0022-3042/79/0I01-0023602 OO/O

TYROSINE HYDROXYLASE ACTIVITY IN NORADRENERGIC NEURONS OF THE LOCUS COERULEUS AFTER RESERPINE ADMINISTRATION: SEQUENTIAL INCREASE IN CELL BODIES AND NERVE TERMINALS R. E. ZIGMOND 'Department of Pharmacology, Harvard Medical School, Boston MA 021 15, U.S.A. and MRC Neurochemical Pharmacology Unit, Hills Road, Cambridge, CB2 2QD, England (Receioed 19 January 1978. Reuised 26 June 1978. Accepred 10 J u l y 1978) Abstract - The effect of a single systemic injection of reserpine on tyrosine hydroxylase activity in the locus coeruleus, cerebellum, hypothalamus, and hippocampus was examined. Increases in enzyme activity were seen in all four brain areas; the time-course of the changes, however, was different in each case. In the locus coeruleus the maximum change in enzyme activity was seen 3 days after drug administration; in the cerebellum, 7-11 days; in the hypothalamus, 8-11 days; and in the hippocampus, 21 days. Since tyrosine hydroxylase in the cerebellum and hippocampus is present in terminals of neurons whose cell bodies are located in the locus coeruleus, the delayed increase in enzyme activity in cerebellum and hippocampus probably depends upon the slow rate of transport of TH molecules in these neurons.

TYROSINEhydroxylase

activity (TH, tyrosine SON et al., 1973). What is required to perform studies 3-monooxygenase, EC 1.14.16.2) increases by about in the CNS comparable to those in the peripheral 2-fold in the noradrenergic cell bodies of the superior nervous system is the ability t o dissect separately cervical, stellate and lumbar sympathetic ganglia 2 areas containing predominantly cell bodies and areas days after a single injection of reserpine (MUELLER containing predominantly nerve terminals. Using a et nl., 1969; THOENEN et al., 1970; MOLINOFFet nl., dissection procedure which allowed the removal of 1972; BLOOMet a / . , 1976). Reserpine also elevates this the locus coeruleus-an area containing primarily enzyme activity in noradrenergic nerve terminals in noradrenergic cell bodies (DAHLSTROM & FUXE,1964; the heart (THOENEN et a/., 1970; MOLINOFFel a/., UNGERSTEDT, 1 9 7 1 t w e showed that T H activity was 1972). The increase in the latter case, however, occurs increased in this area by 140%3 days after the admin4 days after the drug injection and thus 2 days after istration of reserpine (ZIGMOND et al., 19746). This the increase in enzyme activity is seen in ganglion increase in enzyme activity results from an increase cell bodies. Such a sequential change in enzyme ac- in the number of T H molecules in the locus coeruleus tivity in cell bodies and in nerve terminals is what (REGISeb a/., 1974). In the present study we report one would expect if reserpine increased the rate of the time-course of appearance of an increase in T H synthesis of T H molecules in ganglion cell bodies and activity in cell bodies in the locus coeruleus and in ir these molecules were then transported to the nerve nerve terminals in the cerebellum, hypothalamus and terminals. An increased rate of synthesis of T H mol- hippocampus. A report of this work was presented 1975). ecules has been shown to occur in cells in the adrenal to the Society for Neuroscience (ZIGMOND, medulla after animals are subjected to 'cold stress' (CHUANG & COSTA,1974). The difficulty with performing similar experiments MATERIALS AND METHODS on the effects of reserpine (and other treatments) on Adult male Wistar rats (25&350 g) were injected subcuT H activity in central noradrenergic neurons is the anatomical heterogeneity of the CNS. Thus, early taneously with reserpine (5 mg/kg) in 20% ascorbic acid studies showing small and delayed changes in T H ac- or with the vehicle alone. A t various times from I to 42 days later, groups of 5-6 animals were killed by decapitivity in the brain stem compared to those found in tation. The brains were quickly removed and placed on peripheral ganglia may well have resulted from the ice. The locus coeruleus, cerebellum, hypothalamus and simultaneous measurement of enzyme activity in cell hippocampus were diasected according to procedures prebodies and in nerve terminals (SEGALet al., 1971; BES- viously described (ZICMOND ef a[., 1974b; MCEWEN& PFAFF.1970). The tissues were stored at -20°C. Within a week samples were thawed, weighed and homogenized ' Present address. in 5 mw-Tris (pH 8.6) containing 0.1% Triton X-100. The A bhreuiatiori used: TH, tyrosine hydroxylase. 23

R. E. ZIGMOND

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locus coeruleus. cerebellum, and hippocampus were hom- control animals and this increase reached a maximum ogenized in 4 vol of buffer and the hypothalamus in 10 vol. around day 11. Seventeen days after a single injection TH activity was determined in duplicate lop1 aliquots of reserpine, the enzyme activity was still elevated in using a method in which [3H]tyrosine is converted to the cerebellum. [3H]DOPA and precursor and product are separated by The time-course of the change in TH activity in alumina column chromatography (HENDRY& IVEKSEN, the hypothalamus after reserpine treatment was simi1971). The final concentration of tyrosine was 51 PM which is about 7 times the K , for tyrosine in this system. lar to that in the cerebellum in that no change was 5,6,7&tetrahydrobiopterin was used as the cofactor at a seen on days 1-3 and the maximum increase (about final concentration of 0.7 mM. 60x higher than control values) occurred between

RESULTS

Following a single injection of reserpine, T H activity was elevated in all four tissues studied-locus coeruleus, cerebellum, hypothalamus, and hippocampus. However, the time-course of the changes in enzyme activity differed in the different tissues. During the first 2 days after reserpine administration, no difference was seen between T H activity in the loci coerulei of drug-treated and control animals (Fig. I ) . However, by day 3, the enzyme activity was 282% higher in this brain area in reserpine-treated rats. T H activity remained elevated for about 2 weeks, returning to control values by day 17. In the cerebellum, on the other hand, no significant change in enzyme activity was found 3 days after reserpine treatment (Fig. 2). However, by day 5, T H activity was about 50% higher in drug-treated than in

days 8-1 1 (Fig. 3). Interestingly, a small decrease preceeded the rise in enzyme activity. In the hippocampus, also, a decrease in TH activity occurred before an increase was seen (Fig. 4). However, the increase in enzyme activity in this tissue occurred much later than in any other brain area. The maximum increase (about twice control values) was seen on day 21. On day 42, 6 weeks after the drug injection, TH activity was not quite back to normal in the hippocampus. DISCUSSION

.

In an earlier study we showed that, as in peripheral sympathetic ganglia. TH activity is elevated in the locus coeruleus 3 days after an injection of reserpine (ZIGMOND et al., 1974b). The enzyme activity in both these tissues is primarily localized in cell bodies of noradrenergc neurons (PICKEL et al., 1975). In the

LOCUS COERULEUS

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FIG. I . The time-course of the changes in tyrosine hydroxylase activity in the locus coeruleus of the rat after injection of reserpine. Animals were injected with reserpine (5 mgjkg subcutaneously) or vehicle alone and at various times afterwards thcy were killed and their brains were removed, dissected into regions, and frozen. Tyrosine hydroxylase activity was measured in tissue hornogenates and the enzyme activity in drug-treated samples expressed as a percentage of the activity in controls. Eniyme activity in loci cocrulei from control animals was 85.2 8.3nmol DOPA formed per sample per h. Each data point in this figure and in the following four figures represents the mean percentage 2 S.E.M. for 5-6 animals.

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Sequential increase in T H in cell bodies and terminals

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FIG.2. The time course of changes in tyrosine hydroxylase activity in the cerebellum of the rat after reserpine administration. The procedures followed are outlined in the legend to Fig. 1. The tyrosine hydroxylase activity in the cerebellum of drug-treated animals is expressed as a percentage of the values found in vehicle injected animals. Tyrosine hydroxylase activity in the cerebellum of control animals was 4.3 I 0.5 nmol DOPA per sample pcr h.

present study the time-course of this change in accounted for by an increased accumulation of TH enzyme activity was examined. As in peripheral gang- molecules. An elevation of TH activity represents a potential & MACKAY,1974; ZIGMOND el a/., lia (ZIGMOND 1 9 7 4 ~no ) change in TH activity is seen in the locus increase in the transmitter synthesizing capacity of coerulcus 24 h after a single injection of reserpine. a noradrenergic neuron, since this enzyme catalyses et a!., 1969), the rate-limiting step in norepinephrine biosynthesis Also as in peripheral ganglia (MUELLER enzyme activity in the locus coeruleus reaches its (LEVITTet a[., 1965). However, as most transmitter maximum value 3 days after reserpine administration. synthesis takes place within the nerve terminal, rather However, the central noradrenergic neurons behave than in the cell body (GEFFEN& RUSH, 1968), it is somewhat differently from peripheral ones (THOENENimportant to know whether TH activity also increases ut ul., 1970) in that the enzyme activity remains elein noradrenergic nerve terminals. Our finding that vated for a longer period. A similar time-course' for reserpine increases TH activity in both the cerebellum the increase in TH activity in locus coeruleus has and the hippocampus indicates that this drug does been reported by REIS et al. (1975). These authors elevate TH activity in central noradrenergic nerve tershowed that the increase in enzyme activity could be minals since both of these brain regions have been I80

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FIG.3. Thc time course of change in tyrosine hydroxylase activity in the hypothalamus after a n injection of reserpine. Enzyme activity was measured in drug-treated and vehicle-injected controls. Control tyrosine hydroxylase activity in the hypothalamus was 59.7 6.0nmol DOPA formed per sample per h.

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FIG.4. The time course of changes in tyrosine hydroxylase activity in the hippocampus after a single injection of reserpine. Tyrosine hydroxylase activity in hippocampi taken from reserpine-treated rats is compared to that found in vehicle-injected controls. Control tyrosine hydroxylase activity in the hippocampus was 4.6 0.3 nmol DOPA formed per sample per h.

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FIG.5. A comparison of the time courses of the changes in tyrosine hydroxylase activity in the locus coeruleus, cerebellum and hippocampus after a single injection of reserpine. This figure is a composite of the data shown in Figs. 1, 2 and 4 in order to illustrate the sequential nature of the changes in tyrosine hydroxyiase activity in the locus coeruleus (a region containing primarily noradrenergic cell bodies), the cerebellum (a nearby area of termination of some of these neurons), and the hippocampus (a more distant area of termination of the neurons).

Sequential increase in TH in cell bodies and terminals shown to contain noradrenergic nerve terminals but no noradrenergic cell bodies (DAHLSTROM & FUXE, 1964; UNGERSTEDT, 197 I). It is particularly interesting that the increases in enzyme activity in these areas, which contain nerve terminals, occurred later than the increases in the locus coeruleus-an area containing primarily noradrenergic cell bodies. These findings raise the possibility that the increase in TH activity in the cerebellum and hippocampus depends on the transport of TH molecules from the cell bodies of noradrenergic neurons. The cerebellum and hippocampus were chosen for this study specifically because is is known that both of these areas receive a projection from noradrenergic & cell bodies in the locus coeruleus (DAHLSTROM FUXE,1964; UNGERSTEDT, 1971; and references cited below). Thus, for instance, locus coeruleus neurons have been shown to enter the cerebellum via the superior cerebellar peduncle (PICKELet a/., 1973, 1974) and noradrenergic terminals have been found in proximity to cerebellar Purkinje cells (BLOOMet ul., 197 I ; PICKEL et d., 1974). Stimulation of neurons in the locus coeruleus inhibits neural activity in Purkinje cells and this effect can be blocked by pretreating animals with reserpine or a-methyltyrosine (HOFFERet a/., 1973). Similar techniques have also been used to demonstrate a projection of locus coeruleus neurons to the hippocampus via the dorsal noradrenergic bundle (PICKEI. et a/., 1974; JONES& MOORE,1977). Noradrenergic nerve terminals have ef a/., been found in the hippocampus (BLACKSTAD 1967) and stimulation of the locus coeruleus has been shown to inhibit hippocampal pyramidal cell firing via p-adrenergic receptors (SEGAL& BLOOM,1974). Thus, these studies clearly demonstrate that noradrenergic neurons in the locus coeruleus project to the hippocampus and cerebellum (among other areas). The question of whether this is the only adrenergic projection to these areas is more difficult to answer. Lou et al. (in press) found an almost total disappearance of norepinephrine in the hippocampus after bilateral lesions of the locus coeruleus and ROSS& REIS(1974) found that unilateral lesions of the locus coeruleus produced a 46% reduction in dopamine-p-hydroxylase activity in the cerebellum and a 84% reduction in the hippocampus (ROSS& REIS. 1974). It is unclear whether this residual dopamine-P-hydroxylase activity results from an incomplete destruction of the cell bodies in the locus coeruleus or whether it indicates that other groups of adrenergic cell bodies also project to these regions. Perhaps the strongest evidence in favor of a single adrenergic projection to the hippocampus comes from a study in which horseradish peroxidase was injected directly into this region. Following the injection, locus coeruleus cells were the only known adrenergic cell bodies found to be labelled (SEGAL& LANDIS,1974). Similar results have been obtained following injections of horseradish peroxidase into the cerebellum (BLOOM,personal communication).

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Assuming then that thc nerve terminals in the cerebellum and hippocampus derivc solely from cell bodies in the locus coeruleus, it is interesting to note that the increase in TH activity appears first in the locus coeruleus, second in the cerebellum; and last in the hippocampus (Fig. 5). Since the terminals in the cerebellum are much closer to the locus coeruleus than the terminals in the hippocampus one would expect transported material to appear first in the cerebellum. Furthermore, the time lag betwccn the appearance of the increase in TH activity in the locus coeruleus and in the cerebellum and hippocampus might refect the rate of axonal transport of this enzyme. (This assumes there is no significant time delay between the increased accumulation of TH in cell bodies and its transport towards nerve terminals.) Based on the data in Fig. 5 and an estimate of the distance between the locus coeruleus and the cerebellum and hippocampus our results suggest that TH is being transported in these neurons at a rate of approx 1-2 mm/day. BLACK (1975), independently, came to a similar estimate of the rate of T H transport in central noradrenergc neurons based on the appearance of increased TH in the cerebral cortex after reserpine treatment. These rates are much slower than the rates of transport calculated for this enzyme in peripheral noradrenergic neurons based on ligation experiments (THOENEN e t a / . , 1970; JARROT & GEFFEN, 1972; WOOTEN& COYLE,1973). The reason for these different results is not clear but they d o not seem to be due to a general effect of reserpine on the rate of axonal transport. (DAHLSTROM & HAGGENDAL, & MCGEER,1973). 1969; FIBIGER In addition to these changes in TH activity in the cerebellum and in the hippocampus enzymc activity was elevated in the hypothalamus after reserpine. However, the interpretation of the time-course of changes in TH activity in this regon is difficult because the anatomical situation in the hypothalamus is quite complex. First of all, in addition to noradrenergic nerve terminals this region contains dopaminergic cell bodies and nerve terminals which contain TH (UNGERSTEDT, 1971; BJORKLUND & NOBIN, 1973). While reserpine does not seem to elevate TH activity in the dopaminergic cell bodies in the midbrain (REIS et a/., 1975: SORIMACHI, 1975), it is not known whcther the cell bodies in the hypothalamus are affected. Secondly, although the subcoeruleus area and perhaps the locus coeruleus projects to the hypothalamus, other groups of noradrenergc neurons also project to this region (UNGERSTEDT, 1971 ; OLSON & FUXE,1972; KOBAYASHI et al., 1974). The physiological significance of changes in TH activity such as those reported here remains to be determined. In the peripheral nervous system T H activity has been shown to increase rollowing periods of increased nerve activity (ZIGMOND & BEN-ARI, 1977) and it has been hypothesized that the change represents an adaptation to periods of increased trans& OESC~I. 1973). Howmitter utilization (THOENEN

28

R. E. ZIGMOND

ever. d u e t o the long delays involved in this process, it is clear that t h e adaptive significance of such changes m u s t b e in terms of a long-term adjustment t o a chronic alteration in t h e environment rather than a n acute a d a p t a t i o n to a sudden environmental change. T h e mechanism of t h e reserpine stimulated changes in TH a r e u n k n o w n a n d in particular it is unclear what relationship blockade of transmitter storaget h e primary effect of the drug-has t o t h e increase in TH activity. However, the disparity in t h e timecourse of these effects is striking. Thc former occurs in minutes; the latter, i n s o m e regions of t h e brain, in weeks. It is interesting t o n o t c t h a t t h e antipsychotic effects of reserpine have also been f o u n d t o occur only after a lag period of 2-3 weeks (BARSA& KLINE, 1956). In fact a variety of antipsychotic a n d antidepressant d r u g s h a v e been found to have long delays prior lo t h e onset of their therapeutic effects (KLEIN & DAVIS,1969; BALUESSARINI, 1977). I t is intriguing to speculate whether mechanisms analogous to those described h e r e involving changes i n protein metaholisni followed b y slow axonal transport might account for these delays.

CHUAUGD. & COSTAE. (1974) Biosynthesis of tyrosine hydroxylase in rat adrenal medulla after exposure t o cold. Proc. nam. Acad. Sci. U.S.A. 71, 4570-4574. DAHLSTROM A. & FUXEK . (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system. 1. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta physiol. scand. 62, Suppi. 232, 1-55. DAHLSTROM A. & HAGGENDAL J. (1969) Recovery of noradrenaline in adrenergic axons of rat sciatic nerves after reserpine treatment. J . Pharnz. Pharmac. 21, 633-638. FIBIGER H. C. & MCGEERE. G . (1973) Increased axoplasmic transport of [3H]dopamine in nigro-neostriatal neurons after reserpine. Life Sci. 13, 1565-1571. GEFFLNL. B. & RUSHR. A. (1968) Transport of noradrenaline in sympathetic nerves and the erect oC nerve impulses on its contribution to transmitter stores. J . Neurochern. 15, 925-930. HENURY I. A. & IVERSEN L. L. (1971) Effect of nerve growth factor and its antiserum on tyrosine hydroxylase activity in mouse superior cervical sympathetic ganglion. Brain Res. 29. 159-162. HOFFEKB. J., SIGGINSG. R., OLIVER A. P. & BLOOMF. E. (1973) Activation of the pathway from locus coeruleus to rat cerebellar Purkinje neurons: Pharmacological evidence of noradrenergic central inhibition. J . Pharmac. exp. Tker. 184, 553-569. B. & GEFFENL. B. (1972) Rapid axoplasmic transJAKKOT Ackiiowlrdgerjioirs-I would like to thank Mr. C. N. port of tyrosine hydroxylase in relation to other cytoRAYNERfor excellent technical assistance and Dr. L. plasmic constituents. Proc. nafn. Acad. Sci. U.S.A. 69, IVERSENfor helpful discussions. The tetrahydrobiopterin 344s3442. was a generous gift of Dr. R. F. LONGof Roche Products JONES B. E. & MOORER. Y. (1977) Ascending projections Ltd., Hertfordshire. England. The research was supported of the locus coerulcus in the rat. I1 Autoradiographic by funds from the Medical Research Council (U.K.) and study. Brain Res. 127, 23-53. by U.S. Public Health Service Grant NS 12651. KLE~N D. F. & DAVISJ. M. (1969) Diagnosis and Drug Treatment of Psychiatric Disorders, pp. 6&62. Williams & Wilkins, Baltimore. KOBAYASHI R. M., PALKOVITS M., K O P ~ N I. J. & JACOBOWREFERENCES ITZ D. M. (1974) Biochemical mapping of noradrenergic BALUESSARINI R. J . (1977) Chemotherapy i n Psychiatry, p. nerves arising from the locus cocruleus. Brain Res. 77, 96. Harvard University Press, Cambridge, MA. 269-279. BARSAJ. A. & KLIKEN. S. (1956) Use of reserpine in LEVITTM., SPECTORS., SJOERDSMA A. & UDENFRIEND S. disturbed psychotic patients. An?. J . Psychiai. 112, (1965) Elucidation of the rate-limiting step in norepine684-69 I . phrinc biosynthesis in the perfused guinea pig heart. J . BESSONM. J.. CHBRAMY A,, GAUCHYC. & MUSACCHIO Pharnzac. exp. Thrr. 148, 1-18. J. M. (1973) ElTects of some psychotropic drugs on tyro- LOY R., KOZIELL D. A. & MOORE R. Y. Norepinesine hydroxylase activity in different structures of the phrine innervation of the hippocampal formation in the rat brain. Eur. J . Pharmac. 22, 181-186. rat. J . comp. Neurol., in press. BJORKLUND A. & NOBINA. (1973) Fluorescence histoche- MCEWENB. S. & PFAFFD. W. (1970) Factors influencing sex hormone uptake by rat brain regions. 1. Effects of mica1 and microspectrofluorimetric mapping of dopaneonatal treatment, hypophysectomy, and competing mine and noradrenaline cell groups in the rat diencephasteroids on estradiol uptake. Brain Res. 21, 1-28. lon. Brain Res. 51, 193-205. P. B., BRlMlJOlN S. & AXELRODJ. (1972) InducBLACKI. B. (1975) Increased tyrosine hydroxylase activity MOLINOFF tion of dopamine-P-hydroxylase and tyrosine hydroxyin frontal cortex and cerebellum. Brairi Rrs. 95; 17G176. lase in rat hearts and sympathetic ganglia. J . Phannac. BLACKSTAD T. W.. FUXEK. & HOKFELTT. (1967) Noradexp. Ther. 182, 116-129. renaline terminals in the hippocampal region of the rat R. A,, THOENEN H. & AXELROD J. (1969) Increase and the guinca pig. 2. Zel/forsch. rnikrosk. h a t . 78, MUELLER in tyrosine hydroxylase activity after reserpine adminis463-473. tration. J . Phartnac. exp. Ther. 169, 74-79. BLOOMF. E., HOFFERB. J. & SICGINSG. R. (1971) Studies L. & FUXE K. (1972) Further mapping out of cenon norepinephrine-containing afferents t o purkinje cells OLSON tral noradrenaline neuron systems: projections of the of rat cerebellum. I. Localization of the fibers and their 'subcoeruleus' area. Brain Res. 43, 289-295. synapses. Brain Rrs. 25, 501-521. BLOOME. M., HAMILLR. W. & BLACK1. B. (1976) Eleva- PICKELV. M., K R ~ B SH. & BLOOMF. E. (1973) Proliferation of norepinephrine-containing axons in rat ccrebeltion of tyrosinc hydroxylase activity in sympathetic lar cortex after peduncle lesions. Brain Res. 59, 169-179. neurons after reserpine: the role of central nervous sysPICKEL V. M., SEGALM. & BLOOMF. E. (1974) A radioautem. Brain Res. 115, 525-528.

Sequential increase in TH in cell bodies and terminals tographic study of the efferent pathways of the nucleus locus coeruleus. J . comp. Neurol. 155, 15-42. PICKEL V. M.. JOHT. H. & REIS D. J. (1975) Jmmunohistochemical localization of tyrosine hydroxylase in brain by light and electron microscopy. Brairi Rex 85, 295-300. RErs D. J., JOH T. H., Ross R. A. & P I C K ~V. L M. (1974) Reserpine selectively increases tyrosine hydroxylase and dopamine-P-hydroxylase enzyme protein in central noradrenergic neurons. Brairi Res. 81, 38C386. REIS D. J., JOH T. H. & Ross R. A. (1975) Effects of reserpine on activities and amounts of tyrosine hydroxylase and dopamine-/l-hydroxylase in catecholamine neuronal systems in rat brain. J . Pkarmac. e . ~ p . Ther. 193, 775-784. ROSSR. A. & RErs D. J. (1974) Effects of lesions of locus coeruleus on regional distribution of dopamine-/Ghydroxylase activity in rat brain. Brain Re,$. 73, 161-166. SEGALM. & BLOOM F. E. (1974) The action of norepinephrine in the rat hippocampus. 11. Activation of the input pathway. Brain Res. 72, 99-1 14. SEGALM. & LAVDlS S. (1974) Afferents to the hippocampus of the rat studied with the method of retrograde transport of horseradish peroxidase. Brairi Res. 78, 1LI5. SEGALD. S., SULLIVAN J. L.. KUCZENSKI R. T. & MANDELL A. J. (1971) Erects of long-term rcscrpine treatment on brain tyrosine hydroxylase and behavioral activity. Science. N . Y . 173, 847-849. SORIMACHI M. (1975) Increase of tyrosine hydroxylase activity after reserpine: evidence for the selective rcsponse of noradrenergic neurons. Brairi Res. 99, 400-404. THOENEN H. & OESCHF. (1973) New enzyme synthesis as long as a long-term adaptation to increased transmit-

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ter utilization. In N e w Concepts in Neurotranst~iitter A. J., ed.) pp. 33-51. Plenum Press, Regukufion (MANDELL New York. THOENEN H., MUELLER R. A. & AXELROO J. (1970) Phase difference in the induction of tyrosine hydroxylase in cell body and nerve terminals of sympathetic neurones. Proc. iiafiz. Acad. Sci., U.S.A. 65, 58-62. UNGERSTEUT U. (1971) Stereotaxic mapping of the monoamine pathways in the rat brain. Acta physiol. scand. SUPP/.368, 1-48, WOOTENG. F. & COYLEJ. T. (1973) Axonal transport of catecholamine synthesizing and metabolizing enzymes. 1. Nwrocheni. 20, 1361-1371. ZiGMoND R. E. (1975) Time course of the changes in tyrosine hydroxylase in central noradrenergic cell bodies and terminals after reserpine. Proc. Sac. Nrurosci. 1, 355 (Abstract). ZIGMOND R. E. & BEN-ARIY. (1977) Electrical stimulation of preganglionic nerve increases tyrosine hydroxylase activity in sympathetic ganglia. Proc. m n Acad. Sci. U.S.A. 74, 3078-3080. ZIGMOND R. E. & MACKAYA. V. P. (1974) Dissociation of stimulatory and synthetic phases in the induction of tyrosine hydroxylase. Nature, Lond. 247, 1 12-1 13. ZIGMOND R. E., MACKAY A. V. P. & IVERSEN L. L. (19740) Minimum duration of trans-synaptic stimulation required for the induction of tyrosine hydroxylase by reserpine in the rat superior cervical ganglion. J . Neurocheni. 23, 355-358. ZIGMONDR. E., SCHON F. & IVERSEN L. L. (1974b) Increased tyrosine hydroxylase activity in the locus coeruleus of rat brain stem after reserpine treatment and cold stress. Bruin Res. 70, 547-552.

Tyrosine hydroxylase activity in noradrenergic neurons of the locus coeruleus after reserpine administration: sequential increase in cell bodies and nerve terminals.

0022-3042/79/0I01-0023602 OO/O TYROSINE HYDROXYLASE ACTIVITY IN NORADRENERGIC NEURONS OF THE LOCUS COERULEUS AFTER RESERPINE ADMINISTRATION: SEQUENTI...
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