest that some antidepressants can act as weak anticonvnisants (12, 14, 19). Many neurotransmitter systems have been implicated in the general etiology of seizures including noradrenergic, serotonergic, dopaminergic, cholinergic (20), and GABAergic (16) systems. Other agents can act directly at the chloride channel to produce seizures (3, 18). We recently showed that GABA-stimulated chloride influx into membrane vesicles from the rat cerebral cortex can be enhanced by benzodiazepines such as clonazepam, flunitrazepam, and diazepam (17). These compounds are benzodiazepine (BZ) agonists having positive intrinsic efficacy. These drugs also show anticonvulsant as well as anxiolytic and sedative properties. On the other hand, some [3-carbolines such as ethyl [3-carboline-3-carboxylate ([3-CCE) and methyl 6, 7-dimethoxy-4-ethyl-13-carboline-3-13- carboxylate (DMCM) inhibit this biochemical response (17). These drugs are inverse agonists having negative intrinsic efficacy. They can induce convulsions in some animal paradigms. Antidepressants are not generally thought to exert effects on the BZ-GABA-receptor chloride ionophore complex. However, some studies (25, 26) support the idea that an interaction of antidepressants with this complex may be important for their convulsant and therapeutic effects. Since convulsive seizures are an important side-effect of the antidepressants, we investigated the possible interaction of antidepressants with the GABA-receptor chloride ionophore complex. Methods Preparation of membrane vesicles. Adult male Spragne-Dawley rats (200-300g) were decapitated and their brains removed. Cerebral cortices were rapidly dissected and~omogenized in ice-cold buffer (10mM HEPES, 145mM NaCI, 5mM KCI, 1.0mM MgCI2, 1.0raM CaCI2, and 10raM D-glucose; pH adjusted to 7.5 with Tris base) with 12 strokes using a glass-glass homogenizer. A membrane fraction was obtained from the homogenate by eentrifugation at 1000 x g for 15min at *Present address: Ohio State University, Department of Psychiatry, Neuroscience Program, Columbus, Ohio 43210 0024-3205/88 $3.00 + .00 Copyright (c) 1988 Pergamon Press plc