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Species differences in susceptibility to Li-pilocarpine seizures
429 10 or 20 mg/kg 15 min prior to s.c. PTZ did not significantly change the intensity of seizures. Chronic s.c. treatment with Losartan (10 mg/kg) did not induce any significant changes in seizure intensity. Acute i.c.v, injections of PD 123 319 in doses of 5, 10 or 20/~g did not change the threshold of PTZ-induced seizures. Acute s.c. injections of PD 123 319 in doses of 5, 10, 20 or 50 mg/kg 15 rain prior to timed i.v. infusion of PTZ significantly decreased the seizure threshold. Chronic s.c. administration of PD 123 319 at a dose of 10 mg/kg tended to decrease the threshold but did not reach significant difference vs. control. Acute i.c.v, administration of PD 123 319 in a dose of 10/tg decreased the seizure intensity in the s.c. PTZ test. Acute s.c. administration of PD 123 319 at doses of 5, 10, 20 or 50 mg/kg 15 min prior to s.c. PTZ did not significantly change the intensity of seizures. Chronic s.c. administration of PD 123 319 at a dose of 10 mg/kg did not significantly change the seizure intensity in s.c. PTZ test. All these data suggest that the AT1 antagonist Losartan and the AT2 antagonist PD 123 319 have direct or indirect actions in regulating the seizure susceptibility (expressed as seizure threshold and seizure intensity). We will consider these data in relation to the complex participation of AT1 and AT2 receptors in regulation of susceptibility of brain to seizures. These might be related to the widespread distribution of these receptors in the brain areas involved in seizure susceptibility.
Acknowledgements: The authors are grateful to Dr. Ronald Smith of DuPont Merck Pharmaceutical Company, Wilmington, DE, for a generous supply of Losartan potassium, and to Ms Carol L. Germain of Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI, for the generous supply of PD 123 319. This work was supported in part by grant B-65 from the National Fund for Science Research at the Ministry of Science and Education in Bulgaria.
Species differences in susceptibility to Li-pilocarpine seizures
Y. Bersudsky, O. Mahler, O. Kofman and R.H. Belmaker Ida and Solomon Stern Psychiatry Research Unit, Ministry of Health Mental Health Center, Beersheva, Israel Key words. Lithium; Pilocarpine; Species differences Li-pilocarpine seizures are a dramatic, easily quantifiable behavioral effect of Li in rats that can be clearly ascribed to Li inhibition of inositol monophosphatase. Sherman (1991) raised the question of whether it occurred in other species such as mice as well as rats. Oppenheimet al. (1979) gave physostigmine to Li-treated patients and did not observe Li potentiation of the physostigmine effect. Recently Hokin's group (Lee et al., 1992) has studied effects of cholinergic agonists on PI metabolism in cortical slices from several species, including monkeys, rats and guinea pigs. They concluded that Li-pilocarpine interactions occur only in species with low basal brain inositol levels, such as rats, and do not occur in monkeys or guinea pigs. In vitro the phenomenon can be elicited whenever cellular inositol levels are depleted in a low inositol medium. To test Hokin's (Lee et al., 1992) hypothesis in vivo, we attempted to elicit Li-pilocarpine seizures in a wide variety of species. Rats (Sprague-Dawley, ~300 g), mice (ICR, ~25 g), guinea pigs (~250 g), rabbits (.,~500 g), chicks ( ~ 7 0 g) and goldfish ( ~ 30 g) were used. Animals were administered lithium chloride (Li) i.p. before the s.c. injection of pilocarpine (Pi) and were observed for the 2 h following pilocarpine administration. Control groups were administered low-dose pilocarpine alone, after preliminary experiments determined pilocarpine doses necessary to elicit seizures without Li. Rats, mice and goldfish show a standard limbic seizure syndrome after Li-pilocarpine and not with pilocarpine alone, with rhythmic contraction, loss of consciousness, fluctuating improvement and eventual death. One guinea pig out of nine with pilocarpine alone and one with Li-pilocarpine seized in a tonic-clonic manner and died immediately. One of two rabbits treated with Li-pilocarpine died without seizures, but neither had a Li-pilocarpine syndrome. Chicks show pilocarpine effects such as salivation, head bobbing and beak movements but there was no difference between pilocarpine alone versus Li-pilocarpine; there was no loss of consciousness or rhythmic muscle contraction. Frogs showed no pilocarpine (1 g/kg) or carbachol (100 mg/kg) response up to very high dose, and no response to Li-pilocarpine or carbachol. The present results suggest that Li-pilocarpine seizures are unique to rats, mice and goldfish, do not occur in other mammals or birds, or even in other rodents such as guinea pigs. This supports the concept of Hokin (Lee et al., 1992) that Li-pilocarpine interactions are dependent on the low baseline inositol present in rat brain. The fact that goldfish show Li-pilocarpine interactions and guinea pigs do not suggests that the property is not restricted to a specific evolutionary branch of brain development, but is potentially present since at least teleost development (goldfish) but is dependent on specific aspects of brain physiology.
430 It is interesting to speculate on the importance of the above finding for the use of Li-pilocarpine seizures as a model for the testing of Berridge's inositol depletion theory of Li action. Contraction of guinea pig ileum was a key model for the study of serotonin receptors, even though guinea pig ileum is uniquely suited for these experiments. The underlying biochemical principles were generalizable to other species and other serotonin receptors, including brain. Li-pilocarpine seizures may be such a model with no face validity but useful for mechanistic study.
Table 1. Lithium-pilocarpine synergism? LDso Li (mEq/kg)
Convulsive dose (Pi) (mg/kg)
LiC1 (mEq/kg)
Pilocarpine (mg/kg)
Time from Li to Pi (h)
Rats Mice Rabbits Guinea pigs
15-20 30M0
20(P400 >400
Chicks
> 10
3 10 6 6 6 10 10 3 6 10
20 100 30 30 60 100 150 100 100 80
6~ 30 17 20 23 17 18 17 18 6 6 2 2 17
0.96 mM
1.25 mg physo
Goldfish Human (Oppenheim et al., 1979)
>60 > 150 >200
Pi % seized 0 0 ( n - 10) 0 (n-2) 11 ( n - 9 ) 54 ( n - 13) 25 ( n - 4 ) 0 (n - 5) 0 (n-5)
0 (n=5)
Pi + Li % seized 8(~ 100 70 (n = 10) 0 (n - 2) 0 (n-2) 11 ( n - 9 ) 44 ( n - 9 ) 25 ( n - 6 ) 60 (n - 5) 40 (n-5) 80 (n-5)
0 (n=5)
References Lee, C.H., Dixon, J.F., Reichman, M., Moummi, C., Los, G. and Hokin, L.E. (1992) Li + increases accumulation of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in cholinergically stimulated brain cortex slices in guinea pig, mouse and rat. Biochem. J. 282, 377 385. Oppenheim, G., Ebstein, R.P. and Belmaker, R.H. (1979) Effect of lithium on the physostigmine-induced behavioral syndrome and plasma cyclic G M P . J. Psychiatr. Res. 15, 133-138. Sherman, W.R. (1991) Lithium and the phosphoinositide signalling system In: N.J. Birch (Ed.), Lithium and the Cell. Academic Press, London, pp. 121 157.
Serum cholesterol concentration in suicide attempters: a case-control study
M. Abbar, P. Courtet, M.C. Picot a, J. Sultan b a n d D. C a s t e l n a u b Service de Psychiatrie, CHU CarOmeau, rue du Professeur DebrO, 30000 Nimes, France, aDdpartement d'information mOdicale and bService de Psychiatrie, CHU Lapeyronie, route de Ganges, 34000 Montpellier, France Key words. Suicidal behavior; Suicide attempters; Cholesterol; Serotonin
Primary prevention trials have shown that lowering the serum cholesterol concentration in middle-aged subjects by diet, drugs or both leads to a decrease in mortality from coronary heart disease but to an increase in deaths due to suicide or violence (Muldoon et al., 1990). Secondary prevention trials revealed the same trend. Furthermore, a strong negative association between original serum cholesterol levels and short-term suicide in men was found in the largest naturalistic followup study (Lindberg et al., 1992). However, earlier follow-up studies among smaller samples had not revealed this association (Pekkanen et al., 1989; Smith et al., 1990; Chen et al., 1991, cited in Lindberg et al., 1992). The objective of this study was to determine whether total serum cholesterol concentration is associated with a past history of suicide attempts, through a casecontrol study with comparison of total serum cholesterol concentrations among psychiatric inpatients with (n = 509) and without (n = 275) a history of past suicide attempts and non-psychiatric inpatient controls (n = 2421). Mean cholesterol concentration was statistically significantly lower after sex and age adjustment in past suicide attempters when compared with other psychiatric patients. The same difference was found between suicide attempters and sex and age
Acknowledgements: The authors are grateful to Dr. Ronald Smith of DuPont Merck Pharmaceutical Company, Wilmington, DE, for a generous supply of Losartan potassium, and to Ms Carol L. Germain of Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI, for the generous supply of PD 123 319. This work was supported in part by grant B-65 from the National Fund for Science Research at the Ministry of Science and Education in Bulgaria.
Species differences in susceptibility to Li-pilocarpine seizures
Y. Bersudsky, O. Mahler, O. Kofman and R.H. Belmaker Ida and Solomon Stern Psychiatry Research Unit, Ministry of Health Mental Health Center, Beersheva, Israel Key words. Lithium; Pilocarpine; Species differences Li-pilocarpine seizures are a dramatic, easily quantifiable behavioral effect of Li in rats that can be clearly ascribed to Li inhibition of inositol monophosphatase. Sherman (1991) raised the question of whether it occurred in other species such as mice as well as rats. Oppenheimet al. (1979) gave physostigmine to Li-treated patients and did not observe Li potentiation of the physostigmine effect. Recently Hokin's group (Lee et al., 1992) has studied effects of cholinergic agonists on PI metabolism in cortical slices from several species, including monkeys, rats and guinea pigs. They concluded that Li-pilocarpine interactions occur only in species with low basal brain inositol levels, such as rats, and do not occur in monkeys or guinea pigs. In vitro the phenomenon can be elicited whenever cellular inositol levels are depleted in a low inositol medium. To test Hokin's (Lee et al., 1992) hypothesis in vivo, we attempted to elicit Li-pilocarpine seizures in a wide variety of species. Rats (Sprague-Dawley, ~300 g), mice (ICR, ~25 g), guinea pigs (~250 g), rabbits (.,~500 g), chicks ( ~ 7 0 g) and goldfish ( ~ 30 g) were used. Animals were administered lithium chloride (Li) i.p. before the s.c. injection of pilocarpine (Pi) and were observed for the 2 h following pilocarpine administration. Control groups were administered low-dose pilocarpine alone, after preliminary experiments determined pilocarpine doses necessary to elicit seizures without Li. Rats, mice and goldfish show a standard limbic seizure syndrome after Li-pilocarpine and not with pilocarpine alone, with rhythmic contraction, loss of consciousness, fluctuating improvement and eventual death. One guinea pig out of nine with pilocarpine alone and one with Li-pilocarpine seized in a tonic-clonic manner and died immediately. One of two rabbits treated with Li-pilocarpine died without seizures, but neither had a Li-pilocarpine syndrome. Chicks show pilocarpine effects such as salivation, head bobbing and beak movements but there was no difference between pilocarpine alone versus Li-pilocarpine; there was no loss of consciousness or rhythmic muscle contraction. Frogs showed no pilocarpine (1 g/kg) or carbachol (100 mg/kg) response up to very high dose, and no response to Li-pilocarpine or carbachol. The present results suggest that Li-pilocarpine seizures are unique to rats, mice and goldfish, do not occur in other mammals or birds, or even in other rodents such as guinea pigs. This supports the concept of Hokin (Lee et al., 1992) that Li-pilocarpine interactions are dependent on the low baseline inositol present in rat brain. The fact that goldfish show Li-pilocarpine interactions and guinea pigs do not suggests that the property is not restricted to a specific evolutionary branch of brain development, but is potentially present since at least teleost development (goldfish) but is dependent on specific aspects of brain physiology.
430 It is interesting to speculate on the importance of the above finding for the use of Li-pilocarpine seizures as a model for the testing of Berridge's inositol depletion theory of Li action. Contraction of guinea pig ileum was a key model for the study of serotonin receptors, even though guinea pig ileum is uniquely suited for these experiments. The underlying biochemical principles were generalizable to other species and other serotonin receptors, including brain. Li-pilocarpine seizures may be such a model with no face validity but useful for mechanistic study.
Table 1. Lithium-pilocarpine synergism? LDso Li (mEq/kg)
Convulsive dose (Pi) (mg/kg)
LiC1 (mEq/kg)
Pilocarpine (mg/kg)
Time from Li to Pi (h)
Rats Mice Rabbits Guinea pigs
15-20 30M0
20(P400 >400
Chicks
> 10
3 10 6 6 6 10 10 3 6 10
20 100 30 30 60 100 150 100 100 80
6~ 30 17 20 23 17 18 17 18 6 6 2 2 17
0.96 mM
1.25 mg physo
Goldfish Human (Oppenheim et al., 1979)
>60 > 150 >200
Pi % seized 0 0 ( n - 10) 0 (n-2) 11 ( n - 9 ) 54 ( n - 13) 25 ( n - 4 ) 0 (n - 5) 0 (n-5)
0 (n=5)
Pi + Li % seized 8(~ 100 70 (n = 10) 0 (n - 2) 0 (n-2) 11 ( n - 9 ) 44 ( n - 9 ) 25 ( n - 6 ) 60 (n - 5) 40 (n-5) 80 (n-5)
0 (n=5)
References Lee, C.H., Dixon, J.F., Reichman, M., Moummi, C., Los, G. and Hokin, L.E. (1992) Li + increases accumulation of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in cholinergically stimulated brain cortex slices in guinea pig, mouse and rat. Biochem. J. 282, 377 385. Oppenheim, G., Ebstein, R.P. and Belmaker, R.H. (1979) Effect of lithium on the physostigmine-induced behavioral syndrome and plasma cyclic G M P . J. Psychiatr. Res. 15, 133-138. Sherman, W.R. (1991) Lithium and the phosphoinositide signalling system In: N.J. Birch (Ed.), Lithium and the Cell. Academic Press, London, pp. 121 157.
Serum cholesterol concentration in suicide attempters: a case-control study
M. Abbar, P. Courtet, M.C. Picot a, J. Sultan b a n d D. C a s t e l n a u b Service de Psychiatrie, CHU CarOmeau, rue du Professeur DebrO, 30000 Nimes, France, aDdpartement d'information mOdicale and bService de Psychiatrie, CHU Lapeyronie, route de Ganges, 34000 Montpellier, France Key words. Suicidal behavior; Suicide attempters; Cholesterol; Serotonin
Primary prevention trials have shown that lowering the serum cholesterol concentration in middle-aged subjects by diet, drugs or both leads to a decrease in mortality from coronary heart disease but to an increase in deaths due to suicide or violence (Muldoon et al., 1990). Secondary prevention trials revealed the same trend. Furthermore, a strong negative association between original serum cholesterol levels and short-term suicide in men was found in the largest naturalistic followup study (Lindberg et al., 1992). However, earlier follow-up studies among smaller samples had not revealed this association (Pekkanen et al., 1989; Smith et al., 1990; Chen et al., 1991, cited in Lindberg et al., 1992). The objective of this study was to determine whether total serum cholesterol concentration is associated with a past history of suicide attempts, through a casecontrol study with comparison of total serum cholesterol concentrations among psychiatric inpatients with (n = 509) and without (n = 275) a history of past suicide attempts and non-psychiatric inpatient controls (n = 2421). Mean cholesterol concentration was statistically significantly lower after sex and age adjustment in past suicide attempters when compared with other psychiatric patients. The same difference was found between suicide attempters and sex and age