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Platelet 3H-paroxetine binding, serotonin level and personality features in panic disorder patients; effect of longterm fluvoxamine treatment
FIJRTHER EVIDENCE ON THE ROLE OF CENTRAL CHOLECYSTOKINtN-B (CCK-B) RECEPTORS IN ANXIETY: A sTUDY WITH GV 150013 A NOVEL CCK-B ANTAGONIST G. Maraia, E. Patti, D. Trist and G. Gaviraghi Glaxo Research Laboratories, Via A Fleming 4, 37100 Verona, Italy. In the present work we have investigated further the role of CCK-B receptors in anxiety by studying the influence of their pharmacological manipulation in mice. CCK-4, a selective agonist, and GV 150013X (GV), a potent and selective CCK-B antagonist (Corsi et al this meeting), were studied in the black/white box test. As reported in man, also in mice CCK-4 "pet" se" was found to be anxiogenic. The effect was clear between 0.03-1 lag/kg sc, maximal activity was at 1 lag/kg sc and declined at higher doses (bell-shaped dose-response curve). The opposite was found when GV was administered "per se". A powerful anxiolityc activity was seen between 0.01-1 ~tg/kg po and a plateau of maximal effect was achieved at 0.l-1 iag/kg IX). Finally, the anxiogenic efI~ct of CCK4 was blocked by GV. The antagonist, as well as other CCK-B autagouists, but not CCK-A antagonists, was very effective in blocking CCK-4-induced anxiogenesis (full effect at 0. l gg/kg po of GV). These results reinforce the role of CCK-B receptors in anxiety: the main finding was that anxiety level was highly sensitive to CCK-B receptors manipulation, thus opposite effects were seen with agonists and antagonists respectively. The powerful anxiolityc activity of GV was further investigated to understand more about the role of CCK-B receptors. A common effect of classical benzodiazepines (BDZ) is that prolonged treatment induces tolerance to the anxiol~lic effect, as well as anxiogenesis upon abrupt withdrawal. The mechanism of these effects is likely related to the well known facilitation of GABA transmission. A 7 days treatment was made with GV, at fully anxiolytic doses', to assess whether tolerance or,anxiogenesis upon withdrawal might occur. However, in contrast to diazepam, included in the stud)', GV did not cause tolerance or withdrawal symptoms. These results suggest that GV, and peraphs all CCK-B antagonists, would be anxiolytics through a different pathway than BDZ. Whether different pathways really exist or if CCK-B receptors are downstream to GABA receptors in a common pathway remains to be elucidated.
PLATELET 3H-PAROXETINE BINDING,SEROTONIN LEVEL AND PERSONALITY FEATURES IN PANIC DISORDER PATIENTS; EFFECT OF LONGTERM FLUVOXAMINE TREATMENT K.Tekes, G. Faludi*,J.Tarcali,D.Borcsiczky, K . M a g y a r D e p a r t m e n t . o f P h a r m a c o d y n a m i c s and D e p a r t m e n t o f Psychiatry*, S e m m e l w e i s University o f Medicine, Budapest, H- 1089, Nagyvfirad t & 4,Hungary
In the studies 29 panic disorder patients (PDP)and l 8 controls were involved and gave their informed consent.Diagnoses were based on DSM-IiI-R. Patients and controls completed the 566 item MMPI test and were also assesed by SCID-PrD.3HParoxetine (PAR) binding was measured according to Segonzac et al (J.Neurochem.48,331,1987)and serotonin (5HT) level as described by Anderson et al (Life Sci.40,1063,1987).In drugfree PDPs we have f o u n d significantly lower B m a x values without change in KD. 5HT levels were not different from controls.PDPs s h o w e d the h i g h e s t S C I D - P r D ratings for the items concerning "avoidant" and " o b s c e s s i v e ' c o m p u l s i v e " personality features.Longterm f l u v o x a m i n e treatment (2-6 months,75 mg/kg,daily) o f the same P D P s resulted in significant relief o f s y m p t o m s , 5 H T levels b e c o m e markedly r e d u c e d while P A R b i n d i n g B m a x values remained o n the lower level.Data suggest that decrease in platelet 5HT level caused by longterm f l u v o x a m i n e treatment m a y contribute to the depression o f s y m p t o m s , h o w e v e r r e d u c e d n u m b e r o f P A R binding sites m i g h t be a "trait m a r k e r " .
5-HT1A AGONISTS: ANXIOLYTIC-LIKE AND ANTIDEPRESSANTLIKE EFFECTS IN THREE BEHAVIORAL MODELS R.D. Porsolt. S. Roux and J.G. Wettstein I.T.E.M.-Labo, 93 Avenue de Fontainebleau, 94276 Le Kremlin-Bic&re Cedex, France.
IMIDAZENIL
ABECARNIL:
TWO
NEW
The pharmacological efficacy of imidazenil, (IMZ), a benzodiazepine receptor partial agonist is greater when the GABAergic transmission is reduced. Infact, while the intraperitoneal administration of IMZ failed to affect GABAergic transmission m the cerebral cortex of untreated rats and mice, this compound abolished the reduction of GABA A receptor function elicited by isoniazid and stress. This property may confer on this drug the ability to restore impaired central GABAergic transmission to physiological levels without unwanted side effects. Accordingly, a chronic treatment with a pharmacological effective dose of IMZ failed to induce tolerance to its anticonvulsant and GABAareccptor modulatory efficacy. Abecarnil, (AB), a g-carboline derivative with high efficacy on selective GABA A receptor subtype, like IMZ, after long-term treatment did not induce pharmacological and contingent tolerance to its anticonvulsant effect. However. animals treated with increasing doses of AB (0.3-3 mg/kg i.p. or 6 mg/kg s.c.) developed cross-tolerance to IMZ and diazepam (DZ), while AB was able to antagonize the convulsions elicited by isoniazid in DZ-tolerant mice. Should these observations be reproduced at the clinical level, IMZ may be ideal for anxiety being its efficacy increased when GABA tone is reduced, and AB may prove a useful therapeutic agent with which to treat patients who are tolerant to the effects of classical benzodiazepine full agonists.
Clinically, the primary indication for 5-HT1A agonists is the treatment of anxiety, but there has also been considerable interest in their potential antidepressant effects. The present experiments evaluated two novel 5-HT1A agonists. flesinoxan (1 - 16 mg/kg i.p.) and alnespirone (S 20499) (1 - 32 mg/kg i.p.) in three behavioral models for antidepressants: the tail suspension test m mice (TST), the behavioral despair test in mice (BDM) and the behavioral despair test in rats (BDR). Results were compared with two prototype 5-HTIA agonists, buspiroue (t - 16 mg/kg i.p.) and 8-OH-DPAT (0.5 - 8 mg/kg i.p.). All compounds increased the duration of immobility in the TST, In contrast, all compounds but buspirolie decreased_the duration of immobility in the BDR. In the BDM, results were intermediate; alnespirone and 8-OH-DPAT clearly decreased immobility, whereas flesinoxan increased immobility and buspirone was without effect. These results confirm earlier findings suggesting the particular sensitivity of the TST to the anxiolytic actions of 5-HT1A agonists (increased immobility) whereas the BDR appears mainly sensitive to their potential antidepressant action (decreased immobility). Buspirone appeared to have clear anxiolytic activity in the TST yet it showed no signs of antidepressant activity as measured by the BDM or BDR.
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AND
THERAPEUTIC AGENTS FORANXIETY AND EPILEPSY M. Serra Dept. of Exp. Biol. Via Palabanda 12 09123 Cagliari, Italy.
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PLATELET 3H-PAROXETINE BINDING,SEROTONIN LEVEL AND PERSONALITY FEATURES IN PANIC DISORDER PATIENTS; EFFECT OF LONGTERM FLUVOXAMINE TREATMENT K.Tekes, G. Faludi*,J.Tarcali,D.Borcsiczky, K . M a g y a r D e p a r t m e n t . o f P h a r m a c o d y n a m i c s and D e p a r t m e n t o f Psychiatry*, S e m m e l w e i s University o f Medicine, Budapest, H- 1089, Nagyvfirad t & 4,Hungary
In the studies 29 panic disorder patients (PDP)and l 8 controls were involved and gave their informed consent.Diagnoses were based on DSM-IiI-R. Patients and controls completed the 566 item MMPI test and were also assesed by SCID-PrD.3HParoxetine (PAR) binding was measured according to Segonzac et al (J.Neurochem.48,331,1987)and serotonin (5HT) level as described by Anderson et al (Life Sci.40,1063,1987).In drugfree PDPs we have f o u n d significantly lower B m a x values without change in KD. 5HT levels were not different from controls.PDPs s h o w e d the h i g h e s t S C I D - P r D ratings for the items concerning "avoidant" and " o b s c e s s i v e ' c o m p u l s i v e " personality features.Longterm f l u v o x a m i n e treatment (2-6 months,75 mg/kg,daily) o f the same P D P s resulted in significant relief o f s y m p t o m s , 5 H T levels b e c o m e markedly r e d u c e d while P A R b i n d i n g B m a x values remained o n the lower level.Data suggest that decrease in platelet 5HT level caused by longterm f l u v o x a m i n e treatment m a y contribute to the depression o f s y m p t o m s , h o w e v e r r e d u c e d n u m b e r o f P A R binding sites m i g h t be a "trait m a r k e r " .
5-HT1A AGONISTS: ANXIOLYTIC-LIKE AND ANTIDEPRESSANTLIKE EFFECTS IN THREE BEHAVIORAL MODELS R.D. Porsolt. S. Roux and J.G. Wettstein I.T.E.M.-Labo, 93 Avenue de Fontainebleau, 94276 Le Kremlin-Bic&re Cedex, France.
IMIDAZENIL
ABECARNIL:
TWO
NEW
The pharmacological efficacy of imidazenil, (IMZ), a benzodiazepine receptor partial agonist is greater when the GABAergic transmission is reduced. Infact, while the intraperitoneal administration of IMZ failed to affect GABAergic transmission m the cerebral cortex of untreated rats and mice, this compound abolished the reduction of GABA A receptor function elicited by isoniazid and stress. This property may confer on this drug the ability to restore impaired central GABAergic transmission to physiological levels without unwanted side effects. Accordingly, a chronic treatment with a pharmacological effective dose of IMZ failed to induce tolerance to its anticonvulsant and GABAareccptor modulatory efficacy. Abecarnil, (AB), a g-carboline derivative with high efficacy on selective GABA A receptor subtype, like IMZ, after long-term treatment did not induce pharmacological and contingent tolerance to its anticonvulsant effect. However. animals treated with increasing doses of AB (0.3-3 mg/kg i.p. or 6 mg/kg s.c.) developed cross-tolerance to IMZ and diazepam (DZ), while AB was able to antagonize the convulsions elicited by isoniazid in DZ-tolerant mice. Should these observations be reproduced at the clinical level, IMZ may be ideal for anxiety being its efficacy increased when GABA tone is reduced, and AB may prove a useful therapeutic agent with which to treat patients who are tolerant to the effects of classical benzodiazepine full agonists.
Clinically, the primary indication for 5-HT1A agonists is the treatment of anxiety, but there has also been considerable interest in their potential antidepressant effects. The present experiments evaluated two novel 5-HT1A agonists. flesinoxan (1 - 16 mg/kg i.p.) and alnespirone (S 20499) (1 - 32 mg/kg i.p.) in three behavioral models for antidepressants: the tail suspension test m mice (TST), the behavioral despair test in mice (BDM) and the behavioral despair test in rats (BDR). Results were compared with two prototype 5-HTIA agonists, buspiroue (t - 16 mg/kg i.p.) and 8-OH-DPAT (0.5 - 8 mg/kg i.p.). All compounds increased the duration of immobility in the TST, In contrast, all compounds but buspirolie decreased_the duration of immobility in the BDR. In the BDM, results were intermediate; alnespirone and 8-OH-DPAT clearly decreased immobility, whereas flesinoxan increased immobility and buspirone was without effect. These results confirm earlier findings suggesting the particular sensitivity of the TST to the anxiolytic actions of 5-HT1A agonists (increased immobility) whereas the BDR appears mainly sensitive to their potential antidepressant action (decreased immobility). Buspirone appeared to have clear anxiolytic activity in the TST yet it showed no signs of antidepressant activity as measured by the BDM or BDR.
--
AND
THERAPEUTIC AGENTS FORANXIETY AND EPILEPSY M. Serra Dept. of Exp. Biol. Via Palabanda 12 09123 Cagliari, Italy.
169--