Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex
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TRANSLATIONAL NEUROSCIENCES - ORIGINAL ARTICLE
Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex Joanna Wabno • Grzegorz Hess
Received: 13 August 2012 / Accepted: 7 November 2012 / Published online: 21 November 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract Alterations in the functions of brain gammaaminobutyric acid (GABA) inhibitory system and a distortion in the balance between excitatory and inhibitory synaptic transmission have been hypothesized to be possible causes of mood disorders. Experimental evidence points to modifications of GABAergic transmission as a result of prolonged treatment with antidepressant drugs, however, the influence of the tricyclic antidepressant imipramine on inhibitory synaptic transmission in the rat cerebral cortex has not yet been investigated. Therefore, in the present study the effects of single and repeated administration of imipramine were evaluated ex vivo in slices of the rat frontal cortex using electrophysiological approach. In slices prepared 2 days after the last drug administration from animals receiving imipramine for 14 days (dose 10 mg/kg p.o., twice daily) the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from layer II/III pyramidal neurons was decreased, while the mean amplitude of sIPSCs was increased. These effects were absent in slices obtained from rats which received imipramine once. Application of N,N0 -dibenzhydrylethane-1,2-diamine dihydrochloride (AMN 082), a selective mGluR7 allosteric agonist, to the slice incubation medium resulted in a decrease in the mean frequency of sIPSCs in preparations obtained from repeated imipramine-treated animals, in contrast to slices originating from control rats where no AMN 082-induced J. Wabno G. Hess (&) Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krako´w, Poland e-mail: [email protected] G. Hess Institute of Zoology, Jagiellonian University, Gronostajowa 9, 30-387 Krako´w, Poland
effects were observed. Repeated imipramine treatment reduced protein density levels of the three tested GABAA receptor subunits: a1, b2 and c2. These data indicate that repeated treatment of normal rats with imipramine results in a modification of the release mechanism of GABA from presynaptic terminals and its modulation by mGluR7 receptors as well as in an alteration in GABAA receptor subunit protein levels in the rat cerebral cortex. Keywords Tricyclic antidepressant GABAA receptor Pyramidal neuron Spontaneous IPSCs
Introduction A large proportion of the population affected by depression is not responding adequately to current treatments. It has been estimated that only one-third of patients respond to the first medication prescribed and that treatment-resistant depression may represent up to 50–70 % of cases (reviewed in: Duric and Duman 2012; Jenkins and Goldner 2012). Despite many years of research focusing on the efficacy of antidepressan
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