Psychopharmacology
Psychopharmacoligy56, 163 - 166 (1978)
9 by Springer-Verlag 1978
The Effect of Chronic Lithium Administration on Dopamine Metabolism in Rat Striatum J. E. HESKETH*, N. M. NICOLAOU**, G. W. ARBUTHNOTT***, and A. K. WRIGHT MRC Brain Metabolism Unit, 1, George Square, Edinburgh, United Kingdom
Abstract. Striatal dopamine and its metabolites were studied in rats given lithium chloride in the diet. Results showed an increase in homovanillic acid and 3,4-dihydroxyphenylacetic acid levels but no significant change in dopamine concentration after 3 weeks of lithium administration. There was no change in tyrosine hydroxylase activity after 1, 2, and 3 weeks treatment. The results indicate an increase in the release and turnover of dopamine in the lithiumtreated animals. Key words." Lithium treatment olism - Striatum
D o p a m i n e metab-
Studies of the effect of lithium on catecholamine metabolism in the brain have provided few consistent results. The variation in the effects found m a y be due to the differences in length of treatment, m o d e of administration, and dosage of lithium used in the various experiments. Such differences in drug treatment m a k e it difficult to compare results from the various experiments. In the case of noradrenaline metabolism, lithium generally seems to cause an increase in intraneuronal metabolism together with increased reuptake (Shaw, 1975). Less work has been done on the effects of lithium on dopamine metabolism and the results have not been consistent (Corrodi et al., 1969; H o et al., 1970; Friedman and Gershon, 1973; Schubert, 1973; Leonard, 1975; Poitou and Bohuon, 1975). * J.E. Hesketh was an MRC Scholar while this work was in progress. Presentaddress: Centre de Neurochimie, 11, rue Humann, Strasbourg, France ** N.M. Nicolaou is an Edinburgh University Medical Faculty Scholar *** To whom requests for offprints should be sent
In the present work, d o p a m i n e metabolism was studied in striatal material from animals chronically treated with lithium chloride in the same dosage and length of treatment that was found to cause changes in Mg ATPase activity of synaptic plasma membranes prepared from rat cerebral cortex (Hesketh, 1976). The approach used was to measure concentrations of dopamine and its major metabolites Homovanillic Acid (HVA) and 3,4-Dihydroxyphenylacetic Acid (DOPAC) in the neostriatum. The hypothesis that D O P A C is the product of intraneuronal metabolism and H V A the product of extraneuronal metabolism (Roffler-Tarlov et al., 1971; Wilk et al., 1975; Roth et al., 1976) allowed analysis of changes in metabolite concentrations in terms of intraneuronal and extraneuronal compartmentation and release and reuptake of neurotransmitter. Although the use of striatal material suffered from the disadvantage that neurotransmitter metabolism was studied in a brain area other than the cerebral cortex, in which ATPase changes had been found, there were advantages in studying the striatum: the striatum has been shown to have a high concentration of lithium (Bond et al., 1975; Hesketh, 1976b), and it is also associated with a well-characterised dopaminergic neuronal system that has its nerve terminals in the striatum.
MATERIALS AND METHODS All chemicals used were of Analar Grade from British Drug Houses Co. Ltd. unless otherwisestated. S-Adenosyl-L-(Methyl-3H) Methionine, 8.9 Ci/mmol and L- (side chain-2, 3-3H) tyrosine, 22 Ci/mmol were purchased from the Radiochemical centre, Amersham, U.K. Male Wistar rats (200-250 g) were given lithium chloride in the diet (60 mmol LiC1/kg food) for a period of up to 3 weeks. In experiments involving DOPAC, HVA, and dopamine estimations, animals were anaesthetized with nembutal (70mg/kg, i.p.) and blood was taken by cardiac puncture. Animals were then killed by decapitation and the brain removed. In experiments involving tyrosine
0033-3158/78/0056/0163/$1.00
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Psychopharmacology 56 (1978)
hydroxylase estimations, animals were not anaesthetized and were killed by cervical fracture. Striata were dissected out and stored in liquid nitrogen until analysis. HVA and DOPAC were measured in individual striata by gasqiquid chromatography using a HewlettPackard 5710 Gas chromatograph fitted with a 63Nielectron capture detector and a 290 SE 52 liquid phase on a Chromosorb 2 column (Hewlett-Packard, Ltd.) at 115~C. The method of analysis followed that of Pearson and Sharman (1975), except that the tissue was homogenized in 0.1 M perchloric acid (300 gl/10 mg tissue) and the supernatant was not subjected to freeze-thaw treatment but was extracted three times with ethyl acetate. Dopamiue was determined in aliquots of striatal material by the method of Palkovits et al. (1974). The activity of tyrosine hydroxylase (tyros• monooxygenase E.C. 1.14.16.2) was measured in striata by measuring the dopa formed after incubation with L-(side chain-2,3-3H) tyrosine as described by Hendry and Iversen (1971). All samples were corrected for quenching by the external channels ratio method. Plasma lithium was estimated by atomic absorption spectrophotometry using a Perkin Elmer 402 atomic absorptiometer.
Table 1. The effect of chronic lithium administration on concentrations of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and dopamine in the striatum
RESULTS
Table 2. The effect of chronic lithium administration on striatal tyrosine hydroxylase activity
Plasma lithium concentrations in samples taken before decapitation were 0 . 4 8 - 0 . 6 3 raM. Analysis o f H V A , D O P A C , and d o p a m i n e showed the lithium-treated animals to have significantly increased H V A (52 ~ ) and D O P A C (31 ~o) concentrations in the striatum (Table 1). Lithium treatment had no significant effect on the d o p a m i n e concentration in striatum. A n experiment was carried out to investigate whether the increased H V A and D O P A C concentrations f o u n d in lithium-treated animals were associated with changes in tyros• hydroxylase activity. Rats were given lithium chloride in the diet for 1, 2, and 3 weeks. Plasma lithium concentrations in these animals were in the range 0 . 5 - 1 . 0 m M . Striatal tyrosine hydroxylase activity was measured in lithiumtreated animals and controls. The results (Table 2) show no effect o f lithium treatment on the enzyme activity.
DISCUSSION The concentrations o f H V A and D O P A C in striata f r o m control rats were in the range o f values reported by other workers, although the ratio o f H V A : D O P A C was greater than that previously reported (Pearson and Sharman, 1975; Wilk et al., 1975; R o t h et al., 1976; K o r f et al., 1976). C h r o n i c lithium chloride administration for 3 weeks caused a significant increase in rat striatal H V A and D O P A C concentrations, while the dopamine concentration remained unchanged. Changes in H V A and D O P A C concentrations might be caused by interference with transport o f the metabolites f r o m the brain, interference with release o f neurotransmitter, or interference with neurotrans-
Controls
Lithium-treated
HVA (ixg/g wet tissue)
1.03 • 0.20 (8)
1.57 • 0.38 (9)**
DOPAC (gg/g wet tissue)
0.83 • 0.10 (8)
1.09 • 0.25 (9)*
Dopamine (gg/g wet tissue)
9.3 • 1.9 (7)
11.5 • 2.1 (8)
Results are shown from rats given lithium chloride in the diet (60 mmol/kg food) for 3 weeks and control animals. Values given are means • SD with number of animals in parentheses. Groups were compared using a Student's t-test, * P < 0.025, ** P < 0.005 compared to controls
Duration of lithium treatment (weeks) Controls Lithium-treated
Tyrosine hydroxylase activity (nmol dopa/h/g) 22.52 •
1 2 3
4.79 (5)
25.85 • 10.57 (6) 27.40 • 12.08 (4) 23.09 • 5.1 (5)
Results are shown from rats given lithium chloride in the diet (60 mmol/kg food) for 1, 2, and 3 weeks and control animals. Enzyme activity is expressed as nmol dopa formed/h/g wet tissue. Values given are means _+ SD with the number of animals in parentheses
mitter reuptake. Probenecid has been shown to reduce the transport o f H V A f r o m the brain, and this is reflected in increased striatal H V A concentrations (Guldberg and Broch, 1971; Roffler-Tarlov et al., 1971 ; Wilk et al., 1975). However, probenecid administration was not a c c o m p a n i e d by increased D O P A C concentrations. Considering these findings, the increase in b o t h D O P A C and H V A in the present experiments suggests that the effects o f lithium are not due to interference with transport processes for removal o f d o p a m i n e metabolites f r o m the brain. Analysis o f metabolite concentrations in terms o f release and reuptake can be m a d e assuming D O P A C reflects intraneuronal metabolism and H V A extraneuronal metabolism (Roffler-Tarlov et al., 1971; Sharman, 1973; Wilk et al., 1975; R o t h et al., 1976). However, such interpretation m a y be equivocable since the h y p o thesis concerning the c o m p a r t m e n t a t i o n o f d o p a m i n e metabolites has recently been challenged on the evidence that a putative u p t a k e blocker, nomifensine,
J. E. Hesketh et al. : Dopamine Metabolism After Chronic Lithium Treatment does not affect D O P A C metabolism in the striatum ( K o r f et al., 1976). But assuming that D O P A C concentrations do reflect intraneuronal d o p a m i n e metabolism, the increase in striatal D O P A C following lithium administration suggests that lithium does not affect d o p a m i n e metabolite concentrations by inhibiting d o p a m i n e reuptake. I f the increased H V A and D O P A C concentrations are not due to interference with reuptake or transport f r o m the brain, they m u s t reflect increased release o f dopamine. The m o s t likely interpretation o f the present results is that lithium treatment causes an increased release o f dopamine f r o m striatal nerve terminals, but such an increase in reiease was n o t associated with a change in steady-state d o p a m i n e concentration, which suggests that there was an increased turnover o f d o p a m i n e in the lithium-treated striata. Lithium treatment caused an increase in d o p a m i n e turnover, and since b o t h changes in d o p a m i n e t u r n o v e r and nerve activity are t h o u g h t to be associated with changes in tyrosine hydroxylase activity ( R o t h et al., 1975), it was o f interest to investigate whether lithium treatment caused any change in striatal tyrosine hydroxylase activity. However, lithium treatment for 1, 2, and 3 weeks had no effect on tyrosine hydroxylase activity in rat striatum. That lithium treatment increased d o p a m i n e turnover conflicts with previous reports. Lithium administration by i.p. injection for 14 days was shown to reduce striatal d o p a m i n e synthesis ( F r i e d m a n and Gershon, 1973) and other studies have shown that 2 - 3 weeks o f lithium treatment reduces d o p a m i n e turnover and synthesis in whole brain ( C o r r o d i et al., 1969; P o i t o u and B o h u o n , 1975). The picture is not, however, entirely clear since the results o f C o r r o d i et al. suggested that the effects o f lithium treatment on d o p a m i n e t u r n o v e r vary with the area o f the brain studied. F u r t h e r m o r e , other workers have failed to find changes in d o p a m i n e turnover in whole brain following chronic lithium treatment ( H o et al., 1970; Bliss and Ailion, 1970). The differences in the various results reported therefore c a n n o t be readily explained by the different m o d e s o f drug administration. Previous w o r k showed n o effect o f acute lithium administration on striatal H V A concentrations (Perez-Cruet et al., 1971). The m e c h a n i s m by which lithium affects d o p a m i n e metabolism is n o t clear, but there is p r o b a b l y an increase in d o p a m i n e release and turnover in the striatum. Lithium administration for 3 weeks increases cortical synaptic m e m b r a n e M g A T P a s e (Hesketh, 1976), and together with the increase in striatal dopamine metabolites this suggests a possible link between the effects o f lithium on M g A T P a s e activity and amine metabolism. I f synaptic m e m b r a n e A T P a s e
165
activity is due to a contractile protein involved in neurotransmitter release (Berl et al., 1973), it might be that by increasing the M g A T P a s e activity o f such a protein lithium causes an increase in the release o f neurotransmitter.
REFERENCES Berl, S., Puszkin, S., Nicklas, W. J. : Actomyosin-like protein in brain. Science 179, 441-446 (1973) Bliss, E. L., Ailion, J. : The effect of lithium on brain neuroamines. Brain Res. 24, 305--310 (1970) Bond, P. A., Brooks, B. A., Judd, A. : The distribution of lithium, sodium and magnesium in rat brain and plasma after various periods of administration of lithium in the diet. Br. J. Pharmacol. 53, 235-239 (1975) Corrodi, H., Fuxe, F., Schou, M. : The effect of prolonged lithium administration on cerebral monoamine metabolism in the rat. Life Sci. 8, 643-651 (1969) Friedman, E., Gershon, S. : Effect of lithium on brain dopamine. Nature 243, 520-521 (1973) Guldberg, H. C., Broch, O. J. : On the mode of action of reserpine on dopamine metabolism in the rat striatum. Eur. J. Pharmacol. 13, 155-167 (1971) Hendry, I. A., Iversen, L. L. : Effect of nerve growth factor and its antiserum on tyrosine hydroxylase activity in mouse superior cervical sympathetic ganglia. Brain Res. 29, 159-162 (1971) Hesketh, J. E. : Changes in membrane Adenosine Triphosphatases on administration of lithium salts in vivo. Biochem. Soc. Trans. 4, 328-330 (1976) Hesketh, J. E. : The effects of lithium on adenosine triphosphatases and ion transport with respect to affective illness. Ph.D. Thesis, Edinburgh University (1976b) Ho, A. K. S., Loh, H. H., Graves, F., Hitzemann, R. J., Gerson, S.: The effect of prolonged lithium treatment on the synthesis rate and turnover of monoamines in brain regions of the rat. Eur. J. Pharmacol. 10, 72-78 (1970) Korf, J., Zieleman, M., Westernik, B. H. C. : Dopamine release in substantia nigra. Nature 260, 257-258 (1976) Leonard, B. E.: Changes in rat brain monoamine metabolism following acute administration of lithium chloride in combination with antidepressant drugs. Arch. Int. Pharmacodyn. Ther. 215, 202-207 (1975) Palkovits, M., Brownstein, M., Saavedra, J. M., Axelrod, J. : Norepinephrine and dopamine content of hypothalamic nuclei of the rat. Brain Res. 77, 137-149 (1974) Pearson, J. D. M., Sharman, D. F.: The estimation of 3.4 dihydroxyphenylacetic acid, homovanillic acid and homoisovanillic acid in nervous tissue by gas-liquid and electron capture detection. Br. J. Pharmacol. 53, 143-148 (1975) Perez-Cruet, J,, Tagliamonte, A., Tagliamonte, P., Gessa, G. L.: Stimulation of serotonin synthesis by lithium. J. Pharmacol. Exp. Ther. 178, 325-330 (1971) Poitou, P., Bohuon, C. : Catecholamine metabolism in rat brain after short and long-term lithium administration. J. Neurochem. 25, 535-537 (1975) Roffler-Tarlov, S., Sharman, D. F., Tegerodine, P. : 3,4 Dihydroxyphenylacetic acid and 4-hydroxy-3 methoxyphenylacetic acid in the mouse striatum: a reflection of intra and extra-neuronal metabolism of dopamine? Br. J. Pharmacol. 42, 343 - 351 (1971) Roth, R. H., Walter, J. R., Murrin, L. C., Morgenroth, V. H., III: In: Pre and postsynaptic receptors, E. Usdin and W. Bunney, Jr., eds., pp. 5-48. New York: Marcel Dekker 1975
166 Roth, R. H., Murrin, L., Waiters, J . R . : Central dopaminergic neurons: effects of alterations in impulse flow on accumulation of dihydroxyphenylacetic acid. Eur. J. Pharmacol. 36, 163-171 (1976) Schubert, J. : Effect of chronic lithium treatment on monoamine metabolism in rat brain. Psychopharmacologia (Berl.) 32, 301 - 311 (1973) Sharman, D. F. : Catabolism of catecholamines. Br. Med. Bull. 29, 110-115 (1973)
Psychopharmacology 56 (1978) Shaw, D. M. : Lithium and amine metabolism. In: Lithium research and therapy, F. N. Johnson, ed., pp. 411-423. London: Academy Press 1975 Wilk, S., Waston, E., Travis, B. : Evaluation of dopamine metabolism in rat striatum by a gas chromatography technique. Eur. J. Pharmacol. 30, 238-243 (1975)
Received March 20, 1977
Psychopharmacoligy56, 163 - 166 (1978)
9 by Springer-Verlag 1978
The Effect of Chronic Lithium Administration on Dopamine Metabolism in Rat Striatum J. E. HESKETH*, N. M. NICOLAOU**, G. W. ARBUTHNOTT***, and A. K. WRIGHT MRC Brain Metabolism Unit, 1, George Square, Edinburgh, United Kingdom
Abstract. Striatal dopamine and its metabolites were studied in rats given lithium chloride in the diet. Results showed an increase in homovanillic acid and 3,4-dihydroxyphenylacetic acid levels but no significant change in dopamine concentration after 3 weeks of lithium administration. There was no change in tyrosine hydroxylase activity after 1, 2, and 3 weeks treatment. The results indicate an increase in the release and turnover of dopamine in the lithiumtreated animals. Key words." Lithium treatment olism - Striatum
D o p a m i n e metab-
Studies of the effect of lithium on catecholamine metabolism in the brain have provided few consistent results. The variation in the effects found m a y be due to the differences in length of treatment, m o d e of administration, and dosage of lithium used in the various experiments. Such differences in drug treatment m a k e it difficult to compare results from the various experiments. In the case of noradrenaline metabolism, lithium generally seems to cause an increase in intraneuronal metabolism together with increased reuptake (Shaw, 1975). Less work has been done on the effects of lithium on dopamine metabolism and the results have not been consistent (Corrodi et al., 1969; H o et al., 1970; Friedman and Gershon, 1973; Schubert, 1973; Leonard, 1975; Poitou and Bohuon, 1975). * J.E. Hesketh was an MRC Scholar while this work was in progress. Presentaddress: Centre de Neurochimie, 11, rue Humann, Strasbourg, France ** N.M. Nicolaou is an Edinburgh University Medical Faculty Scholar *** To whom requests for offprints should be sent
In the present work, d o p a m i n e metabolism was studied in striatal material from animals chronically treated with lithium chloride in the same dosage and length of treatment that was found to cause changes in Mg ATPase activity of synaptic plasma membranes prepared from rat cerebral cortex (Hesketh, 1976). The approach used was to measure concentrations of dopamine and its major metabolites Homovanillic Acid (HVA) and 3,4-Dihydroxyphenylacetic Acid (DOPAC) in the neostriatum. The hypothesis that D O P A C is the product of intraneuronal metabolism and H V A the product of extraneuronal metabolism (Roffler-Tarlov et al., 1971; Wilk et al., 1975; Roth et al., 1976) allowed analysis of changes in metabolite concentrations in terms of intraneuronal and extraneuronal compartmentation and release and reuptake of neurotransmitter. Although the use of striatal material suffered from the disadvantage that neurotransmitter metabolism was studied in a brain area other than the cerebral cortex, in which ATPase changes had been found, there were advantages in studying the striatum: the striatum has been shown to have a high concentration of lithium (Bond et al., 1975; Hesketh, 1976b), and it is also associated with a well-characterised dopaminergic neuronal system that has its nerve terminals in the striatum.
MATERIALS AND METHODS All chemicals used were of Analar Grade from British Drug Houses Co. Ltd. unless otherwisestated. S-Adenosyl-L-(Methyl-3H) Methionine, 8.9 Ci/mmol and L- (side chain-2, 3-3H) tyrosine, 22 Ci/mmol were purchased from the Radiochemical centre, Amersham, U.K. Male Wistar rats (200-250 g) were given lithium chloride in the diet (60 mmol LiC1/kg food) for a period of up to 3 weeks. In experiments involving DOPAC, HVA, and dopamine estimations, animals were anaesthetized with nembutal (70mg/kg, i.p.) and blood was taken by cardiac puncture. Animals were then killed by decapitation and the brain removed. In experiments involving tyrosine
0033-3158/78/0056/0163/$1.00
164
Psychopharmacology 56 (1978)
hydroxylase estimations, animals were not anaesthetized and were killed by cervical fracture. Striata were dissected out and stored in liquid nitrogen until analysis. HVA and DOPAC were measured in individual striata by gasqiquid chromatography using a HewlettPackard 5710 Gas chromatograph fitted with a 63Nielectron capture detector and a 290 SE 52 liquid phase on a Chromosorb 2 column (Hewlett-Packard, Ltd.) at 115~C. The method of analysis followed that of Pearson and Sharman (1975), except that the tissue was homogenized in 0.1 M perchloric acid (300 gl/10 mg tissue) and the supernatant was not subjected to freeze-thaw treatment but was extracted three times with ethyl acetate. Dopamiue was determined in aliquots of striatal material by the method of Palkovits et al. (1974). The activity of tyrosine hydroxylase (tyros• monooxygenase E.C. 1.14.16.2) was measured in striata by measuring the dopa formed after incubation with L-(side chain-2,3-3H) tyrosine as described by Hendry and Iversen (1971). All samples were corrected for quenching by the external channels ratio method. Plasma lithium was estimated by atomic absorption spectrophotometry using a Perkin Elmer 402 atomic absorptiometer.
Table 1. The effect of chronic lithium administration on concentrations of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), and dopamine in the striatum
RESULTS
Table 2. The effect of chronic lithium administration on striatal tyrosine hydroxylase activity
Plasma lithium concentrations in samples taken before decapitation were 0 . 4 8 - 0 . 6 3 raM. Analysis o f H V A , D O P A C , and d o p a m i n e showed the lithium-treated animals to have significantly increased H V A (52 ~ ) and D O P A C (31 ~o) concentrations in the striatum (Table 1). Lithium treatment had no significant effect on the d o p a m i n e concentration in striatum. A n experiment was carried out to investigate whether the increased H V A and D O P A C concentrations f o u n d in lithium-treated animals were associated with changes in tyros• hydroxylase activity. Rats were given lithium chloride in the diet for 1, 2, and 3 weeks. Plasma lithium concentrations in these animals were in the range 0 . 5 - 1 . 0 m M . Striatal tyrosine hydroxylase activity was measured in lithiumtreated animals and controls. The results (Table 2) show no effect o f lithium treatment on the enzyme activity.
DISCUSSION The concentrations o f H V A and D O P A C in striata f r o m control rats were in the range o f values reported by other workers, although the ratio o f H V A : D O P A C was greater than that previously reported (Pearson and Sharman, 1975; Wilk et al., 1975; R o t h et al., 1976; K o r f et al., 1976). C h r o n i c lithium chloride administration for 3 weeks caused a significant increase in rat striatal H V A and D O P A C concentrations, while the dopamine concentration remained unchanged. Changes in H V A and D O P A C concentrations might be caused by interference with transport o f the metabolites f r o m the brain, interference with release o f neurotransmitter, or interference with neurotrans-
Controls
Lithium-treated
HVA (ixg/g wet tissue)
1.03 • 0.20 (8)
1.57 • 0.38 (9)**
DOPAC (gg/g wet tissue)
0.83 • 0.10 (8)
1.09 • 0.25 (9)*
Dopamine (gg/g wet tissue)
9.3 • 1.9 (7)
11.5 • 2.1 (8)
Results are shown from rats given lithium chloride in the diet (60 mmol/kg food) for 3 weeks and control animals. Values given are means • SD with number of animals in parentheses. Groups were compared using a Student's t-test, * P < 0.025, ** P < 0.005 compared to controls
Duration of lithium treatment (weeks) Controls Lithium-treated
Tyrosine hydroxylase activity (nmol dopa/h/g) 22.52 •
1 2 3
4.79 (5)
25.85 • 10.57 (6) 27.40 • 12.08 (4) 23.09 • 5.1 (5)
Results are shown from rats given lithium chloride in the diet (60 mmol/kg food) for 1, 2, and 3 weeks and control animals. Enzyme activity is expressed as nmol dopa formed/h/g wet tissue. Values given are means _+ SD with the number of animals in parentheses
mitter reuptake. Probenecid has been shown to reduce the transport o f H V A f r o m the brain, and this is reflected in increased striatal H V A concentrations (Guldberg and Broch, 1971; Roffler-Tarlov et al., 1971 ; Wilk et al., 1975). However, probenecid administration was not a c c o m p a n i e d by increased D O P A C concentrations. Considering these findings, the increase in b o t h D O P A C and H V A in the present experiments suggests that the effects o f lithium are not due to interference with transport processes for removal o f d o p a m i n e metabolites f r o m the brain. Analysis o f metabolite concentrations in terms o f release and reuptake can be m a d e assuming D O P A C reflects intraneuronal metabolism and H V A extraneuronal metabolism (Roffler-Tarlov et al., 1971; Sharman, 1973; Wilk et al., 1975; R o t h et al., 1976). However, such interpretation m a y be equivocable since the h y p o thesis concerning the c o m p a r t m e n t a t i o n o f d o p a m i n e metabolites has recently been challenged on the evidence that a putative u p t a k e blocker, nomifensine,
J. E. Hesketh et al. : Dopamine Metabolism After Chronic Lithium Treatment does not affect D O P A C metabolism in the striatum ( K o r f et al., 1976). But assuming that D O P A C concentrations do reflect intraneuronal d o p a m i n e metabolism, the increase in striatal D O P A C following lithium administration suggests that lithium does not affect d o p a m i n e metabolite concentrations by inhibiting d o p a m i n e reuptake. I f the increased H V A and D O P A C concentrations are not due to interference with reuptake or transport f r o m the brain, they m u s t reflect increased release o f dopamine. The m o s t likely interpretation o f the present results is that lithium treatment causes an increased release o f dopamine f r o m striatal nerve terminals, but such an increase in reiease was n o t associated with a change in steady-state d o p a m i n e concentration, which suggests that there was an increased turnover o f d o p a m i n e in the lithium-treated striata. Lithium treatment caused an increase in d o p a m i n e turnover, and since b o t h changes in d o p a m i n e t u r n o v e r and nerve activity are t h o u g h t to be associated with changes in tyrosine hydroxylase activity ( R o t h et al., 1975), it was o f interest to investigate whether lithium treatment caused any change in striatal tyrosine hydroxylase activity. However, lithium treatment for 1, 2, and 3 weeks had no effect on tyrosine hydroxylase activity in rat striatum. That lithium treatment increased d o p a m i n e turnover conflicts with previous reports. Lithium administration by i.p. injection for 14 days was shown to reduce striatal d o p a m i n e synthesis ( F r i e d m a n and Gershon, 1973) and other studies have shown that 2 - 3 weeks o f lithium treatment reduces d o p a m i n e turnover and synthesis in whole brain ( C o r r o d i et al., 1969; P o i t o u and B o h u o n , 1975). The picture is not, however, entirely clear since the results o f C o r r o d i et al. suggested that the effects o f lithium treatment on d o p a m i n e t u r n o v e r vary with the area o f the brain studied. F u r t h e r m o r e , other workers have failed to find changes in d o p a m i n e turnover in whole brain following chronic lithium treatment ( H o et al., 1970; Bliss and Ailion, 1970). The differences in the various results reported therefore c a n n o t be readily explained by the different m o d e s o f drug administration. Previous w o r k showed n o effect o f acute lithium administration on striatal H V A concentrations (Perez-Cruet et al., 1971). The m e c h a n i s m by which lithium affects d o p a m i n e metabolism is n o t clear, but there is p r o b a b l y an increase in d o p a m i n e release and turnover in the striatum. Lithium administration for 3 weeks increases cortical synaptic m e m b r a n e M g A T P a s e (Hesketh, 1976), and together with the increase in striatal dopamine metabolites this suggests a possible link between the effects o f lithium on M g A T P a s e activity and amine metabolism. I f synaptic m e m b r a n e A T P a s e
165
activity is due to a contractile protein involved in neurotransmitter release (Berl et al., 1973), it might be that by increasing the M g A T P a s e activity o f such a protein lithium causes an increase in the release o f neurotransmitter.
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Received March 20, 1977
