REPEATED ADMINISTRATION OF IMIPRAMINE ATTENUATES GLUTAMATERGIC TRANSMISSION IN RAT FRONTAL CORTEX K. TOKARSKI, a B. BOBULA, a J. WABNO a,b AND G. HESS a,b * a Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland b Institute of Zoology, Jagiellonian University, Ingardena 6, 30-060 Krakow, Poland Abstract—The effects of repeated administration of a tricyclic antidepressant, imipramine, lasting 14 days (10 mg/kg p.o., twice daily), were studied ex vivo in rat frontal cortex slices prepared 48 h after last dose of the drug. In slices prepared from imipramine-treated animals the mean frequency, and to a lesser degree the mean amplitude, of spontaneous excita- tory postsynaptic currents recorded from layer II/III pyramidal neurons, were decreased. These effects were accompanied by a reduction of the initial slope ratio of pharmacologically isolated N-methyl-D-aspartate to AMPA/kainate receptor-me- diated stimulation-evoked excitatory postsynaptic currents. Imipramine treatment also resulted in a decrease of extracel- lular field potentials evoked in layer II/III by stimulation of underlying sites in layer V. These results indicate that chronic treatment with imipramine results in an attenuation of the release of glutamate and an alteration in the postsyn- aptic reactivity of ionotropic glutamate receptors in rat cere- bral cortex. © 2008 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: tricyclic antidepressant, neocortex, brain slices, AMPA/kainate receptors, NMDA receptors. Growing evidence indicates that abnormalities in the excitatory amino acid transmission play an important role in the pathophysiology of mood disorders and that a common mechanism of various antidepressant thera- pies may involve modifications in the function of the glutamatergic system (reviewed in: Paul and Skolnick, 2003; Kugaya and Sanacora, 2005; Palucha and Pilc, 2005; Schechter et al., 2005). Recent work has impli- cated dysregulation of AMPA and N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission in de- pression (Bleakman et al., 2007; Pittenger et al., 2007). The effectiveness of the inhibition of glutamate release by lamotrigine and riluzole has been demonstrated in the treatment of certain mood disorders (reviewed in: Carlson et al., 2006). To achieve a therapeutic effect, repetitive administration of antidepressant drugs for at least 2–3 weeks is necessary. This phenomenon has been linked to a slow time course of the development of adaptive modifications in several brain neurotransmitter systems, but mechanisms of these modifications remain incompletely understood (reviewed in: Holtzheimer and Nemeroff, 2006). One of human brain structures, where both structural and functional abnormalities have been found to occur in course of mood disorders, is the frontal cortex (Drevets, 2001). In frontal cortex of rats, chronic treatment with a number of antidepressant drugs, including a tricyclic antidepressant imipramine, reduces radioligand binding to NMDA receptors (Nowak et al., 1993, 1996; Skolnick et al., 1996). Chronic treatment of mice with imipramine induces region-specific effects on the level of mRNAs encoding NMDA receptor subunits (Boyer et al., 1998). NMDA re- ceptor antagonists exhibit antidepressant-like actions in animal models and potentiate the effects of antidepres- sants (Trullas and Skolnick, 1990; Maj et al., 1992; Petrie et al., 2000). It has been hypothesized that the mechanism of antidepressant action involves dampening of the func- tion of NMDA receptors (reviewed in: Skolnick, 1999), however, more recent work has demonstrated that antide- pressant treatment results also in an increased expression of AMPA receptors in rat hippocampus (Martinez-Turrillas et al., 2002). Moreover, a decreased potassium-stimulated glutamate outflow, consistent with a reduced release of synaptic glutamate, has been reported to occur in rat pre- frontal cortex after imipramine treatment (Michael-Titus et al., 2000). We have previously shown that repeated administra- tion of imipramine or citalopram, lasting 2 weeks, resulted in a decrease in the amplitude of glutamate-mediated field potentials evoked in layer II/III of rat frontal cortex by stimulation of underlying sites as well as in a reduction in the amplitude ratio of pharmacologically isolated NMDA to AMPA/kainate receptor-mediated components of the field potential (Bobula et al., 2003). These results suggested that chronic treatment with antidepressants may attenuate glutamatergic transmission in the cerebral cortex. How- ever, the extracellular recording technique does not allow for investigating the mechanism of this effect in more de- tail. Therefore, in the present study we aimed at finding the effects of repeated administration of imipramine on gluta- matergic transmission in rat frontal cortex using whole-cell recording. *Correspondence to: G. Hess, Institute of Pharmacology, Polish Acad- emy of Sciences, Smetna 12, 31–343 Krakow, Poland. Tel: +48-12- 662-3212; fax: +48-12-637-4500. E-mail address: Hess@if-pan.krakow.pl (G. Hess). Abbreviations: aCSF, artificial cerebrospinal fluid; CGP 37849, ()-2- amino-4-methyl-5-phosphono-3-pentenoic acid; eEPSC, evoked exci- tatory postsynaptic current; NBQX, 2,3-dioxo-6-nitro-1,2,3,4-tetrahy- drobenzo[f]quinoxaline-7-sulfonamide; NMDA, N-methyl-D-aspartate; sEPSC, spontaneous excitatory postsynaptic current; TTX, tetrodo- toxin. Neuroscience 153 (2008) 789 –795 0306-4522/08$32.00+0.00 © 2008 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2008.03.007 789