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Importance of protein synthesis for the development of chemical kindling
P Poster Presentations
54
I P-5-15 ! Sertraline Did Not Affect Monoamine Receptors
and Adenylate Cyclase Activity in Rat Brain C. Tadokoro, Y. Kiuchi, A. Ota, K Oguchi, K. Kamijima. Department of Psychiatry. Showa University School ofMedicine Tokyo Japan
It has been well established that chronic administration of imipramine, a tricyclic antidepressant, results in down-regulation of fJ and 5-HT2 receptors and reduction of fJ receptor-associated adenylate cyclase (AC)
activity in rats. However. the effect of SSRls. selective 5-HT reuptake inhibitors, on these parameters has not been well investigated. Then. we compared the effects of three-week treatment (10 mglkg, ip, twice a day) with sertr aline, a new SSRI compound, to those of imipramine, on monoamine receptors and aden ylate cyclase (AC) activity in the rat brain. Despite reducing immobility in forced swimming test, sertraline did not change Kd and Bmax of [3H1CGP I2177 (fJ ) and e H1ketanserin (5-HT2) binding in the cortex and ['H]8-0H-DPAT (5-HT 1A ) binding in the hippocampus. nor affect cAMP accumulation in the membrane preparation by norepinephrine. isoproterenol. Gpp(NH)p and forskolin (cerebral cortex) and suppression of forskolin-stimulated cAMP accumulation by 5-HT (hippocampus). compared with vehicle treated rats. Imipramine decreased Bmax of f3 and 5-HT2 receptor and norepinephrine or isoproterenol-stimulated cAl\l1P production. These results suggested that the pharmacological properties of sertraline are different from those of imipramine and that down-regulation of f3 and 5-HT2 receptors may not be necessarily involved in their antidepressant effect.
I P-5-1S ! Endogenous Mono-ADP-Ribosylation in the Hippocampus of Amygdaloid Kindled Rat
K Suzuki, H. Iwasa, S. Kikuchi, T. Sato, N. Morinaga I. M. Noda I. Depar tment ofNeuropsychiatry, Chiba University School of Medicine. Chiba, Japan : 1 Second Departm ent of Microbiology, Chiba University School ofMedicine, Chiba, Japan
We examined the alteration of endogenous mono-ADP-ribosylation in the hippocampus of amygdaloid kindled rat to elucidate the neurochemical mechanisms of epilepsy. The hippocampal membrane fraction obtained from the kindled or control rats was incubated with [32 P1NAD. The endogenous mono-ADP-ribosylation occured on several proteins, predominantly 38 kDa protein. Significant increase in the level of the ADPribosylation of the 38 kDa protein was observed in the kindled group at four weeks after the last generalized seizure. The degree in the level of the ADP-ribosylation of the 38 kDa protein was largely increased by sodium nitroprusside, a nitric oxide generating compound, in both the kindled and control animals. Several antiepileptic drugs (carbarnazepine, phenytoin, phenobarbital) decreased the level in the ADP-ribosylation of the 38 kDa protein. The amino acids sequence of the ADP-ribosylated 38 kDa protein was same as that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH}. These results suggest that nitric oxide-sensitive ADPribosylation of the 38 kDa protein is closely associated with not only the acquisition mechanisms of the kindling-induced epileptogenesis but also with the pharmacological basis of the antiepileptic action of the drugs.
IP-5-17 I Importance of Protein Synthesis for the Development of Chemical Kindling
G. Grecksch, A. Becker. Institut e of Pharma cology and Toxicology, Oi-v-Guericke Universi ty Magdeburg, German y
Kindling, a phenomenon characterised by the progression of behavioural and electrographic seizures, induced by repeated activation of neural pathways with initially subconvulsive electrical or chemical stimulations represents an accepted experimental model for human epilepsy. Furthermore, kindling is also a model for neuronal plasticity with a particularly long time-course of retention as well as long-lasting robustness and endurance. Therefore, this phenomenon seems to represent a suitable model for studying the process of engram formation. It is well known that for electrical kindling as well as for memory storage protein synthesis inhibition retards or blocks these processes. The question arises if chemical kindling induced by pentetrazol (PTZ) as a model of a primarily generalised epilepsy can be influenced by protein synthesis inhibition. When the protein synthesis inhibitor anisornycin was injected
intracerebroventricularly before each PTZ kindling injection no alteration of the kindling development was found. But intrahippocampal injections inducing an inhibition of protein synthesis of about 94% in the hippocampus lead to a significant retardation of the kindling development. This result supports the importance of a sufficient protein synthesis for the induction of a chemical kindling and. moreover the important role of the hippocampal formation in this model for primarily generalised epilepsy.
IP-5-18 I Effects of Verapamil and Ethaverine on the Behavioral Despair Testin Rats
Y.H. Kim, S.K Lee, lH. Kim, T.M. Gang, KT. Kim. Depart of Psychiatry, Pusan Paik Hospital, Pusan, Korea
Most of studies of calcium channel blockers in psychiatric disorders have been conducted with verapamil, and recently diltiazem, nimodipine, and nifedipine have also been used in a few clinical trials of psychiatric patients. Ethaverine, a L-type calcium channel blocker, is a derivative of papaverine used in the treatment of hypertension and peripheral vascular disease, but has never been used in psychiatric fields. Possible antidepressant properties of calcium channel blockers could be expected. In present study, we investigatethe effects of veraparnil and ethaverine in the behavioral despair test in rats. Daily treatment for IO days with imipramine (20 mg/kg) and ethaverine( I0 mg/kg) reduced the immobilization time in the behavioral despair test. But the same treatment with verapamil(10 mglkg) did not reduce the immobilization time significantly. It was strongly suggested that ethaverine concomitently administered potentiated the long-term effect of imipramine on the reduction of immobilization time. In a half of those rats(3/6) which were repeatedly treated with both imipramineand ethaverine, vigorous swimming was observed during the most of the test time despite of no increased motor activity in open field observation. The data suggest that ethaverine alone has a weak anti-immobilization effect in the behavioral despair test in rats and that it can be used clinically in potentiating the antidepressant effects of imipramine.
I P-5-19I Antidepressant-Like Effects of the 12 Ligands Idazoxan and2-BFI in the Rat Porsolt Test H.C. Jackson, S. Jordan I , S.L. Handley I, N.R. Mirza, DJ. NUll. Psychopharma cology Unit. Univ of Bristol, Bristol, UK; 1 Pharmaceutical Sci lnst, Aston Univ; Birmingham , UK
Idazoxan has been shown to have antidepressant actions [11. This may be due to its a2-adrenoceptor antagonist properties and/or its high affinity for imidazoline 12binding sites [see 2]. This study compares the effects of idazoxan and the 12 ligand, 2-BFI (2-(2-benzofuranyl)-2-imidazoline [2]), in the rat Porsolt test - an animal model of depression. Male Wistar rats (200- 350 g; n =8) were subject to a 8 min swim on day I and re-tested 24 h later. Rats were injected i.p. with vehicle or drug 30 min, 19 h and 23 h following the swim on day I. Immobility (measured during the last 5 min of the test on day 2) was significantl y decreased by desipramine (15 mglkg}; idazoxan (3 mglkg) and 2-BFI(3. 10 mglkg}. Idazo xan (3 mglkg) and 2-BFI (3 mglkg) did not alter locomotor activity in rats in the hour after injection whereas 2-BFI (10 mglkg) produced a transient decrease in locomotion. These results suggest that the antidepressant potential of 12ligands should be explored further. [tl Osman O'I, Rudorfer MV, Potter WZ. Arch . Gen Psychiat. 46 (1989 ) 958- 959. [21 Hudson AL , Mallard NJ, Nutt OJ, Chapleo CB , Brit. J. Phannacol. tl4 (1995) 41 1.
IP-5-20 I L Deprenyl Versus Moclobemide in Animal Model of Depression -
C.D. Milijet
J.
"Swim Test"
D. Djorgovic 2, A. Darnjanovic3, C. Cmobaric 4,
Y.R. Paunovic '.
J Special neuropsychiatr ic hospital "dr Laza K. Laza revic" Be/grade; 2 Immun ology research center "B. Janko vic " Belgrade; , Institute ofpsychiatry. University Clinical Cente r, Belgrade; 4 Clinical center "Z vezdara " Belgrade
The antidepressant effects ofL-deprenyl (MAO-Binhibitor and moclobemide (MAO-A inhibitor) were examined in the procedure known as swim
54
I P-5-15 ! Sertraline Did Not Affect Monoamine Receptors
and Adenylate Cyclase Activity in Rat Brain C. Tadokoro, Y. Kiuchi, A. Ota, K Oguchi, K. Kamijima. Department of Psychiatry. Showa University School ofMedicine Tokyo Japan
It has been well established that chronic administration of imipramine, a tricyclic antidepressant, results in down-regulation of fJ and 5-HT2 receptors and reduction of fJ receptor-associated adenylate cyclase (AC)
activity in rats. However. the effect of SSRls. selective 5-HT reuptake inhibitors, on these parameters has not been well investigated. Then. we compared the effects of three-week treatment (10 mglkg, ip, twice a day) with sertr aline, a new SSRI compound, to those of imipramine, on monoamine receptors and aden ylate cyclase (AC) activity in the rat brain. Despite reducing immobility in forced swimming test, sertraline did not change Kd and Bmax of [3H1CGP I2177 (fJ ) and e H1ketanserin (5-HT2) binding in the cortex and ['H]8-0H-DPAT (5-HT 1A ) binding in the hippocampus. nor affect cAMP accumulation in the membrane preparation by norepinephrine. isoproterenol. Gpp(NH)p and forskolin (cerebral cortex) and suppression of forskolin-stimulated cAMP accumulation by 5-HT (hippocampus). compared with vehicle treated rats. Imipramine decreased Bmax of f3 and 5-HT2 receptor and norepinephrine or isoproterenol-stimulated cAl\l1P production. These results suggested that the pharmacological properties of sertraline are different from those of imipramine and that down-regulation of f3 and 5-HT2 receptors may not be necessarily involved in their antidepressant effect.
I P-5-1S ! Endogenous Mono-ADP-Ribosylation in the Hippocampus of Amygdaloid Kindled Rat
K Suzuki, H. Iwasa, S. Kikuchi, T. Sato, N. Morinaga I. M. Noda I. Depar tment ofNeuropsychiatry, Chiba University School of Medicine. Chiba, Japan : 1 Second Departm ent of Microbiology, Chiba University School ofMedicine, Chiba, Japan
We examined the alteration of endogenous mono-ADP-ribosylation in the hippocampus of amygdaloid kindled rat to elucidate the neurochemical mechanisms of epilepsy. The hippocampal membrane fraction obtained from the kindled or control rats was incubated with [32 P1NAD. The endogenous mono-ADP-ribosylation occured on several proteins, predominantly 38 kDa protein. Significant increase in the level of the ADPribosylation of the 38 kDa protein was observed in the kindled group at four weeks after the last generalized seizure. The degree in the level of the ADP-ribosylation of the 38 kDa protein was largely increased by sodium nitroprusside, a nitric oxide generating compound, in both the kindled and control animals. Several antiepileptic drugs (carbarnazepine, phenytoin, phenobarbital) decreased the level in the ADP-ribosylation of the 38 kDa protein. The amino acids sequence of the ADP-ribosylated 38 kDa protein was same as that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH}. These results suggest that nitric oxide-sensitive ADPribosylation of the 38 kDa protein is closely associated with not only the acquisition mechanisms of the kindling-induced epileptogenesis but also with the pharmacological basis of the antiepileptic action of the drugs.
IP-5-17 I Importance of Protein Synthesis for the Development of Chemical Kindling
G. Grecksch, A. Becker. Institut e of Pharma cology and Toxicology, Oi-v-Guericke Universi ty Magdeburg, German y
Kindling, a phenomenon characterised by the progression of behavioural and electrographic seizures, induced by repeated activation of neural pathways with initially subconvulsive electrical or chemical stimulations represents an accepted experimental model for human epilepsy. Furthermore, kindling is also a model for neuronal plasticity with a particularly long time-course of retention as well as long-lasting robustness and endurance. Therefore, this phenomenon seems to represent a suitable model for studying the process of engram formation. It is well known that for electrical kindling as well as for memory storage protein synthesis inhibition retards or blocks these processes. The question arises if chemical kindling induced by pentetrazol (PTZ) as a model of a primarily generalised epilepsy can be influenced by protein synthesis inhibition. When the protein synthesis inhibitor anisornycin was injected
intracerebroventricularly before each PTZ kindling injection no alteration of the kindling development was found. But intrahippocampal injections inducing an inhibition of protein synthesis of about 94% in the hippocampus lead to a significant retardation of the kindling development. This result supports the importance of a sufficient protein synthesis for the induction of a chemical kindling and. moreover the important role of the hippocampal formation in this model for primarily generalised epilepsy.
IP-5-18 I Effects of Verapamil and Ethaverine on the Behavioral Despair Testin Rats
Y.H. Kim, S.K Lee, lH. Kim, T.M. Gang, KT. Kim. Depart of Psychiatry, Pusan Paik Hospital, Pusan, Korea
Most of studies of calcium channel blockers in psychiatric disorders have been conducted with verapamil, and recently diltiazem, nimodipine, and nifedipine have also been used in a few clinical trials of psychiatric patients. Ethaverine, a L-type calcium channel blocker, is a derivative of papaverine used in the treatment of hypertension and peripheral vascular disease, but has never been used in psychiatric fields. Possible antidepressant properties of calcium channel blockers could be expected. In present study, we investigatethe effects of veraparnil and ethaverine in the behavioral despair test in rats. Daily treatment for IO days with imipramine (20 mg/kg) and ethaverine( I0 mg/kg) reduced the immobilization time in the behavioral despair test. But the same treatment with verapamil(10 mglkg) did not reduce the immobilization time significantly. It was strongly suggested that ethaverine concomitently administered potentiated the long-term effect of imipramine on the reduction of immobilization time. In a half of those rats(3/6) which were repeatedly treated with both imipramineand ethaverine, vigorous swimming was observed during the most of the test time despite of no increased motor activity in open field observation. The data suggest that ethaverine alone has a weak anti-immobilization effect in the behavioral despair test in rats and that it can be used clinically in potentiating the antidepressant effects of imipramine.
I P-5-19I Antidepressant-Like Effects of the 12 Ligands Idazoxan and2-BFI in the Rat Porsolt Test H.C. Jackson, S. Jordan I , S.L. Handley I, N.R. Mirza, DJ. NUll. Psychopharma cology Unit. Univ of Bristol, Bristol, UK; 1 Pharmaceutical Sci lnst, Aston Univ; Birmingham , UK
Idazoxan has been shown to have antidepressant actions [11. This may be due to its a2-adrenoceptor antagonist properties and/or its high affinity for imidazoline 12binding sites [see 2]. This study compares the effects of idazoxan and the 12 ligand, 2-BFI (2-(2-benzofuranyl)-2-imidazoline [2]), in the rat Porsolt test - an animal model of depression. Male Wistar rats (200- 350 g; n =8) were subject to a 8 min swim on day I and re-tested 24 h later. Rats were injected i.p. with vehicle or drug 30 min, 19 h and 23 h following the swim on day I. Immobility (measured during the last 5 min of the test on day 2) was significantl y decreased by desipramine (15 mglkg}; idazoxan (3 mglkg) and 2-BFI(3. 10 mglkg}. Idazo xan (3 mglkg) and 2-BFI (3 mglkg) did not alter locomotor activity in rats in the hour after injection whereas 2-BFI (10 mglkg) produced a transient decrease in locomotion. These results suggest that the antidepressant potential of 12ligands should be explored further. [tl Osman O'I, Rudorfer MV, Potter WZ. Arch . Gen Psychiat. 46 (1989 ) 958- 959. [21 Hudson AL , Mallard NJ, Nutt OJ, Chapleo CB , Brit. J. Phannacol. tl4 (1995) 41 1.
IP-5-20 I L Deprenyl Versus Moclobemide in Animal Model of Depression -
C.D. Milijet
J.
"Swim Test"
D. Djorgovic 2, A. Darnjanovic3, C. Cmobaric 4,
Y.R. Paunovic '.
J Special neuropsychiatr ic hospital "dr Laza K. Laza revic" Be/grade; 2 Immun ology research center "B. Janko vic " Belgrade; , Institute ofpsychiatry. University Clinical Cente r, Belgrade; 4 Clinical center "Z vezdara " Belgrade
The antidepressant effects ofL-deprenyl (MAO-Binhibitor and moclobemide (MAO-A inhibitor) were examined in the procedure known as swim