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Effects of acute and chronic administration of CCKB antagonist on conditioned fear stress
III
P Poster Presentations
IP-1 0-41 Effect of Dilithium N-Acetyl-L-Aspartate on Stress-Induced Dopamine Release in Hypothalamus
v. Petrov, I. Grigoryev, D. Zaretsky, V. Sergeyev. Lab. of Psychopharmacology, Institute of Pharmacology, Volgograd, Russia Previous studies have provided evidence that exitatory amino acid (EAA) plays an important role in the dorsomedial hypothalamus (DMH) in regulating the cardiovascular and behavioral responses to stress [I]. The novel psychotropic compound dilithium N-acetyl-L- aspartate (AKF-94) had an antistressor effect on a rat model of depression based on the deficit in open field activity observed after 2 h restraint. Thus, when AKF-94 (10 mglkg IP) was given I h before the restrain to either untreated rats or to animals previously given 10 mglkg of drug daily for 7 days, then the deficit was opposed. Two hours of immobilisation stress significantly elevated extracellular dopamine (DA) 250% end its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) 165% and homovanillic acid (HVA) 160% in DMH of freely moving rats as measured with in vivo microdialysis. Injection of AKF-94 (10 mglkg IP) had no influence on the basal concenration of DA, but reliably (p < 0.05) increase the stress-indused alteration of extracellular dopamine 355%. This changes in DA release supported with reliable (p < 0.05) increase of its metabolites DOPAC and HVA (245% and 255% accordingly). These results confirm an important role for the hypothalamic dopaminergic system in differential behavioral responses to stress. [1] Soltis R, DiMicco J, Am. 1. Physiol. 261 (1991) R427-R433.
I P-1 0-51 Stress-Induced Phase-Shifts in the Locomotor Activity Rhythm and Increases in Noradrenaline Turnover in the Locus Coeruleus Region S. Tsujimaru, Y. Ida, H. Egami. Department ofNeuropsychiatry, Kurume University School ofMedicine, Kurume, Japan In the present study we investigated effects of stress on the locomotor activity rhythm and noradrenaline (NA) turnover in the locus coeruleus (LC) region. Male Wistar rats were used as subjects. After a stable free-running rhythm was obtained, the animals were exposed to immobilization stress with a wire mesh for 60 min at six circadian time (CT) points (CT 2, CT 6, CT 10, cr 14, CT 18, CT 22). At the end of each stress session, the levels of the major metabolite of NA in the rat brain, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-S04), in the LC region, were determined by the fluorometric method. Phase advances were observed at CT 2, CT 6, CT 18 and CT 22 with the maximum phase advance at CT 22. Phase delays were found at between CT 10 and CT 14 with the maximum phase delay at CT 10. Free-running periods prolonged significantly after stress at CT 6, CT 10 and CT 22. Immobilization stress caused significant increases in the MHPG-S04 levels at all CT points examined as compared to the respective controls. Moreover, the stress-induced increases in the MHPG-S04 levels were significantly higher at both cr 10 and CT 22 than when exposed to the stress at other CT points. These results suggest that stress-induced phase-shifts in the locomotor activity rhythm may be mediated through the changes in NA turnover in the LC region.
IP-1 0-61 The Effect of Prenatal Stress on the Development of the Rat Aminergic Receptors and Behavior
T. Asou, S, Yoshimoto, T. Tsujimura, Y. Tomimatsu, Y. Kakumoto, Y. Okazaki, Y. Nakane. Department ofNeuropsychiatry, Nagasaki University, Nagasaki, Japan We have tried to produce an animal model of affective disorder with biological vulnerability. Pregnant rats were given saline injection treatment in the last week of gestation. Control rats were left undisturbed throughout pregnancy except for routine animal care. The frontal cortex of prenatally stressed offspring has an increased number of 5-HT 2 receptors in the early adult stage and increased number of tl-adrenergic receptors at the neonates stage. There was a significant increase of immobility time on forced swimming test for 4 week male prenatally stressed offspring. There was a significant decrease of locomotor activity and increase of drinking time for 16 week old female prenatally stressed offspring.
Imipramine treatment for 1, 3, 7 or 14 days produced no difference on 3H-ketanserin binding as between prenatally stressed and control groups. But on 3H-CGPI2177 binding, there was a significant decrease of the Bmax for 3 and 7 days of imipramine treatment in prenatally stressed offspring. These results suggest that the tl -adrenergic receptor shows hypersensitivity in prenatally stressed offspring, All these results suggest that prenatally stressed offspring could be used as a partial model of affective disorder.
IP-1 0-71
Effects of Acute and Chronic Administration of CCKB Antagonist on Conditioned FearStress
T. Izumi, T. Inoue, K. Tsuchiya, S. Hashimoto, T. Ohmori, T. Koyama. Department of Psychiatry, Hokkaido University School ofMedicine, Sapporo, Japan Recent studies have indicated a role of cholecystokinin (eCK) in anxiety. We investigated the effects of acute and chronic administration of nonpeptide CCKB antagonist LY288513 on conditioned fear stress (CFS) in rats, an animal model of anxiety. CFS (exposure to an environment paired previously with footshock) 24 hours after single footshock induced marked freezing behavior. Acute administration of LY288513 (0.03-0.3 mg/kg, s.c.) 30 min before CFS significantly reduced freezing, suggesting that LY288513 has an anxiolytic activity. Chronic administration of LY288513 (once daily for 10 days at I mglkg, s.c.) significantly reduced conditioned freezing 24 hr after cessation of treatment. The possibility that the effects of the LY2885l3, administered on the previous day, remained at the time of testing and directly affected the expression of conditioned freezing was obviated, because the single administration of LY288513 on the previous day failed to reduce freezing behavior. These results suggest an important role of brain CCKB receptors in anxiety.
IP-1 0-81
Pharmacological Regulation of Anxiety in Dependence on Stress Reaction Phenotype
S.B. Seredenim. Institute of Pharmacology Russian Acad. Med. Sci., Moscow, Russia Earlier performed set of pharmacogenetic studies in C571B 1/6 and BALB/c mice, MR and NMRA rats with different open field (OF) behaviors, in healthy volunteers, showed that in case of active phenotype of emotional stress reaction (ESR) the benzodiazepines produce tranquillizing-sedative action, whereas in freezing reaction with pronounced anxiety response the benzodiazepines at low doses had tranquillizing-activatory effect. Hence the purpose to search for a selective anxiolytic agent with tranquillizing-activatory effect in subjects with clear anxiety response, without altering the behavior of those with active phenotype of ESR. The study on the mechanisms of individual stress reaction development revealed a substantial reduction of H''diazepam binding in BALB/c mice with freezing reaction in OF, unlike that in C57B 1/6 mice with the active ESR in OF. The found compounds, trioxypyridine and mercaptobenzimidazole derivatives, were found to prevent the decrease in benzodiazepine reception. The antioxidant activity was identified as their physico-chemical feature in common. Mexidol (2 ethyl-e-methyl3-oxypyridine), bemethyl (2-elhylthyobenzimidazole) and SM-346 (5etoxy-2-(morpholinoethylthyo) benzimidazole dihydrochloride) exert the traquillizing-activatory effect in BALB/c mice with no sedation observed in C57B1/6 mice. The above compounds had no myorelaxant effect and in wide dose range did not cause memory disorders. The anxiolytic effect was confirmed by the results obtained from Vogel' conflict test and elevated plus maze test. The preferred substances show promising potential to be developed as selective anxiolytic agents.
I P-1 0-91 Comorbidity and Treatment Features in Social Phobia A.E. Nardi. Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil 157 social phobic patients were examined using the SCID-I and II (DSMIII-R). Generalized social phobia was more prevalent (73.2%), 54.8% of the patients didn't fulfill any other axis I diagnostic criteria. Panic
P Poster Presentations
IP-1 0-41 Effect of Dilithium N-Acetyl-L-Aspartate on Stress-Induced Dopamine Release in Hypothalamus
v. Petrov, I. Grigoryev, D. Zaretsky, V. Sergeyev. Lab. of Psychopharmacology, Institute of Pharmacology, Volgograd, Russia Previous studies have provided evidence that exitatory amino acid (EAA) plays an important role in the dorsomedial hypothalamus (DMH) in regulating the cardiovascular and behavioral responses to stress [I]. The novel psychotropic compound dilithium N-acetyl-L- aspartate (AKF-94) had an antistressor effect on a rat model of depression based on the deficit in open field activity observed after 2 h restraint. Thus, when AKF-94 (10 mglkg IP) was given I h before the restrain to either untreated rats or to animals previously given 10 mglkg of drug daily for 7 days, then the deficit was opposed. Two hours of immobilisation stress significantly elevated extracellular dopamine (DA) 250% end its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) 165% and homovanillic acid (HVA) 160% in DMH of freely moving rats as measured with in vivo microdialysis. Injection of AKF-94 (10 mglkg IP) had no influence on the basal concenration of DA, but reliably (p < 0.05) increase the stress-indused alteration of extracellular dopamine 355%. This changes in DA release supported with reliable (p < 0.05) increase of its metabolites DOPAC and HVA (245% and 255% accordingly). These results confirm an important role for the hypothalamic dopaminergic system in differential behavioral responses to stress. [1] Soltis R, DiMicco J, Am. 1. Physiol. 261 (1991) R427-R433.
I P-1 0-51 Stress-Induced Phase-Shifts in the Locomotor Activity Rhythm and Increases in Noradrenaline Turnover in the Locus Coeruleus Region S. Tsujimaru, Y. Ida, H. Egami. Department ofNeuropsychiatry, Kurume University School ofMedicine, Kurume, Japan In the present study we investigated effects of stress on the locomotor activity rhythm and noradrenaline (NA) turnover in the locus coeruleus (LC) region. Male Wistar rats were used as subjects. After a stable free-running rhythm was obtained, the animals were exposed to immobilization stress with a wire mesh for 60 min at six circadian time (CT) points (CT 2, CT 6, CT 10, cr 14, CT 18, CT 22). At the end of each stress session, the levels of the major metabolite of NA in the rat brain, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-S04), in the LC region, were determined by the fluorometric method. Phase advances were observed at CT 2, CT 6, CT 18 and CT 22 with the maximum phase advance at CT 22. Phase delays were found at between CT 10 and CT 14 with the maximum phase delay at CT 10. Free-running periods prolonged significantly after stress at CT 6, CT 10 and CT 22. Immobilization stress caused significant increases in the MHPG-S04 levels at all CT points examined as compared to the respective controls. Moreover, the stress-induced increases in the MHPG-S04 levels were significantly higher at both cr 10 and CT 22 than when exposed to the stress at other CT points. These results suggest that stress-induced phase-shifts in the locomotor activity rhythm may be mediated through the changes in NA turnover in the LC region.
IP-1 0-61 The Effect of Prenatal Stress on the Development of the Rat Aminergic Receptors and Behavior
T. Asou, S, Yoshimoto, T. Tsujimura, Y. Tomimatsu, Y. Kakumoto, Y. Okazaki, Y. Nakane. Department ofNeuropsychiatry, Nagasaki University, Nagasaki, Japan We have tried to produce an animal model of affective disorder with biological vulnerability. Pregnant rats were given saline injection treatment in the last week of gestation. Control rats were left undisturbed throughout pregnancy except for routine animal care. The frontal cortex of prenatally stressed offspring has an increased number of 5-HT 2 receptors in the early adult stage and increased number of tl-adrenergic receptors at the neonates stage. There was a significant increase of immobility time on forced swimming test for 4 week male prenatally stressed offspring. There was a significant decrease of locomotor activity and increase of drinking time for 16 week old female prenatally stressed offspring.
Imipramine treatment for 1, 3, 7 or 14 days produced no difference on 3H-ketanserin binding as between prenatally stressed and control groups. But on 3H-CGPI2177 binding, there was a significant decrease of the Bmax for 3 and 7 days of imipramine treatment in prenatally stressed offspring. These results suggest that the tl -adrenergic receptor shows hypersensitivity in prenatally stressed offspring, All these results suggest that prenatally stressed offspring could be used as a partial model of affective disorder.
IP-1 0-71
Effects of Acute and Chronic Administration of CCKB Antagonist on Conditioned FearStress
T. Izumi, T. Inoue, K. Tsuchiya, S. Hashimoto, T. Ohmori, T. Koyama. Department of Psychiatry, Hokkaido University School ofMedicine, Sapporo, Japan Recent studies have indicated a role of cholecystokinin (eCK) in anxiety. We investigated the effects of acute and chronic administration of nonpeptide CCKB antagonist LY288513 on conditioned fear stress (CFS) in rats, an animal model of anxiety. CFS (exposure to an environment paired previously with footshock) 24 hours after single footshock induced marked freezing behavior. Acute administration of LY288513 (0.03-0.3 mg/kg, s.c.) 30 min before CFS significantly reduced freezing, suggesting that LY288513 has an anxiolytic activity. Chronic administration of LY288513 (once daily for 10 days at I mglkg, s.c.) significantly reduced conditioned freezing 24 hr after cessation of treatment. The possibility that the effects of the LY2885l3, administered on the previous day, remained at the time of testing and directly affected the expression of conditioned freezing was obviated, because the single administration of LY288513 on the previous day failed to reduce freezing behavior. These results suggest an important role of brain CCKB receptors in anxiety.
IP-1 0-81
Pharmacological Regulation of Anxiety in Dependence on Stress Reaction Phenotype
S.B. Seredenim. Institute of Pharmacology Russian Acad. Med. Sci., Moscow, Russia Earlier performed set of pharmacogenetic studies in C571B 1/6 and BALB/c mice, MR and NMRA rats with different open field (OF) behaviors, in healthy volunteers, showed that in case of active phenotype of emotional stress reaction (ESR) the benzodiazepines produce tranquillizing-sedative action, whereas in freezing reaction with pronounced anxiety response the benzodiazepines at low doses had tranquillizing-activatory effect. Hence the purpose to search for a selective anxiolytic agent with tranquillizing-activatory effect in subjects with clear anxiety response, without altering the behavior of those with active phenotype of ESR. The study on the mechanisms of individual stress reaction development revealed a substantial reduction of H''diazepam binding in BALB/c mice with freezing reaction in OF, unlike that in C57B 1/6 mice with the active ESR in OF. The found compounds, trioxypyridine and mercaptobenzimidazole derivatives, were found to prevent the decrease in benzodiazepine reception. The antioxidant activity was identified as their physico-chemical feature in common. Mexidol (2 ethyl-e-methyl3-oxypyridine), bemethyl (2-elhylthyobenzimidazole) and SM-346 (5etoxy-2-(morpholinoethylthyo) benzimidazole dihydrochloride) exert the traquillizing-activatory effect in BALB/c mice with no sedation observed in C57B1/6 mice. The above compounds had no myorelaxant effect and in wide dose range did not cause memory disorders. The anxiolytic effect was confirmed by the results obtained from Vogel' conflict test and elevated plus maze test. The preferred substances show promising potential to be developed as selective anxiolytic agents.
I P-1 0-91 Comorbidity and Treatment Features in Social Phobia A.E. Nardi. Institute of Psychiatry, Federal University of Rio de Janeiro, Brazil 157 social phobic patients were examined using the SCID-I and II (DSMIII-R). Generalized social phobia was more prevalent (73.2%), 54.8% of the patients didn't fulfill any other axis I diagnostic criteria. Panic