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Pjp2'2002.Vp:Corelventura Copyright © 2002 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2002, 54, 8993 ISSN 1230-6002 EFFECT OF IMIPRAMINE ON BRAIN D-1 AND 5-HT-2A RECEPTORS IN A CHRONIC UNPREDICTABLE STRESS MODEL IN RATS Gra¿yna Ossowska1,#, Gabriel Nowak2,3, Bo¿ena Klenk-Majewska1, Zofia Danilczuk1, Iwona ¯ebrowska-£upina1 Department of Clinical Pharmacology, Medical University School, Jaczewskiego 8, PL 20-090 Lublin, Poland, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland, !Department of Pharmacobiology, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland Effect of imipramine on brain D-1 and 5-HT-2A receptors in chronic un- predictable stress model in rats. G. OSSOWSKA, G. NOWAK, B. KLENK- -MAJEWSKA, Z. DANILCZUK, I. ¯EBROWSKA-£UPINA. Pol. J. Phar- macol., 2002, 54, 89–93. Chronic unpredictable stress (CUS) model of depression is one of the well validated animal models of depression. In this paper, we report the re- sults of investigations into dopaminergic D-1 and serotonergic 5-HT-2A re- ceptors in the brain of rats subjected to CUS procedure and treated chroni- cally with imipramine. We have examined the dopaminergic D-1 ([!H-SCH 23390) in the limbic area and serotonergic 5-HT-2A ([!H-ketanserin) recep- tors in the cerebral cortex by a saturation radioligand binding method in rats subjected to CUS paradigm, imipramine, both CUS and imipramine and control animals. CUS procedure resulted in a significant 36% increase in the D-1 receptor density in the limbic system, which was attenuated by chronic imipramine treatment. Also a 21% increase in the density of 5-HT-2A recep- tors in the cerebral cortex induced by CUS was reduced by chronic imi- pramine treatment. The present data indicate that the increases in the density of brain D-1 and 5-HT-2A receptors of rats subjected to CUS, which are “normalized” by imipramine, might be involved in the pathophysiology of “animal depression” (and, thus, in pathophysiology of human depression) and in the mechanism of antidepressant therapy. Key words: imipramine, chronic stress, brain, D-1, 5-HT-2A receptors, rats correspondence G. Ossowska, G. Nowak, B. Klenk-Majewska, Z. Danilczuk, I. ¯ebrowska-£upina INTRODUCTION animals was subjected to a CUS procedure for a pe- riod of 16 consecutive days. The rats were subjec- The most significant behavioral changes ob- ted, to the following kinds of stressors (one stress served in animals following exposure to chronic a day): 20 s exposure to electric footshock (3 mA, stress (i.e. motor activation deficit, reduced food 0.2 s impulse duration, every 2 s), 2 h period of im- and water consumption, decrease in responsiveness mobilization at 20°C or at 4°C, 5 min exposure to to rewarding stimuli, loss of normal aggressiveness) electric bell, 3 min period of swimming in cold resemble clinical depression with respect to etiolo- water (12°C) or 5 min period of illumination (80 ± gy, symptomatology and responsiveness to treat- 1 klx) and 48 h period of food deprivation. Each ment [15, 17, 32, 36]. Among the variety of proce- stressor was repeated 2 times during the 16 day dures leading to human depressive-like symptoms stress procedure (for details [39]). The second group in animals, stress procedures take place among the of control (sham) animals was housed in a separate well validated models [15, 28, 36]. A chronic un- room and had no contact with the stressed animals. predictable stress (CUS) procedure was introduced Imipramine (HCl, 10 mg/kg, Polfa, Poland) was in- by Katz et al. [15, 16]. Our previous studies have jected ip once daily (1 h before the stress proce- shown that the rats subjected to chronic stress pro- dure), during 14 days. cedure (various stressors over 16 days) exhibited the decrease in the footshock-induced fighting be- Tissue preparation and binding procedures havior. We have also demonstrated that antidepres- sant drugs with various profiles of pharmacological Forty eight hours after the last stressor or imi- action, i.e. tricyclic drugs [22, 39], MAO inhibitors pramine, the animals were decapitated, their brains [23] or SSRI (unpublished data) given repeatedly were removed, and cortices (neocortex) and limbic prevented the behavioral “depression” (deficit of systems (containing olfactory tubercle, preoptic aggression) induced by this kind of chronic stress. area, nucleus accumbens, septum, amygdala and It is known that the brain monoamines play overlying limbic cortex) were dissected and imme- a key role in the stress responses and adaptation, diately frozen over solid CO2. The frozen tissue and possible in the development of the depressive was stored at –80°C for 2–4 weeks before the as- symptoms [1, 6, 30, 34, 35, 37]. Evidence also sug- say. Tissues were thawed in 50 volumes of ice-cold gests that the stress-related behavioral alterations 50 mM potassium phosphate buffer, pH 7.4, (for are accompanied by adaptive changes in a large dopaminergic receptors) or 50 mM TRIS-HCl buf- number of neurotransmitters and their receptors in fer, pH 7.4 (for serotonergic receptors), homoge- the brain [13, 20, 26, 27, 33, 38–40]. Since we have nized and centrifuged at 20,000 × g for 20 min (i.e. recently demonstrated CUS-induced increase in the washed). Tissue pellets were washed once more. Assay tubes contained membrane suspension (~0.15 density of D-1 and 5-HT-2A receptors in the rat 3 brain [24], in the present study we investigated the mg of protein), 7–8 concentrations of [ H]ligand effect of chronic imipramine treatment on these re- and buffer and/or the nonspecific-binding defining ceptors altered by CUS paradigm. drug in a final volume of 0.350 ml. The following [3H]ligands, nonspecific-binding defining drugs and incubation parameters were applied: D-1 recep- MATERIALS and METHODS tors – [3H]SCH 23390 (70 Ci/mmol, NEN), cis(Z)- flupentixol (5 mM), 60 min at 30°C; 5-HT-2A re- All procedures were conducted according to ceptors – [3H]ketanserin (60 Ci/mmol, NEN), mi- NIH Animal Care and Use Committee guidelines, anserin (1 mM), 30 min at 25°C. The samples were and approved by the Ethics Committee of the Me- incubated for appropriate time and at the above- dical University School, Lublin. mentioned temperature. The incubation was termi- nated by rapid filtration over glass fiber filters Chronic unpredictable stress (CUS) procedure (Whatman GF/B or GF/C). The filters were then Male Wistar rats (180–220 g) were housed six washed 2 times with 0.1 ml of ice-cold buffer and to a cage with food and water freely available, and placed in scintillation vials with liquid scintillation maintained under a 12 h light-dark cycle (lights on cocktail. Radioactivity was measured in a Beckman at 8:00 a.m.). The chronic stress regimen was a va- LS 6500 liquid scintillation counter. All assays riant of Katz et al. method [15, 16]. One group of were done in duplicates. 90 Pol. J. Pharmacol., 2002, 54, 89–93 IMIPRAMINE EFFECTS ON BRAIN D-1 AND 5-HT-2A RECEPTORS IN CHRONIC STRESS Data analysis and statistics Table 2. Effect of imipramine and chronic unpredictable stress on serotonin 5-HT-2A receptors in the rat cerebral cortex Data were analyzed using iterative curve fitting Group Bmax (fmol/mg KD (nM) routines (GraphPAD/Prism, v. 3.0 – San Diego, protein) CA). Group differences were assessed using the one-way analysis of variance (ANOVA), followed Control 40.0 ± 3.0 0.59 ± 0.07 by Dunnett’s multiple comparisons test (Graph- Stress 48.6 ± 2.2* 0.54 ± 0.06 PAD/Instat v. 2.04). Data were deemed significant Imipramine 44.4 ± 1.7 0.75 ± 0.12 when p < 0.05. Stress + imipramine 38.7 ± 1.1# 0.58 ± 0.03 Values are the means ± SEM of 4–7 animals per group. Bmax and KD values were calculated using the Gauss-Marquardt me- RESULTS thod with an iterative curve fitting routine (GraphPAD/Prism, v 3.0, San Diego, CA). * p < 0.05 vs control, # p < 0.05 vs stress The CUS procedure significantly increased (by (Dunnett’s Multiple Comparisons Test) 36%) the density (Bmax) of D-1 dopamine receptors (labelled by [3H]SCH 23390) in the limbic system (Tab. 1). Analysis of variance (ANOVA) revealed DISCUSSION F(3,16) = 2.722, p = 0.0788. Chronic imipramine The previous studies from our laboratories have treatment was without effect on the density of D-1 indicated that the repeated stress with application receptors (in non-stressed rats), however it attenu- of various unpredictable stressors (CUS) caused ated their increase produced by CUS (Tab. 1). CUS the reduction of footshock-induced fighting behav- also increased (by 21%) the density of 5-HT-2A re- 3 ior by about 60–70%, when observed 48 h after the ceptors (labelled by [ H]ketanserin) in the cerebral last session of chronic stress [22, 23, 39, 40]. It was cortex (Tab. 2). Analysis of variance (ANOVA) re- also shown that antidepressant drugs given repeat- vealed F(3,17) = 3.693, p = 0.0326. Similarly to the edly counteracted the behavioral “depression” (the effect on D-1 receptors, imipramine did not affect deficit of aggression) induced by CUS [22, 23, 39, the density of 5-HT-2A receptors (in non-stressed 40]. Moreover, we have demonstrated that the ap- rats), but it prevented their CUS-induced increase plication of CUS increased the density of D-1 do- (Tab. 2). CUS did not influence the binding affini- pamine receptors in the limbic system and 5-HT- ties (K values) of radioligand to any of the recep- D 2A receptors in the cerebral cortex [24 ].
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