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Inhibitory effect of lithium on neuroleptic and serotonin receptors in rat brain
148
Brain Research, 265 (1983) 148- 151 Elsevier Biomedical Press
Inhibitory effect of lithium on neuroleptic and serotonin receptors in rat brain KENJI TANIMOTO, KIYOSHI M A E D A and T E R U H I S A T E R A D A
Department of Psychiatry, Kobe University, School of Medicine, 7 Kusunoki-eho, Chuo-ku, Kobe 650 (Japan) (Accepted November 30th, 1982)
Key words: lithium - neuroleptic receptor - serotonin receptor
We investigated the effect of acute and chronic administration of lithium on neuroleptic receptors ([3H]spiroperidol binding sites) and serotonin receptors ([3 H]]serotonin binding sites) in rat brain. In the limbic-forebrain, both acute and chronic lithium treatment significantly reduced the density (Bmax) of neuroleptic receptors, without affecting the affinity (Ka) of those receptors. However, lithium treatment had no apparent effect on neuroleptic receptors in the caudate-putamen and frontal cortex in either acute or chronic administrations. On the other hand, acute lithium administration markedly decreased the Ka and Bmax ofserotonin receptors in the hippocampus, but not in the cerebral cortex; this distinct observation was also found in animals chronically treated with lithium. These results indicate that lithium has an inhibitory effect on neuroleptic receptors in the limbic-forebrain and on serotonin receptors in the hippocampus. Therefore, it is possible to postulate that these effects of lithium in specific brain regions may be related to the therapeutic mechanism of this drug in affective disorders.
The therapeutic mechanism of lithium in manic-depressive diseases has been thought to be related to biogenic monoamine metabolisms. Our previous reports have suggested that lithium has an inhibitory effect on dopamine receptor sensitivity and on the development ofdopamine receptor supersensitivity in prolactin release9-11. Recently, the development of the radioreceptor assay has revealed the detailed mechanism of action of neuroleptic drugs, including lithium. We considered it relevant to investigate the effect of lithium on various neurotransmitter receptors in specific brain regions. Rosenblatt et al. 7 have observed no significant effect of chronic lithium treatment on the [3H]spiroperidol binding in the caudate. It has also been reported that chronic administration for 21 days in rat results in a significant decrease in the serotonin receptor binding in the hippocampus and striatumL Previous reports have not indicated whether those results were observed after acute administration of lithium. In the present study, we examined the acute and chronic effect of lithium on neuroleptic and serotonin receptors in various brain regions. Male Wistar rats (200-250 g) were housed in a 0006-8993/83/000(~0000/$03.00 ©1983 Elsevier Science Publishers
light-controlled room (12 h light, 12 h dark) with temperature maintained at 22 _+ 2 °C, and were given Oriental Laboratory Chew (Oriental Yeast, Tokyo) and water ad libitum. In acute experiments, rats were intraperitoneally injected with LiC1 (5 mmol/kg) 4 h before sacrifice. Control animals were administered NaC1. In chronic experiments, animals were fed a diet containing 0.15% lithium carbonate and controls a similar diet without lithium for 30 days. All rats were sacrificed by decapitation and blood was collected for the measurement of lithium. Plasma lithium levels were estimated by atomic absorption spectrophotometry. The brain was dissected on ice according to the method of Howlett and Nahorski 3 as follows. A coronal cut was made 1 m m foreward of the point of optic chiasma and a further cut 1 m m caudal to this point. From this slice the caudateputamen was removed with excisions of the septum and callosal corpus, and frontal cortex and limbic-forebrain were separated with cuts through the rhinal fissure. In addition, the cerebral cortex and hippocampus were dissected from the remaining tissue. [3H]spiroperidol binding assay: [3H]spiro-
149 peridol binding assay was performed in the caudate-putamen, limbic-forebrain and frontal cortex, as described by Creese et al.2. The tissues were homogenized in 100 vols. of an ice-cold buffer (50 mM Tris-HCl, pH 7.7 at 25 °C). The homogenates were centrifuged twice at 50,000 g for 10 min with resuspension of the intermediate pellet in this buffer. The final pellets were resuspended in a 50 mM Tris-HC1 buffer (pH 7.1 at 37 °C) containing 0.1% ascorbic acid, 10 ~M pargyline, 120 m M NaCI, 5 m M KCI, 2 mM CaC12 and 1 mM MgC12. The homogenates were incubated at 37 °C for 10 min and returned to ice. Incubation tubes received 1.5 ml of tissue homogenate (0.4 mg protein), 0.1 ml of [3H]spiroperidol (0.075-2.4 nM) and 0.1 ml of (+)-butaclamol or this buffer. Incubation was carried out at 37 °C for 15 min, and terminated by rapid filtration (Whatman G F / B filters) under a vacuum with three 5 ml rinses of the ice-cold buffer. The filters were counted by liquid scintillation spectrometry in 5 ml of Aquasol-2 (NEN, U.S.A.) at efficiencies of 35-40%. Specific binding was measured as excess over blanks taken in the presence of 1 ~M (+)-butaclamol. [3H]serotonin binding assay: this binding as reported by Bergstrom and Kellar t was performed with a slight modification in the cerebral cortex and hippocampus. The tissues were homogenized in 20 vols. of an ice-cold 50 mM TrisHC1 buffer (pH 7.7 at 25 °C). After two centrifugations at 50,000 g for 10 min followed by washing, the pellet was resuspended in a 50 mM TrisHC1 buffer containing 0.1% ascorbic acid, 10 /zM pargyline and 4 mM CaC12. The tissue suspension was preincubated at 37 °C for 10 min and stored on ice. Each tube received 1.5 ml of tissue homogenate (0.6 mg protein), 0.1 ml of [3H]serotonin (1.25-20 nM) and 0.1 ml of serotonin or this buffer. Incubation was carried out as described in the [3H]spiroperidol binding assay. Specific binding was defined as the difference between the absence and presence of 20 ~M serotonin. Chemicals and drugs: [3H]spiroperidol (29.9 Ci/mmol) and [3H]serotonin (29.0 Ci/mmol) were purchased from New England Nuclear. The sources of the drugs are as follows: ( + ) - b u -
taclamol from Ayerst (Canada) and serotonin creatinine sulfate from Merck (F.R.G.). Student's t-test was used for statistical analysis. In all regions studied, specific binding of [3H]spiroperidol and [3H]serotonin plateaued at a concentration of approximately 0.8 nM and 8 nM, respectively. Scatchard analyses gave straight lines in all regions, indicating a single population of binding sites. The highest specific binding of [3H]spiroperidol was observed in the caudate-putamen and represented 51 82% of the total binding depending on the concentration of [3H]ligand. In the [3H]serotonin binding assay, the specific binding in the hippocampus was higher than that in the cerebral cortex and revealed 34-61% of the total binding. In chronic experiments, the mean ( ___S.E.M.) weight of the rats treated with lithium was not significantly different from that in the controls (318 ___ 6 vs 332___ 16 g, respectively). Scatchard analyses of the data in all regions are summarized in Table I. In the [3H]spiroperidol binding assay, the density of receptors (Bmax) in the limbic-forebrain was significantly lower in rats treated both acutely and chronically with lithium than in the controls. However, the affinity of receptors (Kd) in the region was not affected by lithium. There was no significant effect of lithium on neuroleptic receptors in the caudateputamen and frontal cortex. Acute lithium treatment significantly reduced both Bm~x and Kd of serotonin receptors in the hippocampus, but not in the cerebral cortex. This observation was also found after chronic lithium treatment. Plasma lithium levels were 1.2 + 0.1 mEq/1 and 0.60 __ 0.10 m E q / l in acute and chronic administrations, respectively. We have found that lithium treatment significantly reduces the density of neuroleptic receptors in the limbic-forebrain, not in the caudateputamen. Rosenblatt et al. 8 have also observed that the density of the [3H]spiroperidol binding site in the caudate is significantly lower in the rats chronically treated with lithium than in the controls. However, we could not demonstrate any significant effect of lithium on this binding in the caudate-putamen. It is very difficult to explain the difference between our results and
150 TABLE I
Effect of lithium on neuroleptic and serotonin receptors in rat brain. All values are the m e a n ± S.E.M. C-P, c a u d a t e - p u t a m e n ; L-F, limbic-forebrain; H-C, h i p p o c a m p u s .
A cute lithium administration
Chronic lithium administration
B.,ax
Ka (nM)
/(d
B.,ax
(pmol / mg prot.) [3H]spiroperidol
C-P L-F Cortex
[3H]serotonin
H-C Cortex
Lithium Control Lithium Control Lithium Control
0.61 0.69 0.51 0.71 O.89 0.83
± 0.03 ± 0.08 ___ 0.06 ± 0.09 ± 0.05 ___ 0.08
Lithium Control Lithium Control
6.37 11.8 5.15 5.03
± 0.18"* ± 0.75 _ 0.27 ___ 0.22
0.22 0.24 0.042 0.093 0.12 0.12
___ 0.03 ___ 0.02 __+0.001"* ___ 0.010 + 0.01 ± 0.01
0.55 0.42 0.36 0.45 1.21 1.17
0.22 0.36 0.12 0.14
___ 0.02** --- 0.02 ___ 0.01 __. 0.01
6.70 11.20 5.20 5.07
___ 0.04 ___0.04 ___ 0.03 ___0.06 ___0.01 ± 0.03 ___ 0.06** ___0.44 "4- 0.40 __. 0.29
0.16 0.16 0.093 0.140 0.098 0.103
__. 0.01 ___ 0.02 ___0.002* __. 0.020 __. 0.003 ___ 0.002
0.23 0.37 0.12 0.13
+ 0.02** ___ 0.01 ___0.01 ___ 0.01
* P < 0.05 vs control. ** P < 0.01 vscontrol.
theirs. The weight of each caudate (35 mg) in their experiment was much lower compared with the fragment of the caudate-putamen (100 mg) in our study. Therefore, in the caudate-putamen, we might be unable to find difference between the lithium group and controls. We have demonstrated that the Bmax and Kj of serotonin receptors in the hippocampus are significantly lower in the lithium group than those in ihe controls. Treiser and Kellar ~2have also reported that chronic lithium administration resuits in reduced density ofserotonin receptors in the rat hippocampus with no apparent effects in the cortex. In addition, it has been observed by Maggi and Enna 5 that chronic lithium treatment leads to a significant decrease in serotonin receptors in the rat hippocampus and striatum. Previous reports 4-6 have suggested that neuroleptic receptors ([3H]spiroperidol binding sites) involve serotonin receptors, especially in the frontal cortex, as well as dopamine receptors. Therefore, the low Bmax of [3H]spiroperidol binding sites in the limbic-forebrain observed in
our experiment may be due to the reduction of serotonin receptors, not to that ofneuroleptic receptors. However, this is unlikely because the limbic-forebrain is thought to be poor in serotonin receptors. The effect of acute administration of lithium on the neurotransmitter receptor binding has not been investigated. Lithium has been demonstrated to be ineffective on the binding of both neuroleptic and serotonin receptors in vitro 8.~2. Therefore, it is concluded that lithium, whether acutely or chronically given in vivo, induces receptor subsensitivities of neuroleptics and serotonin. The therapeutic effect of lithium on manic patients appears within 3-5 days. On the other hand, the long-term administration of lithium is necessary to the prophylactic effect on recurrent manic-depressive diseases. The acute effect of lithium on the receptor function may represent the therapeutic effect of the ion, and the alteration of that function by chronic lithium administration may be related to the prophylactic action of lithium.
1 Bergstrom, D. A. and Kellar, K. J., Effect o f electroconvulsive shock on m o n o a m i n e r g i c receptor binding sites in rat brain, Nature (Lond.), 278 (1979) 4 6 ~ 4 6 6 . 2 Creese, I., Schneider, R. and Snyder, S. H., [3H]spiroperidol labels d o p a m i n e receptors in pituitary and brain, Europ. J. Pharmacol., 46 (1977) 3 7 2 3 8 1 .
3 Howlett, D. R. and Nahorski, S. R., A comparative study o f [3H]haloperidol a n d [3H]spiroperidol b i n d i n g to receptors on rat cerebral m e m b r a n e s , F E B S Lett., 87 (1978) 1 5 ~ 156. 4 Leysen, J. E., Niemegeers, C. J. E., Tollenaere, J. P. a n d Laduron, P. M., Serotonergic c o m p o n e n t o f neuroleptic
151 receptors, Nature (Lond.), 272 (1978) 168- 171. 5 Maggi, A. and Enna, S. J., Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment, J. Neurochem., 34 (1980) 888- 892. 6 Quik, M., Iversen, L. L., Larder, A. and Mackay, A. V. P., Use of ADTN to define specific [3H]spiperone binding to receptors in brain, Nature (Lond.), 274 (1978) 513-514. 7 Rosenblatt, J. E., Pert, C. B., Tallman, J. F., Pert, A. and Bunney, W. E., Jr., The effect of imipramine and lithium on a- and fl-receptor binding in rat brain, Brain Research, 160(1979) 186-191. 8 Rosenblatt, J. E., Pert, A., Layton, B. and Bunney, W. E., Jr., Chronic lithium reduces [3H]spiroperidol binding in rat striatum, Europ. J. Pharmacol., 67 (1980) 321-322.
9 Tanimoto, K., Maeda, K., Yamaguchi, N., Chihara, K. and Fujita, T., Effect of lithium on prolactin response to thyrotropin releasing hormone in patients with manic state, Psychopharmacology, 72 (1981) 129-133. 10 Tanimoto, K., Maeda, K. and Chihara, K., Inhibition by lithium of dopamine receptors in rat prolactin release, Brain Research, 223 (1981) 335-342. 11 Tanimoto, K., Maeda, K. and Chihara, K., Antagonizing effect of lithium on the development of dopamine supersensitivity in the tuberoinfundibular system, Brain Research, 245 (1982) 163- 166. 12 Treiser, S. and Kellar, K. J., Lithium: effects on serotonin receptors in rat brain, Europ. J. Pharrnacol., 64 (1980) 183-185.
Brain Research, 265 (1983) 148- 151 Elsevier Biomedical Press
Inhibitory effect of lithium on neuroleptic and serotonin receptors in rat brain KENJI TANIMOTO, KIYOSHI M A E D A and T E R U H I S A T E R A D A
Department of Psychiatry, Kobe University, School of Medicine, 7 Kusunoki-eho, Chuo-ku, Kobe 650 (Japan) (Accepted November 30th, 1982)
Key words: lithium - neuroleptic receptor - serotonin receptor
We investigated the effect of acute and chronic administration of lithium on neuroleptic receptors ([3H]spiroperidol binding sites) and serotonin receptors ([3 H]]serotonin binding sites) in rat brain. In the limbic-forebrain, both acute and chronic lithium treatment significantly reduced the density (Bmax) of neuroleptic receptors, without affecting the affinity (Ka) of those receptors. However, lithium treatment had no apparent effect on neuroleptic receptors in the caudate-putamen and frontal cortex in either acute or chronic administrations. On the other hand, acute lithium administration markedly decreased the Ka and Bmax ofserotonin receptors in the hippocampus, but not in the cerebral cortex; this distinct observation was also found in animals chronically treated with lithium. These results indicate that lithium has an inhibitory effect on neuroleptic receptors in the limbic-forebrain and on serotonin receptors in the hippocampus. Therefore, it is possible to postulate that these effects of lithium in specific brain regions may be related to the therapeutic mechanism of this drug in affective disorders.
The therapeutic mechanism of lithium in manic-depressive diseases has been thought to be related to biogenic monoamine metabolisms. Our previous reports have suggested that lithium has an inhibitory effect on dopamine receptor sensitivity and on the development ofdopamine receptor supersensitivity in prolactin release9-11. Recently, the development of the radioreceptor assay has revealed the detailed mechanism of action of neuroleptic drugs, including lithium. We considered it relevant to investigate the effect of lithium on various neurotransmitter receptors in specific brain regions. Rosenblatt et al. 7 have observed no significant effect of chronic lithium treatment on the [3H]spiroperidol binding in the caudate. It has also been reported that chronic administration for 21 days in rat results in a significant decrease in the serotonin receptor binding in the hippocampus and striatumL Previous reports have not indicated whether those results were observed after acute administration of lithium. In the present study, we examined the acute and chronic effect of lithium on neuroleptic and serotonin receptors in various brain regions. Male Wistar rats (200-250 g) were housed in a 0006-8993/83/000(~0000/$03.00 ©1983 Elsevier Science Publishers
light-controlled room (12 h light, 12 h dark) with temperature maintained at 22 _+ 2 °C, and were given Oriental Laboratory Chew (Oriental Yeast, Tokyo) and water ad libitum. In acute experiments, rats were intraperitoneally injected with LiC1 (5 mmol/kg) 4 h before sacrifice. Control animals were administered NaC1. In chronic experiments, animals were fed a diet containing 0.15% lithium carbonate and controls a similar diet without lithium for 30 days. All rats were sacrificed by decapitation and blood was collected for the measurement of lithium. Plasma lithium levels were estimated by atomic absorption spectrophotometry. The brain was dissected on ice according to the method of Howlett and Nahorski 3 as follows. A coronal cut was made 1 m m foreward of the point of optic chiasma and a further cut 1 m m caudal to this point. From this slice the caudateputamen was removed with excisions of the septum and callosal corpus, and frontal cortex and limbic-forebrain were separated with cuts through the rhinal fissure. In addition, the cerebral cortex and hippocampus were dissected from the remaining tissue. [3H]spiroperidol binding assay: [3H]spiro-
149 peridol binding assay was performed in the caudate-putamen, limbic-forebrain and frontal cortex, as described by Creese et al.2. The tissues were homogenized in 100 vols. of an ice-cold buffer (50 mM Tris-HCl, pH 7.7 at 25 °C). The homogenates were centrifuged twice at 50,000 g for 10 min with resuspension of the intermediate pellet in this buffer. The final pellets were resuspended in a 50 mM Tris-HC1 buffer (pH 7.1 at 37 °C) containing 0.1% ascorbic acid, 10 ~M pargyline, 120 m M NaCI, 5 m M KCI, 2 mM CaC12 and 1 mM MgC12. The homogenates were incubated at 37 °C for 10 min and returned to ice. Incubation tubes received 1.5 ml of tissue homogenate (0.4 mg protein), 0.1 ml of [3H]spiroperidol (0.075-2.4 nM) and 0.1 ml of (+)-butaclamol or this buffer. Incubation was carried out at 37 °C for 15 min, and terminated by rapid filtration (Whatman G F / B filters) under a vacuum with three 5 ml rinses of the ice-cold buffer. The filters were counted by liquid scintillation spectrometry in 5 ml of Aquasol-2 (NEN, U.S.A.) at efficiencies of 35-40%. Specific binding was measured as excess over blanks taken in the presence of 1 ~M (+)-butaclamol. [3H]serotonin binding assay: this binding as reported by Bergstrom and Kellar t was performed with a slight modification in the cerebral cortex and hippocampus. The tissues were homogenized in 20 vols. of an ice-cold 50 mM TrisHC1 buffer (pH 7.7 at 25 °C). After two centrifugations at 50,000 g for 10 min followed by washing, the pellet was resuspended in a 50 mM TrisHC1 buffer containing 0.1% ascorbic acid, 10 /zM pargyline and 4 mM CaC12. The tissue suspension was preincubated at 37 °C for 10 min and stored on ice. Each tube received 1.5 ml of tissue homogenate (0.6 mg protein), 0.1 ml of [3H]serotonin (1.25-20 nM) and 0.1 ml of serotonin or this buffer. Incubation was carried out as described in the [3H]spiroperidol binding assay. Specific binding was defined as the difference between the absence and presence of 20 ~M serotonin. Chemicals and drugs: [3H]spiroperidol (29.9 Ci/mmol) and [3H]serotonin (29.0 Ci/mmol) were purchased from New England Nuclear. The sources of the drugs are as follows: ( + ) - b u -
taclamol from Ayerst (Canada) and serotonin creatinine sulfate from Merck (F.R.G.). Student's t-test was used for statistical analysis. In all regions studied, specific binding of [3H]spiroperidol and [3H]serotonin plateaued at a concentration of approximately 0.8 nM and 8 nM, respectively. Scatchard analyses gave straight lines in all regions, indicating a single population of binding sites. The highest specific binding of [3H]spiroperidol was observed in the caudate-putamen and represented 51 82% of the total binding depending on the concentration of [3H]ligand. In the [3H]serotonin binding assay, the specific binding in the hippocampus was higher than that in the cerebral cortex and revealed 34-61% of the total binding. In chronic experiments, the mean ( ___S.E.M.) weight of the rats treated with lithium was not significantly different from that in the controls (318 ___ 6 vs 332___ 16 g, respectively). Scatchard analyses of the data in all regions are summarized in Table I. In the [3H]spiroperidol binding assay, the density of receptors (Bmax) in the limbic-forebrain was significantly lower in rats treated both acutely and chronically with lithium than in the controls. However, the affinity of receptors (Kd) in the region was not affected by lithium. There was no significant effect of lithium on neuroleptic receptors in the caudateputamen and frontal cortex. Acute lithium treatment significantly reduced both Bm~x and Kd of serotonin receptors in the hippocampus, but not in the cerebral cortex. This observation was also found after chronic lithium treatment. Plasma lithium levels were 1.2 + 0.1 mEq/1 and 0.60 __ 0.10 m E q / l in acute and chronic administrations, respectively. We have found that lithium treatment significantly reduces the density of neuroleptic receptors in the limbic-forebrain, not in the caudateputamen. Rosenblatt et al. 8 have also observed that the density of the [3H]spiroperidol binding site in the caudate is significantly lower in the rats chronically treated with lithium than in the controls. However, we could not demonstrate any significant effect of lithium on this binding in the caudate-putamen. It is very difficult to explain the difference between our results and
150 TABLE I
Effect of lithium on neuroleptic and serotonin receptors in rat brain. All values are the m e a n ± S.E.M. C-P, c a u d a t e - p u t a m e n ; L-F, limbic-forebrain; H-C, h i p p o c a m p u s .
A cute lithium administration
Chronic lithium administration
B.,ax
Ka (nM)
/(d
B.,ax
(pmol / mg prot.) [3H]spiroperidol
C-P L-F Cortex
[3H]serotonin
H-C Cortex
Lithium Control Lithium Control Lithium Control
0.61 0.69 0.51 0.71 O.89 0.83
± 0.03 ± 0.08 ___ 0.06 ± 0.09 ± 0.05 ___ 0.08
Lithium Control Lithium Control
6.37 11.8 5.15 5.03
± 0.18"* ± 0.75 _ 0.27 ___ 0.22
0.22 0.24 0.042 0.093 0.12 0.12
___ 0.03 ___ 0.02 __+0.001"* ___ 0.010 + 0.01 ± 0.01
0.55 0.42 0.36 0.45 1.21 1.17
0.22 0.36 0.12 0.14
___ 0.02** --- 0.02 ___ 0.01 __. 0.01
6.70 11.20 5.20 5.07
___ 0.04 ___0.04 ___ 0.03 ___0.06 ___0.01 ± 0.03 ___ 0.06** ___0.44 "4- 0.40 __. 0.29
0.16 0.16 0.093 0.140 0.098 0.103
__. 0.01 ___ 0.02 ___0.002* __. 0.020 __. 0.003 ___ 0.002
0.23 0.37 0.12 0.13
+ 0.02** ___ 0.01 ___0.01 ___ 0.01
* P < 0.05 vs control. ** P < 0.01 vscontrol.
theirs. The weight of each caudate (35 mg) in their experiment was much lower compared with the fragment of the caudate-putamen (100 mg) in our study. Therefore, in the caudate-putamen, we might be unable to find difference between the lithium group and controls. We have demonstrated that the Bmax and Kj of serotonin receptors in the hippocampus are significantly lower in the lithium group than those in ihe controls. Treiser and Kellar ~2have also reported that chronic lithium administration resuits in reduced density ofserotonin receptors in the rat hippocampus with no apparent effects in the cortex. In addition, it has been observed by Maggi and Enna 5 that chronic lithium treatment leads to a significant decrease in serotonin receptors in the rat hippocampus and striatum. Previous reports 4-6 have suggested that neuroleptic receptors ([3H]spiroperidol binding sites) involve serotonin receptors, especially in the frontal cortex, as well as dopamine receptors. Therefore, the low Bmax of [3H]spiroperidol binding sites in the limbic-forebrain observed in
our experiment may be due to the reduction of serotonin receptors, not to that ofneuroleptic receptors. However, this is unlikely because the limbic-forebrain is thought to be poor in serotonin receptors. The effect of acute administration of lithium on the neurotransmitter receptor binding has not been investigated. Lithium has been demonstrated to be ineffective on the binding of both neuroleptic and serotonin receptors in vitro 8.~2. Therefore, it is concluded that lithium, whether acutely or chronically given in vivo, induces receptor subsensitivities of neuroleptics and serotonin. The therapeutic effect of lithium on manic patients appears within 3-5 days. On the other hand, the long-term administration of lithium is necessary to the prophylactic effect on recurrent manic-depressive diseases. The acute effect of lithium on the receptor function may represent the therapeutic effect of the ion, and the alteration of that function by chronic lithium administration may be related to the prophylactic action of lithium.
1 Bergstrom, D. A. and Kellar, K. J., Effect o f electroconvulsive shock on m o n o a m i n e r g i c receptor binding sites in rat brain, Nature (Lond.), 278 (1979) 4 6 ~ 4 6 6 . 2 Creese, I., Schneider, R. and Snyder, S. H., [3H]spiroperidol labels d o p a m i n e receptors in pituitary and brain, Europ. J. Pharmacol., 46 (1977) 3 7 2 3 8 1 .
3 Howlett, D. R. and Nahorski, S. R., A comparative study o f [3H]haloperidol a n d [3H]spiroperidol b i n d i n g to receptors on rat cerebral m e m b r a n e s , F E B S Lett., 87 (1978) 1 5 ~ 156. 4 Leysen, J. E., Niemegeers, C. J. E., Tollenaere, J. P. a n d Laduron, P. M., Serotonergic c o m p o n e n t o f neuroleptic
151 receptors, Nature (Lond.), 272 (1978) 168- 171. 5 Maggi, A. and Enna, S. J., Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment, J. Neurochem., 34 (1980) 888- 892. 6 Quik, M., Iversen, L. L., Larder, A. and Mackay, A. V. P., Use of ADTN to define specific [3H]spiperone binding to receptors in brain, Nature (Lond.), 274 (1978) 513-514. 7 Rosenblatt, J. E., Pert, C. B., Tallman, J. F., Pert, A. and Bunney, W. E., Jr., The effect of imipramine and lithium on a- and fl-receptor binding in rat brain, Brain Research, 160(1979) 186-191. 8 Rosenblatt, J. E., Pert, A., Layton, B. and Bunney, W. E., Jr., Chronic lithium reduces [3H]spiroperidol binding in rat striatum, Europ. J. Pharmacol., 67 (1980) 321-322.
9 Tanimoto, K., Maeda, K., Yamaguchi, N., Chihara, K. and Fujita, T., Effect of lithium on prolactin response to thyrotropin releasing hormone in patients with manic state, Psychopharmacology, 72 (1981) 129-133. 10 Tanimoto, K., Maeda, K. and Chihara, K., Inhibition by lithium of dopamine receptors in rat prolactin release, Brain Research, 223 (1981) 335-342. 11 Tanimoto, K., Maeda, K. and Chihara, K., Antagonizing effect of lithium on the development of dopamine supersensitivity in the tuberoinfundibular system, Brain Research, 245 (1982) 163- 166. 12 Treiser, S. and Kellar, K. J., Lithium: effects on serotonin receptors in rat brain, Europ. J. Pharrnacol., 64 (1980) 183-185.