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Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat
Neuroscience Letters 224 (1997) 25–28
Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat Sophie Dethy a , b ,*, Mario Manto a, Enrico Bastianelli c, Vale´rie Gangji c, Marie Aline Laute a, Serge Goldman b, Jerzy Hildebrand a a
Service de Neurologie, ULB-Hoˆpital Erasme, 808, route de Lennik, B-1070 Brussels, Belgium b PET/Biomedical Cyclotron Unit, ULB-Hoˆpital Erasme, Brussels, Belgium c Service d’Anatomie Pathologique, ULB-Hoˆpital Erasme, Brussels, Belgium
Received 8 January 1997; revised version received 5 February 1997; accepted 5 February 1997
Abstract Cerebellar syndrome has been described after acute lithium intoxication in human. Neuropathological studies have demonstrated neuronal loss and spongiosis in the cerebellum. We describe an animal model of acute lithium-induced cerebellar degeneration. Five hours following administration of lithium chloride (250 mg/kg, i.p.), the cerebellar white matter of seven rats out 14 exhibited extensive spongiform changes. Microdialysis study in the rat cerebellar cortex demonstrated basal concentrations of dopamine (DA), hydroxy-3methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA). These metabolites were unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of dopaminergic or serotoninergic neurotransmission. 1997 Elsevier Science Ireland Ltd. Keywords: Lithium salt; Cerebellum; Microdialysis; Dopamine; Serotonin
Lithium salt is widely used in the treatment of acute mania and bipolar manic-depressive disorders. This drug has a narrow therapeutic range. Neurotoxic effects may occur at supratherapeutic levels and, less frequently, at therapeutic levels. Encephalopathy, seizures, ataxia, tremor, dyskinesia and rigidity appear at the acute stage of lithium intoxication. These signs are usually reversible but persistent neurological sequelae have been observed [11]. Cerebellar signs are predominant manifestations of lithium neurotoxicity [11,15] and neuropathological studies have demonstrated Purkinje cell loss and spongiform changes in the white matter of the cerebellum [15]. The mechanism of lithium neurotoxicity remains uncertain. It has been demonstrated in rats that chronic administration of lithium modulates the dopamine (DA) striatal release and synthesis, and enhances the hippocampal serotonin release produced by 4-aminopyridine [2,14]. Serotonin is a well known cerebellar neuromodulator [7] and,
* Corresponding author. Tel.:+32 2 5554711; fax: +32 2 5554701.
more recently, DA was identified in the rat cerebellum, mainly in the cortex [5,12]. In this study, we investigated cerebellar dopaminergic and serotoninergic neurotransmission and pathological changes after acute lithium intoxication in the rat. The microdialysis procedure has been described elsewhere [6]. Five male Wistar rats (250–350 g) were anesthetized with sodium pentobarbital (Nembutal; 5 mg/100 g, i.p.). A microdialysis probe (CMA 12, Carnegie Medicin, Sweden) was implanted into the right cerebellum (crus 1, parafloculus) at the following coordinates from bregma: A/P −10.52 mm, LAT −4.7 mm, D/V −6.4 mm [13]. The probe was perfused with a modified Ringer’s solution at a flow rate of 1.5 ml/min. Samples were collected every 20 min. When a baseline was achieved, lithium chloride (250 mg/kg; Vel, Belgium) was injected intraperitoneally and samples collected every 20 min for 5 h. Twenty minutes after lithium injection, all rats presented drowsiness and mobility decrease. Ten microliters from each sample were injected into a high-performance liquid chromatography (HPLC) system with amperometric electrochemical detection for
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940 (97 )1 3461-9
26
S. Dethy et al. / Neuroscience Letters 224 (1997) 25–28
simultaneous determination of DA, hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA) [6]. At the end of the experiment, the rat was decapitated, a carotid blood sample was collected for plasmatic lithium level determination and the brain was dissected. The placement of the probe was verified. Metabolite levels following lithium injection were compared with the mean of three basal values by one-factor analysis of variance (ANOVA) with repeated measures. We injected 30 male Wistar rats (250–350 g) with lithium chloride (250 mg/kg, i.p.). One rat died the day
Fig. 1. Effect of systemic administration of lithium (250 mg/kg, i.p.) on basal cerebellar EC levels of DA (A), HVA (B) and 5-HIAA (C). Metabolite levels are expressed as % (mean ± SEM, n = 5) of the mean of three control samples taken immediately before drug administration.
following the injection. Rats were decapitated after 5 h (n = 14) and after 15 days (n = 15). Cerebellum of the 29 lithium-intoxicated rats and five control rats was dissected, fixed in Helly’s fluid (68 mM potassium dichromate, 70 mM sodium sulfate, 180 mM HgCl2 and 4% formaldehyde), dehydrated, embedded in paraffin, sectioned at 5 mm and stained with hematoxylin-eosin and violet Cresyl. Rabbit antiserum against chick duodenal calbindin-D28K was prepared and used at 1:6000 dilution. Its specificity was previously demonstrated [3]. Dewaxed and hydrated sections were processed for immunohistochemistry according to the peroxidase-antiperoxidase procedure [3]. The basal concentrations were the following: DA, 0.024 ± 0.005; HVA, 0.40 ± 0.037; 5-HIAA, 0.16 ± 0.017 (mean ± SEM, pmol/20 min; n = 5). Mean serum lithium chloride level was 1.54 ± 0.66 mEq/l. Systemic administration of lithium (250 mg/kg, i.p.) (n = 5) did not change the DA (P = 0.9), HVA (P = 0.1) and 5-HIAA (P = 0.7) EC levels in the cerebellum (Fig. 1). Cerebellum of seven lithium-intoxicated rats examined 5 h after lithium injection (n = 14) presented extensive vacuolation in the intrafolial and deep cerebellar white matter (Fig. 2A). The diameter of the vacuoles varied from 10 to 50 mm. No loss of Purkinje cells was observed. There was also mild vacuolation in the brainstem. The absence of axonal injuries was demonstrated by the calbindin-D28K immunoreactivity. None of the 15 lithium-intoxicated rats examined 15 days after lithium injection (n = 15) and none of the control rats (n = 5) presented vacuolation (Fig. 2B). This cerebellar microdialysis study performed in freely moving rats demonstrates that both cerebellar DA release and DA and serotonin turnover are unaffected by an acute lithium intoxication. Actually, this is the first microdialysis study demonstrating DA release in the rat cerebellar cortex. Recently, Ikai et al. have found dopaminergic fibers projecting from the ventral tegmental area to the rat cerebellar cortex [8]. These projections were distributed mainly in the crus 1 ansiform lobule and the paraflocculus. The role of cerebellar dopaminergic projections is not established. However, the cerebellar dopamine release seems to be regulated in a different way than in the striatum [5]. In other experimental studies, an acute administration of lithium did not modify the striatal release of DA and the hippocampal release of serotonin [2,14]. Taken together, these results suggest that brain toxicity due to acute lithium intoxication is not directly related to a modification of the extracellular levels of DA and serotonin which reflect mainly DA and serotonin vesicular release. There are few neuropathological reports of lithium intoxication in humans [9,15]. Recently, cerebellar degeneration was found in a patient with persistent cerebellar features following acute lithium intoxication [15]. Diffuse spongiosis in the cerebellar white matter associated with Purkinje cell loss was observed. In our study, we found a major spongiform degeneration in 50% of the rats examined 5 h
S. Dethy et al. / Neuroscience Letters 224 (1997) 25–28
27
Fig. 2. Cerebellar pathology. (A) Cerebellum of a lithium-intoxicated rat showed widespread vacuolization in the cerebellar white matter. Calbindin-D28K fixation revealed no loss of Purkinje cells. (B) Cerebellum of a control rat. (Magnification (A,B) × 350).
after lithium injection, in absence of Purkinje cell destruction. Purkinje cell sparing, which differentiates our findings from human case reports, might be related to the absence of concomitant factor such as neuroleptic treatment, fever and renal failure which were mentioned in patients reports [11,15]. Spongiform-like vacuolation in the brain is seen in several metabolic and toxic encephalopathies [4,10]. Electron microscopy studies have shown that in such spongiform encephalopathies the vacuoles are intra-myelinic in contrast with the dementia-related spongiform encephalopathies in which vacuoles are intra-axonal [1]. In our study, the calbindin-D28K immunolabeling demonstrates the absence of axonal injuries suggesting that the pathophysiological mechanism was the same than in metabolic spongiform encephalopathies. Absence of vacuolation in half of the rats 5 h after lithium injection despite the appearance of neurological signs might be related to impairment of electrolyte balance or carbohydrate metabolism only in rats exhibiting spongiform degeneration [15]. An individual vulnerability could have also played a role in the genesis of histological changes. Vacuolation seems to be a reversible phenomenon since it was not found in the lithium-intoxicated rats examined 15 days after lithium injection. Restoration of energetic metabolism and ionic pump functions may be the cause of this reversibility.
In conclusion, we suggest to add lithium to the list of exogenous toxins causing a white matter cerebellar spongiosis. Cerebellar DA and DA and serotonin metabolites are unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of the dopaminergic and serotoninergic neurotransmission. S.D. is a Research Assistant of the Belgian National Fund for Scientific Research. [1] Agamanolis, D.P., Victor, M., Harris, J.W., Hines, J.D., Chester, E.M. and Kark, J.A., An ultrastructural study of subacute combined degeneration of the spinal cord in vitamine B12 deficient Rhesus monkeys, J. Neuropathol. Exp. Neurol., 37 (1978) 273– 299. [2] Baptista, T., Teneu´d, L., Contreras, Q., Burguera, J.L., Burguera, M. and Herna´ndez, L., Effects of acute and chronic lithium treatment on amphetamine-induced dopamine increase in the nucleus accumbens and prefrontal cortex in rats as studied by microdialysis, J. Neural Transm., 94 (1993) 75–89. [3] Bastianelli, E., Polans, A.S., Hidaka, H. and Pochet, R., Differential distribution of six calcium-binding proteins in the rat olfactory epithelium during postnatal development and adulthood, J. Comp. Neurol., 354 (1995) 395–409. [4] Bell, J.E., Neuropathology of spongiform encephalopathies in humans, Br. Med. Bull., 49 (1993) 738–777. [5] Chrapusta, S.J., Egan, M.F., Masserano, J.M. and Wyatt, R.J., Dopa-
28
[6]
[7]
[8]
[9] [10]
S. Dethy et al. / Neuroscience Letters 224 (1997) 25–28 mine release in the rat cerebellum and hippocampus: a tissue 3methoxytyramine study, Brain Res., 655 (1994) 271–275. Dethy, S., Laute, M.A., Luxen, A., Hildebrand, J. and Goldman, S., Effect of pergolide on endogenous and exogenous l-dopa metabolism in the rat striatum: a microdialysis study, J. Neural Transm., 101 (1995) 1–11. Hokfelt, T. and Fuxe, K., Cerebellar monoamine nerve terminals, a new type of afferent fibers to the cortex cerebelli, Exp. Brain Res., 9 (1969) 63–72. Ikai, Y., Takada, M., Shinonaga, Y. and Mizuno, N., Dopaminergic and non-dopaminergic neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and deep cerebellar nuclei, Neuroscience, 51 (1992) 719–728. Jacob, H., Neuropathologisches syndrom nach lithium-intoxikation, Zentralbl. Allg. Pathol., 122 (1978) 587. Jacob, J.M. and Quesne, P.M.L., Toxic disorders. In J.H. Adams and L.W. Duchen (Eds.), Greenfield’s Neuropathology, Oxford University Press, New York, 1992, pp. 881–987.
[11] Nagaraja, D., Taly, A.B., Sahu, R.N., Channabasavanna, S.M. and Narayanan, H.S., Permanent neurological sequelae due to lithium toxicity, Clin. Neurol. Neurosurg., 89 (1987) 31–34. [12] Panagopoulos, N.T., Panadopoulos, G.C. and Matsokis, N.A., Dopaminergic innervation and binding in the rat cerebellum, Neurosci. Lett., 130 (1991) 213–216. [13] Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Coordinates, Academic Press, San Diego, CA, 1986. [14] Pei, Q., Leslie, R.A., Grahame-Smith, D.G. and Zetterstro¨m, T.S.C., 5-HT Efflux from rat hippocampus in vivo produced by 4-aminopyridine is increased by chronic lithium administration, NeuroReport, 6 (1995) 716–720. [15] Schneider, J.A. and Mirra, S.S., Neuropathologic correlates of persistent neurologic deficit in lithium intoxication, Ann. Neurol., 36 (1994) 928–931.
Cerebellar spongiform degeneration induced by acute lithium intoxication in the rat Sophie Dethy a , b ,*, Mario Manto a, Enrico Bastianelli c, Vale´rie Gangji c, Marie Aline Laute a, Serge Goldman b, Jerzy Hildebrand a a
Service de Neurologie, ULB-Hoˆpital Erasme, 808, route de Lennik, B-1070 Brussels, Belgium b PET/Biomedical Cyclotron Unit, ULB-Hoˆpital Erasme, Brussels, Belgium c Service d’Anatomie Pathologique, ULB-Hoˆpital Erasme, Brussels, Belgium
Received 8 January 1997; revised version received 5 February 1997; accepted 5 February 1997
Abstract Cerebellar syndrome has been described after acute lithium intoxication in human. Neuropathological studies have demonstrated neuronal loss and spongiosis in the cerebellum. We describe an animal model of acute lithium-induced cerebellar degeneration. Five hours following administration of lithium chloride (250 mg/kg, i.p.), the cerebellar white matter of seven rats out 14 exhibited extensive spongiform changes. Microdialysis study in the rat cerebellar cortex demonstrated basal concentrations of dopamine (DA), hydroxy-3methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA). These metabolites were unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of dopaminergic or serotoninergic neurotransmission. 1997 Elsevier Science Ireland Ltd. Keywords: Lithium salt; Cerebellum; Microdialysis; Dopamine; Serotonin
Lithium salt is widely used in the treatment of acute mania and bipolar manic-depressive disorders. This drug has a narrow therapeutic range. Neurotoxic effects may occur at supratherapeutic levels and, less frequently, at therapeutic levels. Encephalopathy, seizures, ataxia, tremor, dyskinesia and rigidity appear at the acute stage of lithium intoxication. These signs are usually reversible but persistent neurological sequelae have been observed [11]. Cerebellar signs are predominant manifestations of lithium neurotoxicity [11,15] and neuropathological studies have demonstrated Purkinje cell loss and spongiform changes in the white matter of the cerebellum [15]. The mechanism of lithium neurotoxicity remains uncertain. It has been demonstrated in rats that chronic administration of lithium modulates the dopamine (DA) striatal release and synthesis, and enhances the hippocampal serotonin release produced by 4-aminopyridine [2,14]. Serotonin is a well known cerebellar neuromodulator [7] and,
* Corresponding author. Tel.:+32 2 5554711; fax: +32 2 5554701.
more recently, DA was identified in the rat cerebellum, mainly in the cortex [5,12]. In this study, we investigated cerebellar dopaminergic and serotoninergic neurotransmission and pathological changes after acute lithium intoxication in the rat. The microdialysis procedure has been described elsewhere [6]. Five male Wistar rats (250–350 g) were anesthetized with sodium pentobarbital (Nembutal; 5 mg/100 g, i.p.). A microdialysis probe (CMA 12, Carnegie Medicin, Sweden) was implanted into the right cerebellum (crus 1, parafloculus) at the following coordinates from bregma: A/P −10.52 mm, LAT −4.7 mm, D/V −6.4 mm [13]. The probe was perfused with a modified Ringer’s solution at a flow rate of 1.5 ml/min. Samples were collected every 20 min. When a baseline was achieved, lithium chloride (250 mg/kg; Vel, Belgium) was injected intraperitoneally and samples collected every 20 min for 5 h. Twenty minutes after lithium injection, all rats presented drowsiness and mobility decrease. Ten microliters from each sample were injected into a high-performance liquid chromatography (HPLC) system with amperometric electrochemical detection for
0304-3940/97/$17.00 1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940 (97 )1 3461-9
26
S. Dethy et al. / Neuroscience Letters 224 (1997) 25–28
simultaneous determination of DA, hydroxy-3-methoxyphenylacetic acid (HVA) and 5-hydroxy-3-indolacetic acid (5-HIAA) [6]. At the end of the experiment, the rat was decapitated, a carotid blood sample was collected for plasmatic lithium level determination and the brain was dissected. The placement of the probe was verified. Metabolite levels following lithium injection were compared with the mean of three basal values by one-factor analysis of variance (ANOVA) with repeated measures. We injected 30 male Wistar rats (250–350 g) with lithium chloride (250 mg/kg, i.p.). One rat died the day
Fig. 1. Effect of systemic administration of lithium (250 mg/kg, i.p.) on basal cerebellar EC levels of DA (A), HVA (B) and 5-HIAA (C). Metabolite levels are expressed as % (mean ± SEM, n = 5) of the mean of three control samples taken immediately before drug administration.
following the injection. Rats were decapitated after 5 h (n = 14) and after 15 days (n = 15). Cerebellum of the 29 lithium-intoxicated rats and five control rats was dissected, fixed in Helly’s fluid (68 mM potassium dichromate, 70 mM sodium sulfate, 180 mM HgCl2 and 4% formaldehyde), dehydrated, embedded in paraffin, sectioned at 5 mm and stained with hematoxylin-eosin and violet Cresyl. Rabbit antiserum against chick duodenal calbindin-D28K was prepared and used at 1:6000 dilution. Its specificity was previously demonstrated [3]. Dewaxed and hydrated sections were processed for immunohistochemistry according to the peroxidase-antiperoxidase procedure [3]. The basal concentrations were the following: DA, 0.024 ± 0.005; HVA, 0.40 ± 0.037; 5-HIAA, 0.16 ± 0.017 (mean ± SEM, pmol/20 min; n = 5). Mean serum lithium chloride level was 1.54 ± 0.66 mEq/l. Systemic administration of lithium (250 mg/kg, i.p.) (n = 5) did not change the DA (P = 0.9), HVA (P = 0.1) and 5-HIAA (P = 0.7) EC levels in the cerebellum (Fig. 1). Cerebellum of seven lithium-intoxicated rats examined 5 h after lithium injection (n = 14) presented extensive vacuolation in the intrafolial and deep cerebellar white matter (Fig. 2A). The diameter of the vacuoles varied from 10 to 50 mm. No loss of Purkinje cells was observed. There was also mild vacuolation in the brainstem. The absence of axonal injuries was demonstrated by the calbindin-D28K immunoreactivity. None of the 15 lithium-intoxicated rats examined 15 days after lithium injection (n = 15) and none of the control rats (n = 5) presented vacuolation (Fig. 2B). This cerebellar microdialysis study performed in freely moving rats demonstrates that both cerebellar DA release and DA and serotonin turnover are unaffected by an acute lithium intoxication. Actually, this is the first microdialysis study demonstrating DA release in the rat cerebellar cortex. Recently, Ikai et al. have found dopaminergic fibers projecting from the ventral tegmental area to the rat cerebellar cortex [8]. These projections were distributed mainly in the crus 1 ansiform lobule and the paraflocculus. The role of cerebellar dopaminergic projections is not established. However, the cerebellar dopamine release seems to be regulated in a different way than in the striatum [5]. In other experimental studies, an acute administration of lithium did not modify the striatal release of DA and the hippocampal release of serotonin [2,14]. Taken together, these results suggest that brain toxicity due to acute lithium intoxication is not directly related to a modification of the extracellular levels of DA and serotonin which reflect mainly DA and serotonin vesicular release. There are few neuropathological reports of lithium intoxication in humans [9,15]. Recently, cerebellar degeneration was found in a patient with persistent cerebellar features following acute lithium intoxication [15]. Diffuse spongiosis in the cerebellar white matter associated with Purkinje cell loss was observed. In our study, we found a major spongiform degeneration in 50% of the rats examined 5 h
S. Dethy et al. / Neuroscience Letters 224 (1997) 25–28
27
Fig. 2. Cerebellar pathology. (A) Cerebellum of a lithium-intoxicated rat showed widespread vacuolization in the cerebellar white matter. Calbindin-D28K fixation revealed no loss of Purkinje cells. (B) Cerebellum of a control rat. (Magnification (A,B) × 350).
after lithium injection, in absence of Purkinje cell destruction. Purkinje cell sparing, which differentiates our findings from human case reports, might be related to the absence of concomitant factor such as neuroleptic treatment, fever and renal failure which were mentioned in patients reports [11,15]. Spongiform-like vacuolation in the brain is seen in several metabolic and toxic encephalopathies [4,10]. Electron microscopy studies have shown that in such spongiform encephalopathies the vacuoles are intra-myelinic in contrast with the dementia-related spongiform encephalopathies in which vacuoles are intra-axonal [1]. In our study, the calbindin-D28K immunolabeling demonstrates the absence of axonal injuries suggesting that the pathophysiological mechanism was the same than in metabolic spongiform encephalopathies. Absence of vacuolation in half of the rats 5 h after lithium injection despite the appearance of neurological signs might be related to impairment of electrolyte balance or carbohydrate metabolism only in rats exhibiting spongiform degeneration [15]. An individual vulnerability could have also played a role in the genesis of histological changes. Vacuolation seems to be a reversible phenomenon since it was not found in the lithium-intoxicated rats examined 15 days after lithium injection. Restoration of energetic metabolism and ionic pump functions may be the cause of this reversibility.
In conclusion, we suggest to add lithium to the list of exogenous toxins causing a white matter cerebellar spongiosis. Cerebellar DA and DA and serotonin metabolites are unaffected by acute lithium intoxication suggesting that the cerebellar toxicity is not due to a modification of the dopaminergic and serotoninergic neurotransmission. S.D. is a Research Assistant of the Belgian National Fund for Scientific Research. [1] Agamanolis, D.P., Victor, M., Harris, J.W., Hines, J.D., Chester, E.M. and Kark, J.A., An ultrastructural study of subacute combined degeneration of the spinal cord in vitamine B12 deficient Rhesus monkeys, J. Neuropathol. Exp. Neurol., 37 (1978) 273– 299. [2] Baptista, T., Teneu´d, L., Contreras, Q., Burguera, J.L., Burguera, M. and Herna´ndez, L., Effects of acute and chronic lithium treatment on amphetamine-induced dopamine increase in the nucleus accumbens and prefrontal cortex in rats as studied by microdialysis, J. Neural Transm., 94 (1993) 75–89. [3] Bastianelli, E., Polans, A.S., Hidaka, H. and Pochet, R., Differential distribution of six calcium-binding proteins in the rat olfactory epithelium during postnatal development and adulthood, J. Comp. Neurol., 354 (1995) 395–409. [4] Bell, J.E., Neuropathology of spongiform encephalopathies in humans, Br. Med. Bull., 49 (1993) 738–777. [5] Chrapusta, S.J., Egan, M.F., Masserano, J.M. and Wyatt, R.J., Dopa-
28
[6]
[7]
[8]
[9] [10]
S. Dethy et al. / Neuroscience Letters 224 (1997) 25–28 mine release in the rat cerebellum and hippocampus: a tissue 3methoxytyramine study, Brain Res., 655 (1994) 271–275. Dethy, S., Laute, M.A., Luxen, A., Hildebrand, J. and Goldman, S., Effect of pergolide on endogenous and exogenous l-dopa metabolism in the rat striatum: a microdialysis study, J. Neural Transm., 101 (1995) 1–11. Hokfelt, T. and Fuxe, K., Cerebellar monoamine nerve terminals, a new type of afferent fibers to the cortex cerebelli, Exp. Brain Res., 9 (1969) 63–72. Ikai, Y., Takada, M., Shinonaga, Y. and Mizuno, N., Dopaminergic and non-dopaminergic neurons in the ventral tegmental area of the rat project, respectively, to the cerebellar cortex and deep cerebellar nuclei, Neuroscience, 51 (1992) 719–728. Jacob, H., Neuropathologisches syndrom nach lithium-intoxikation, Zentralbl. Allg. Pathol., 122 (1978) 587. Jacob, J.M. and Quesne, P.M.L., Toxic disorders. In J.H. Adams and L.W. Duchen (Eds.), Greenfield’s Neuropathology, Oxford University Press, New York, 1992, pp. 881–987.
[11] Nagaraja, D., Taly, A.B., Sahu, R.N., Channabasavanna, S.M. and Narayanan, H.S., Permanent neurological sequelae due to lithium toxicity, Clin. Neurol. Neurosurg., 89 (1987) 31–34. [12] Panagopoulos, N.T., Panadopoulos, G.C. and Matsokis, N.A., Dopaminergic innervation and binding in the rat cerebellum, Neurosci. Lett., 130 (1991) 213–216. [13] Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Coordinates, Academic Press, San Diego, CA, 1986. [14] Pei, Q., Leslie, R.A., Grahame-Smith, D.G. and Zetterstro¨m, T.S.C., 5-HT Efflux from rat hippocampus in vivo produced by 4-aminopyridine is increased by chronic lithium administration, NeuroReport, 6 (1995) 716–720. [15] Schneider, J.A. and Mirra, S.S., Neuropathologic correlates of persistent neurologic deficit in lithium intoxication, Ann. Neurol., 36 (1994) 928–931.