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Repeated antidepressant drugs affect dopamine D3 receptors in the rat brain
s44
Poster C. Experimental-Animal
found highly significant changes in the test of ‘open field’ comparatively with 1 and 2 group (P
References Brennan, T.J., Vandermeulen, E.P., Gebhart, G.F., 1996. Characterization of a rat model of incisional pain, Pain 64(3), 493-521. Status of ketamine in anesthesiology, Edited by E.F. Domino, 1990, NPP Books, 583 p. Proceedings of the 8th World Congress on Pain, Edited by TX Jensen, J.A. Turner, Z. Wiesenfeld-Hallin, Progress in pain research and management, Volume 8, 1997. In IASP Press, 965 p.
El
C-122
Effects of repeated administration of diazepam on serotonergic receptors of 1A, 2 and 3 type in the rat brain
Rump S., Jakowicz I. and Kowalczyk M.. Dept. of Pharmacology and Toxicology, Military Institute of Hygiene and Epidemiology, 01-163 Warszawa, Poland The interactions of benzodiazepines (BDZ) and serotonergic (5HT) system have been reported by many authors. It is of interest to study the influence of BDZ on various types of central 5-HT receptors. Method: Experiments have been performed on rats treated daily for 14 days with diazepam (5 mglkg SC). On the Ist, 7th and 14th day after the treatment animals were killed, brains were removed and dissected. Binding reactions were performed for 5-HT,, receptors in hippocampus using [3H]8-OH-DPAT according to the method described previously (Rump and Jakowicz, 1995) for 5-HT, receptors in frontal cortex using [‘H] ketanserin according to the method by Pazos et al. (1985) and for 5-HT, receptors using [3H] GR65630 according to Kilpatrick et al. (1987). Results were- expressed as B,,, (receptor density) and K, (affinitv constant) values for unlabelled 8-OH-DPAT, ketanserin and GR 65630,’ respectively, in control and experimental groups and were calculated according to the program set up by Munson (1987). Results: Repeated administration of diazepam resulted in a decrease of B,,, and K, for 5-HT,, receptors (from 198 to 130 fmol/mg, and from 2.8 to 1.4 nM/L, respectively). Effects on 5-HT, receptors were transient and were expressed in an increase of B,,, and K, only on the 1st day after the treatment (from 160 to 190 fmol/mg and from 0.5 to 0.8 &l/L). Effects on 5-HT, receptors were unsignificant. Conclusion: These results suggest that activation of BDZ receptors affects 5-HT system, especially its subtype 1A receptors, and to a lesser extent its subtype 2 receptors, having no significant influence on subtype 3 receptors.
References Rump, S., Jakowicz, I., 1995. Europ Neuropsychopharmacol Pazos, A. et al., 1985. Europ J Pharmacol 106, 521. Kilpatrick, G.J. et al., 1987. Nature 330, 746. Munson, P.J., 1987. Ligand: Data Analysis and Curve-Fitting Binding Experiments. NIH, Bethesda.
C-123 El
5, 49.
for Ligand
Repeated antidepressant drugs affect dopamine D, receptors in the rat brain
J. Maj, M. Dziedzicka-Wasylewska, R. Rogoi, Z. Rogbi. Znstitute of Pharmacology, Polish Academy of Sciences, 12 Sm@na St., PL 31-343 Krakdw, Poland Our previous studies indicated that antidepressant drugs with different pharmacological profiles, administered repeatedly, increased the locomotor hyperactivity induced by various dopaminomimetics, e.g. by quinpirole. As - according to the recent study - this drug shows high affinity not only for dopamine D,, but also for D, receptors, question
studies
arises whether D, receptors are involved in the increased response to dopaminomimetics, induced by repeated treatment with antidepressants. In the present paper we used imipramine, amitriptyline (both being noradrenaline - and serotonin, uptake inhibitors), citalopram (a selective serotonin uptake inhibitor), trimipramine and mianserin (both being noninhibitors of amine uptake). All antidepressants tested were administered in a dose of 10 mg/kg p.o., twice a day for 14 days, to male Wistar rats; afterwards, (?)-7-OH-DPAT, a dopamine D, receptor agonist, was injected (3 mg/kg s.c.). (I)-7-OH-DPAT was chosen, because nafadotride, a D, receptor antagonist, inhibits the (?)-7-OH-DPAT hyperlocomotion, but does not affect the hyperlocomotion induced by d-amphetamine or quinpirole. The hyperlocomotion induced by (t)-7-OH-DPAT was significantly increased by repeated administration of all the antidepressants studied. Moreover, a receptor autoradiography technique using [‘HI-7-OH-DPAT as a radioligand was applied to assess the effects of repeated treatment (14 days) with antidepressants on dopamine D, receptors in of Calleja’s islands and in the shell of the nucleus accumbens septi, which are brain regions with a highly selective expression of dopamine D, receptors. The results indicate that in both the examined brain regions there takes place an increase in the binding of [3H]-7-OHDPAT following repeated administration of the antidepressants tested. The results obtained in the present study show that antidepressants administered repeatedly enhance the responsiveness of dopamine D, receptors - most likely via an increase in the density of these receptors. It seems that a mechanism similar to that already observed in the case of dopamlne D, receptors is involved in the effect found in the present paper. Therefore it is hypothesized that the increased responsiveness of dopamine D, and D, receptors is involved in the mechanism of action of antidepressant drugs.
C 124 El
SSRI normalizes f3-adrenoceptor down-regulation in rat brain under chronic unpredtctable stress
T. Matsushita, M. Asakura, Y. Sasuga, N. Bodaiji, K. Osada, S. Miyamoto, J. Imafuku, H. Hasegawa, A. Aoba. Department of Neuropsychiatry, St. Marianna University School of Medicine, Z-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216 Japan Long-term treatment with tricyclic antidepressants and monoamine oxidase inhibitors, and repeated electroconvulsive treatment are known to cause a B-adrenergic receptor (R) down-regulation in the rat brain. Since long-term treatment with the selective serotonin reuptake inhibitor (SSRI), such as fluoxetine and citalopram has no effect on the Badrenoceptors in the intact rat brain, the B-R down-regulation is not regarded as a common mechanism in all type of antidepressant agents. On the other hand, the B-R down-regulation is also induced by an exposure to acute and chronic predictable stress, implying an adaptation or habituation to stress. However, chronic unpredictable and inescapable (variable) stress (CVS), a model for depression could not yield this receptor change. In this study we found that concurrent treatment with fluoxetine or citalopram caused the B-R down-regulation in the cerebral cortex of rats treated with CVS for 14 days. As previously reported by authors, mianserin and maprotiline decreased B-R after repeated treatment (twice daily) and this decrease in the receptor was only observed 6 hours after the final injection and was rapidly recovered 24 hours later [l]. The period of the B-R down-regulation was lengthened by increasing serotonin (5-HT) availability with concomitant fluoxetine or 5-hydroxyttyptophan treatment, and shortened by p-chrolophenylalanine administration, indicating that an increase in 5-HT availability plays a role in preserving the B-R down-regulation by noradrenergic potentiating agents (Asakura et al., 1987). In depressed patients, an excess activation of the corticotropin releasing hormone (CRH)-noradrenergic systems is thought to be involved in generating anxiety, sympathetic activation and hyperarousal although an appropriate noradrenergic activation might be required for a relief of a part of depressive symptoms. Moreover, a decrease in the 5-HT turnover in depressed patients has been reported. Accordingly, it is proposed that an increase in 5-HT availability by SSRI might contribute to normalize the B-R down-regulation, an adaptive regulatory mechanism to the hyperactivation of CRH-noradrenergic systems under a stressful situation.
Reference Asakura, M. et al,, 1987. Role of serotonin in the regulation of Badrenoceptors by antidepressants, European J. Pharmacol. 14, 95-100.
Poster C. Experimental-Animal
found highly significant changes in the test of ‘open field’ comparatively with 1 and 2 group (P
References Brennan, T.J., Vandermeulen, E.P., Gebhart, G.F., 1996. Characterization of a rat model of incisional pain, Pain 64(3), 493-521. Status of ketamine in anesthesiology, Edited by E.F. Domino, 1990, NPP Books, 583 p. Proceedings of the 8th World Congress on Pain, Edited by TX Jensen, J.A. Turner, Z. Wiesenfeld-Hallin, Progress in pain research and management, Volume 8, 1997. In IASP Press, 965 p.
El
C-122
Effects of repeated administration of diazepam on serotonergic receptors of 1A, 2 and 3 type in the rat brain
Rump S., Jakowicz I. and Kowalczyk M.. Dept. of Pharmacology and Toxicology, Military Institute of Hygiene and Epidemiology, 01-163 Warszawa, Poland The interactions of benzodiazepines (BDZ) and serotonergic (5HT) system have been reported by many authors. It is of interest to study the influence of BDZ on various types of central 5-HT receptors. Method: Experiments have been performed on rats treated daily for 14 days with diazepam (5 mglkg SC). On the Ist, 7th and 14th day after the treatment animals were killed, brains were removed and dissected. Binding reactions were performed for 5-HT,, receptors in hippocampus using [3H]8-OH-DPAT according to the method described previously (Rump and Jakowicz, 1995) for 5-HT, receptors in frontal cortex using [‘H] ketanserin according to the method by Pazos et al. (1985) and for 5-HT, receptors using [3H] GR65630 according to Kilpatrick et al. (1987). Results were- expressed as B,,, (receptor density) and K, (affinitv constant) values for unlabelled 8-OH-DPAT, ketanserin and GR 65630,’ respectively, in control and experimental groups and were calculated according to the program set up by Munson (1987). Results: Repeated administration of diazepam resulted in a decrease of B,,, and K, for 5-HT,, receptors (from 198 to 130 fmol/mg, and from 2.8 to 1.4 nM/L, respectively). Effects on 5-HT, receptors were transient and were expressed in an increase of B,,, and K, only on the 1st day after the treatment (from 160 to 190 fmol/mg and from 0.5 to 0.8 &l/L). Effects on 5-HT, receptors were unsignificant. Conclusion: These results suggest that activation of BDZ receptors affects 5-HT system, especially its subtype 1A receptors, and to a lesser extent its subtype 2 receptors, having no significant influence on subtype 3 receptors.
References Rump, S., Jakowicz, I., 1995. Europ Neuropsychopharmacol Pazos, A. et al., 1985. Europ J Pharmacol 106, 521. Kilpatrick, G.J. et al., 1987. Nature 330, 746. Munson, P.J., 1987. Ligand: Data Analysis and Curve-Fitting Binding Experiments. NIH, Bethesda.
C-123 El
5, 49.
for Ligand
Repeated antidepressant drugs affect dopamine D, receptors in the rat brain
J. Maj, M. Dziedzicka-Wasylewska, R. Rogoi, Z. Rogbi. Znstitute of Pharmacology, Polish Academy of Sciences, 12 Sm@na St., PL 31-343 Krakdw, Poland Our previous studies indicated that antidepressant drugs with different pharmacological profiles, administered repeatedly, increased the locomotor hyperactivity induced by various dopaminomimetics, e.g. by quinpirole. As - according to the recent study - this drug shows high affinity not only for dopamine D,, but also for D, receptors, question
studies
arises whether D, receptors are involved in the increased response to dopaminomimetics, induced by repeated treatment with antidepressants. In the present paper we used imipramine, amitriptyline (both being noradrenaline - and serotonin, uptake inhibitors), citalopram (a selective serotonin uptake inhibitor), trimipramine and mianserin (both being noninhibitors of amine uptake). All antidepressants tested were administered in a dose of 10 mg/kg p.o., twice a day for 14 days, to male Wistar rats; afterwards, (?)-7-OH-DPAT, a dopamine D, receptor agonist, was injected (3 mg/kg s.c.). (I)-7-OH-DPAT was chosen, because nafadotride, a D, receptor antagonist, inhibits the (?)-7-OH-DPAT hyperlocomotion, but does not affect the hyperlocomotion induced by d-amphetamine or quinpirole. The hyperlocomotion induced by (t)-7-OH-DPAT was significantly increased by repeated administration of all the antidepressants studied. Moreover, a receptor autoradiography technique using [‘HI-7-OH-DPAT as a radioligand was applied to assess the effects of repeated treatment (14 days) with antidepressants on dopamine D, receptors in of Calleja’s islands and in the shell of the nucleus accumbens septi, which are brain regions with a highly selective expression of dopamine D, receptors. The results indicate that in both the examined brain regions there takes place an increase in the binding of [3H]-7-OHDPAT following repeated administration of the antidepressants tested. The results obtained in the present study show that antidepressants administered repeatedly enhance the responsiveness of dopamine D, receptors - most likely via an increase in the density of these receptors. It seems that a mechanism similar to that already observed in the case of dopamlne D, receptors is involved in the effect found in the present paper. Therefore it is hypothesized that the increased responsiveness of dopamine D, and D, receptors is involved in the mechanism of action of antidepressant drugs.
C 124 El
SSRI normalizes f3-adrenoceptor down-regulation in rat brain under chronic unpredtctable stress
T. Matsushita, M. Asakura, Y. Sasuga, N. Bodaiji, K. Osada, S. Miyamoto, J. Imafuku, H. Hasegawa, A. Aoba. Department of Neuropsychiatry, St. Marianna University School of Medicine, Z-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216 Japan Long-term treatment with tricyclic antidepressants and monoamine oxidase inhibitors, and repeated electroconvulsive treatment are known to cause a B-adrenergic receptor (R) down-regulation in the rat brain. Since long-term treatment with the selective serotonin reuptake inhibitor (SSRI), such as fluoxetine and citalopram has no effect on the Badrenoceptors in the intact rat brain, the B-R down-regulation is not regarded as a common mechanism in all type of antidepressant agents. On the other hand, the B-R down-regulation is also induced by an exposure to acute and chronic predictable stress, implying an adaptation or habituation to stress. However, chronic unpredictable and inescapable (variable) stress (CVS), a model for depression could not yield this receptor change. In this study we found that concurrent treatment with fluoxetine or citalopram caused the B-R down-regulation in the cerebral cortex of rats treated with CVS for 14 days. As previously reported by authors, mianserin and maprotiline decreased B-R after repeated treatment (twice daily) and this decrease in the receptor was only observed 6 hours after the final injection and was rapidly recovered 24 hours later [l]. The period of the B-R down-regulation was lengthened by increasing serotonin (5-HT) availability with concomitant fluoxetine or 5-hydroxyttyptophan treatment, and shortened by p-chrolophenylalanine administration, indicating that an increase in 5-HT availability plays a role in preserving the B-R down-regulation by noradrenergic potentiating agents (Asakura et al., 1987). In depressed patients, an excess activation of the corticotropin releasing hormone (CRH)-noradrenergic systems is thought to be involved in generating anxiety, sympathetic activation and hyperarousal although an appropriate noradrenergic activation might be required for a relief of a part of depressive symptoms. Moreover, a decrease in the 5-HT turnover in depressed patients has been reported. Accordingly, it is proposed that an increase in 5-HT availability by SSRI might contribute to normalize the B-R down-regulation, an adaptive regulatory mechanism to the hyperactivation of CRH-noradrenergic systems under a stressful situation.
Reference Asakura, M. et al,, 1987. Role of serotonin in the regulation of Badrenoceptors by antidepressants, European J. Pharmacol. 14, 95-100.