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Arginine vasopressin-neurophysin and DST in major depression: Relationship with suicidal behavior
S249
PI Affective disorders and antidepressants P < O.OOl]. Interestingly, spontaneous ‘helplessness’ slightly increased under maintained selection pressure from the S3 generation until the S6 generation. Among individuals of the ‘non-helpless’ line, immobility scores were extremely low and maintained across the generations: [S3 generation males = 6 i 2 (n = 27); females = 8 f 1 (n = 22) S6 generation males = 6 f 1 (n = 69); females = 8 f 1 (n = 38)]. Second, ‘helpless’ female mice exhibited a significantly higher anxiety in both the elevated plus-maze (% entries in open arms: 21.2 + 1.8 for ‘helpless’ and 29.3 f 2.3 for ‘non-helpless’ mice) and light/dark box tests (lit compartment entering latency (s): 69.0 & 10.2 for ‘helpless’ and 29.3 f 7.1 for ‘non-helpless’ mice) than the female mice of the ‘nonhelpless’ line. No differences in anxiety levels were found in male mice. Third, ‘helpless’ mice showed significantly higher immobility scores (s) in the Porsolt’s forced swimming test (‘helpless’ males + females: 160 f 4, ‘non-helpless’ males + females: 92 f S), another screening procedure for antide ressants. Fourth, as observed for a genetic rat model of depression P, the higher susceptibility to behavioural despair was associated with a decrease in exploratory behaviour in a novel environment, assessed with Digiscan actometers. Fifth, pain thresholds, as assessed in the hot plate test, were similar in ‘helpless’ and ‘nonhelpless’ mice. Conclusion: The selected ‘helpless’ line of mice represents an interesting tool for investigating factors (genetic and/or environmental) resulting in vulnerability to anxious-depressive disorders, and for discovering novel potential antidepressant&.
for 8 days) remained active in the tail suspension test whereas caffeine (50 m&g i.p.b.i.d, for 8 days) was ineffective. Administration of the dopamine D2 receptor antagonist haloperidol (50-200 pg/kg i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10 m&g - - i.p.) in forced swimming test whereas it left unaltered the stimulant locomotor effects induced by the AZA receptor antagonist. The interaction profile of caffeine with haloperidol differed markedly from that of SCH 58261 in these two tests. SCH 58261 (3-10 mg/kg i.p.) did not reverse reserpine (2 mg/kg s.c.)-induced akinesia or hypothermia, whereas it slightly affected ptosis scores. Conclusion: Further studies are underway to show that ADA receptor antagonists may represent a promising new class of antidepressants with fast onset of action.
References
Recently, a relationship between HPA axis overactivity and arginine vasopressin (AVP) has been reported (1). Moreover, in this study, depressed patients with a history of suicide attempt exhibited higher plasma AVP concentrations than depressed controls without history of suicidal behavior. The purpose of the present study was to assess if AVPneurophysin is associated with hypercortisolemia and suicidal behavior in depressed patients. The study included 28 patients (19 M, 9 F) subgrouped into suicide attempters (n = 13) and nonattempters (n = 15). In all subjects, we measured basal plasma levels of AVP-Neurophysin ans post-DST cortisol concentrations. We did not observe any correlation between AVP-neurophysins and post-DST cortisol levels (r = -0.07, p = 0.72). Moreover, AVPneurophysin levels did not differ between DST suppressors and nonsuppressors. Suicide attempters did not differ from nonattempters for AVP-neurophysin levels: 0.34 i 0.16 ng/ml vs 0.31 f 0.18 ng/ml (F = 0.14, p = 0.7). Our results did not confirm the hypothesis of a relationship between hypercortisolemia and AVP AVP does not seem to be implicated as an etiological factor of increased cortisol levels observed in some depressed patients. Moreover, AVP-neurophysins did not seem to play a major role in the biology of suicidal behavior.
[I] Kendler K.S., et al., Am. J. Psychiatry 1994, 151, 1605-1614. 121 Tmllas R.. et al.. Psvchoohannacoloav 1989. 99. 287-288. i3j Vaugeois j.-M., kt ai., P&hopharmkology 199?, 134, 387-391 [4] Vaugeois J.-M., et al., Eur. J. Phamacol. 1996, 316, Rl-R2. [5] O&street D.H., et al., Psychopharmacology 1995, 121, 27-37. [6] El Yacoubi M., et al., Eur. Neuropsychophamacol. 1999, (this meeting)
Ip.1.1241
Selective adenosine AU receptor antagonists are potential antidepressants: evidence based on the activity of SCH 58261 and Aa knockout mice in screening procedures
M. El Yacoubi’, C. Ledent2, M. Parmentie?, J. Costentin’, J.-M. Vaugeois’. ‘UPRESA 6036 CNRS, IFRh4P 23, Site unioersitaire du Madrillet, 76800 Saint Etienne du Rouoray, Fmnce 21RIBHN, U L B, Campus Emsme, 808 route de Lennik, B-1070 Bruxelles. Belgium Purpose: The understanding of adenosine-dopamine interactions in the basal ganglia have led to the development of Azp, receptor antagonists as potential therapeutic agents in Parkinson’s disease. Similar purinergic modulation of dopaminergic function also occurs in the mesolimbic dopaminergic pathway. An increase in dopaminergic transmission may be involved in the adaptative processes leading to the antidepressant effect. Therefore, based on neuromodulatory interactions, purinergic modulation may be therapeutically beneficial in the treatment of depression or drug abuse. Methods and Results: The effect of disrupting the gene encoding AZA receptor (APAR-/-) as compared to wild-type (ALAR+/+) mice was investigated in two behavioural tests aimed at screening potential antidepressants: Porsolt’s forced swimming and tail suspension tests. In both tests, naive ALAR-/- mice displayed less immobility than ALAR+/+ mice, whereas their exploratory locomotion was previously shown to be reduced as compared to wild-type controls’. In the tail suspension test, the adenosine ADA receptor antagonists SCH 58261 (l-10 m&g i.p.) and ZM 241385 (15-60 m&g i.p.) showed antidepressant-like effects in selected “high-immobility” outbred CD1 mice. In a new genetic mouse model of depression’ both imipramine (30 mg/kg i.p.) and SCH 58261 (10 mg/kg i.p.) reduced immobility in the tail suspension test. In Porsolt’s forced swimming test, SCH 58261 dosedependently decreased “behavioural despair” and caffeine was also effective at stimulant doses. The selective A?p, receptor antagonist SCH 58261 (3 mgikg i.p.b.i.d,
References [1] Ledent C., et al., Nature 1997, 388, 674678 [2] Vaugeois J.-M., et al., Eur. J. Phamacol. 1996, 316, Rl-R2
(p.1.1251
Arginlne vasopressin-neurophysin and DST in major depression: relationship with suicidal behavior
W. Pitchot, M. Ansseau, J.-J. Legros. Psychiatric B-4000 Lisge, Belgium
Unit, CHUSart
Tilman,
References [1] Inder WJ, Donald RA, Prick&t TCR et al: Biol Psychiatry 42 (1997) 744-747
If?I.1261 Open
naturalistic study of adjunctive gabapentin in the treatment of bipolar spectrum disorder
M. Raja, A. Azzoni. Seruizio Psichiatrico Santo Spirito, Rome, Italy
di Diagnosi e Cura. Ospedale
Introduction and Purpose: Gabapentin (GBP) is an antiepileptic drug with an unknown mechanism of action apparently dissimilar to that of other antiepileptic agents, and possessing some desirable pharmacokinetic traits. Preliminary evidence suggests that GBP may have moodstabilizing properties (1-2). The propose of this open study was to determine if GBP is effective as adjunctive treatment for major affective disorders in a naturalistic setting. Methods: We started GBP treatment in 10 men and 11 women who presented an exacerbation of their bipolar spectrum disorder or other disorders characterized by impulsiveness and aggressiveness. Their mean age (*SD) was 42.2 (kl5.1) years. Eighteen of them were in-patients
PI Affective disorders and antidepressants P < O.OOl]. Interestingly, spontaneous ‘helplessness’ slightly increased under maintained selection pressure from the S3 generation until the S6 generation. Among individuals of the ‘non-helpless’ line, immobility scores were extremely low and maintained across the generations: [S3 generation males = 6 i 2 (n = 27); females = 8 f 1 (n = 22) S6 generation males = 6 f 1 (n = 69); females = 8 f 1 (n = 38)]. Second, ‘helpless’ female mice exhibited a significantly higher anxiety in both the elevated plus-maze (% entries in open arms: 21.2 + 1.8 for ‘helpless’ and 29.3 f 2.3 for ‘non-helpless’ mice) and light/dark box tests (lit compartment entering latency (s): 69.0 & 10.2 for ‘helpless’ and 29.3 f 7.1 for ‘non-helpless’ mice) than the female mice of the ‘nonhelpless’ line. No differences in anxiety levels were found in male mice. Third, ‘helpless’ mice showed significantly higher immobility scores (s) in the Porsolt’s forced swimming test (‘helpless’ males + females: 160 f 4, ‘non-helpless’ males + females: 92 f S), another screening procedure for antide ressants. Fourth, as observed for a genetic rat model of depression P, the higher susceptibility to behavioural despair was associated with a decrease in exploratory behaviour in a novel environment, assessed with Digiscan actometers. Fifth, pain thresholds, as assessed in the hot plate test, were similar in ‘helpless’ and ‘nonhelpless’ mice. Conclusion: The selected ‘helpless’ line of mice represents an interesting tool for investigating factors (genetic and/or environmental) resulting in vulnerability to anxious-depressive disorders, and for discovering novel potential antidepressant&.
for 8 days) remained active in the tail suspension test whereas caffeine (50 m&g i.p.b.i.d, for 8 days) was ineffective. Administration of the dopamine D2 receptor antagonist haloperidol (50-200 pg/kg i.p.) prevented the antidepressant-like effects elicited by SCH 58261 (10 m&g - - i.p.) in forced swimming test whereas it left unaltered the stimulant locomotor effects induced by the AZA receptor antagonist. The interaction profile of caffeine with haloperidol differed markedly from that of SCH 58261 in these two tests. SCH 58261 (3-10 mg/kg i.p.) did not reverse reserpine (2 mg/kg s.c.)-induced akinesia or hypothermia, whereas it slightly affected ptosis scores. Conclusion: Further studies are underway to show that ADA receptor antagonists may represent a promising new class of antidepressants with fast onset of action.
References
Recently, a relationship between HPA axis overactivity and arginine vasopressin (AVP) has been reported (1). Moreover, in this study, depressed patients with a history of suicide attempt exhibited higher plasma AVP concentrations than depressed controls without history of suicidal behavior. The purpose of the present study was to assess if AVPneurophysin is associated with hypercortisolemia and suicidal behavior in depressed patients. The study included 28 patients (19 M, 9 F) subgrouped into suicide attempters (n = 13) and nonattempters (n = 15). In all subjects, we measured basal plasma levels of AVP-Neurophysin ans post-DST cortisol concentrations. We did not observe any correlation between AVP-neurophysins and post-DST cortisol levels (r = -0.07, p = 0.72). Moreover, AVPneurophysin levels did not differ between DST suppressors and nonsuppressors. Suicide attempters did not differ from nonattempters for AVP-neurophysin levels: 0.34 i 0.16 ng/ml vs 0.31 f 0.18 ng/ml (F = 0.14, p = 0.7). Our results did not confirm the hypothesis of a relationship between hypercortisolemia and AVP AVP does not seem to be implicated as an etiological factor of increased cortisol levels observed in some depressed patients. Moreover, AVP-neurophysins did not seem to play a major role in the biology of suicidal behavior.
[I] Kendler K.S., et al., Am. J. Psychiatry 1994, 151, 1605-1614. 121 Tmllas R.. et al.. Psvchoohannacoloav 1989. 99. 287-288. i3j Vaugeois j.-M., kt ai., P&hopharmkology 199?, 134, 387-391 [4] Vaugeois J.-M., et al., Eur. J. Phamacol. 1996, 316, Rl-R2. [5] O&street D.H., et al., Psychopharmacology 1995, 121, 27-37. [6] El Yacoubi M., et al., Eur. Neuropsychophamacol. 1999, (this meeting)
Ip.1.1241
Selective adenosine AU receptor antagonists are potential antidepressants: evidence based on the activity of SCH 58261 and Aa knockout mice in screening procedures
M. El Yacoubi’, C. Ledent2, M. Parmentie?, J. Costentin’, J.-M. Vaugeois’. ‘UPRESA 6036 CNRS, IFRh4P 23, Site unioersitaire du Madrillet, 76800 Saint Etienne du Rouoray, Fmnce 21RIBHN, U L B, Campus Emsme, 808 route de Lennik, B-1070 Bruxelles. Belgium Purpose: The understanding of adenosine-dopamine interactions in the basal ganglia have led to the development of Azp, receptor antagonists as potential therapeutic agents in Parkinson’s disease. Similar purinergic modulation of dopaminergic function also occurs in the mesolimbic dopaminergic pathway. An increase in dopaminergic transmission may be involved in the adaptative processes leading to the antidepressant effect. Therefore, based on neuromodulatory interactions, purinergic modulation may be therapeutically beneficial in the treatment of depression or drug abuse. Methods and Results: The effect of disrupting the gene encoding AZA receptor (APAR-/-) as compared to wild-type (ALAR+/+) mice was investigated in two behavioural tests aimed at screening potential antidepressants: Porsolt’s forced swimming and tail suspension tests. In both tests, naive ALAR-/- mice displayed less immobility than ALAR+/+ mice, whereas their exploratory locomotion was previously shown to be reduced as compared to wild-type controls’. In the tail suspension test, the adenosine ADA receptor antagonists SCH 58261 (l-10 m&g i.p.) and ZM 241385 (15-60 m&g i.p.) showed antidepressant-like effects in selected “high-immobility” outbred CD1 mice. In a new genetic mouse model of depression’ both imipramine (30 mg/kg i.p.) and SCH 58261 (10 mg/kg i.p.) reduced immobility in the tail suspension test. In Porsolt’s forced swimming test, SCH 58261 dosedependently decreased “behavioural despair” and caffeine was also effective at stimulant doses. The selective A?p, receptor antagonist SCH 58261 (3 mgikg i.p.b.i.d,
References [1] Ledent C., et al., Nature 1997, 388, 674678 [2] Vaugeois J.-M., et al., Eur. J. Phamacol. 1996, 316, Rl-R2
(p.1.1251
Arginlne vasopressin-neurophysin and DST in major depression: relationship with suicidal behavior
W. Pitchot, M. Ansseau, J.-J. Legros. Psychiatric B-4000 Lisge, Belgium
Unit, CHUSart
Tilman,
References [1] Inder WJ, Donald RA, Prick&t TCR et al: Biol Psychiatry 42 (1997) 744-747
If?I.1261 Open
naturalistic study of adjunctive gabapentin in the treatment of bipolar spectrum disorder
M. Raja, A. Azzoni. Seruizio Psichiatrico Santo Spirito, Rome, Italy
di Diagnosi e Cura. Ospedale
Introduction and Purpose: Gabapentin (GBP) is an antiepileptic drug with an unknown mechanism of action apparently dissimilar to that of other antiepileptic agents, and possessing some desirable pharmacokinetic traits. Preliminary evidence suggests that GBP may have moodstabilizing properties (1-2). The propose of this open study was to determine if GBP is effective as adjunctive treatment for major affective disorders in a naturalistic setting. Methods: We started GBP treatment in 10 men and 11 women who presented an exacerbation of their bipolar spectrum disorder or other disorders characterized by impulsiveness and aggressiveness. Their mean age (*SD) was 42.2 (kl5.1) years. Eighteen of them were in-patients