- Email: [email protected]
Histaminergic neuron system in the brain: Distribution and possible functions
Brain
Research
Bulletin,
0361-9230191 $3.00 + .CUI
Vol. 27, PP. 367-370. 0 Pergamon Press plc, 1991. Printed in the U.S.A
Histaminergic Neuron System in the Brain: Distribution and Possible Functions HIROSHI WADA,
NAOYUKI
INAGAKI,
NOBUKO
ITOWI AND ATSUSHI
YAMATODANI
Department of Pharmacology II, Osaka University Faculty of Medicine Yamadaoka 2-2, Suita 565, Japan
WADA, H., N. INAGAKI, N. ITOWI AND A. YAMATODANI. Histaminergic neuron system in the brain: Distribution and possible functions. BRAIN RES BULL 27(3/4) 367-370, 1991.-Recent immunocytochemical studies have identified the histaminergic neuron system in the brain. In the rat brain, histaminergic neuronal cell bodies are located in the tuberomammillary nucleus in the posterior hypothalamus, while histaminergic fibers are distributed in almost all regions of the brain. Similar distributions of histaminergic neuronal cell bodies and fibers have been reported in the brains of other mammals and nonmammalian vertebrates. As expected from the widespread distributions of the efferent fibers, the central histaminergic neuron system seems to be involved in multiple functions in the brain. The results of intracerebral injection of histamine and administration of a-fluoromethylhistidine (FMH), which depletes brain histamine level, suggest that the central histaminergic system may modulate feeding, drinking and sexual behaviors, sleep-wakefulness and circadian rhythm, neuroendocrine and cardiovascular controls and thennoregulation. Histaminergic
system
Tuberomammillary
nucleus
E groups
a-Fluoromethylhistidine
mammillary body. The E4 group is the neuron clusters on the dorsolateral side of the mammillary recess. The E.5 group is the neurons scattered between the E2 and E4 groups. The histaminergic neurons have 2-4 well-developed dendrites with a few dendritic spines, and some of their cell bodies or dendrites seem to contact with cerebrospinal fluid (14, 17, 61). Like many other neuron systems, the histaminergic neuron system contains other neuroactive substances and related enzymes, such as glutamate decarboxylase (46,52), adenosine deaminase (46), Met-Enkephalin-Arg-Phe (31), substance P (31), and galanin (32). In the developing brain, the histaminergic neurons undergo their final mitotic division between the embryonic days 13-18 and begin to express HDC and histamine-immunoreactivities on the embryonic days 16 and 20, respectively (4,42).
has been shown to act as a neuroregulator or neuin the mammalian central nervous system (19, 4 1, 44, 59, 66). The central histaminergic neuron system has been identified by morphological studies with antibodies against histidine decarboxylase (HDC) (50, 60, 61) or histamine (37,48) as markers. Efferent fibers of the histaminergic system are distributed in almost all regions of the brain. Consistent with this morphological feature, accumulating evidence indicates that the histaminergic system is involved in diverse functions of the brain. In this brief review, we report recent studies on the distribution and possible functions of the histaminergic neuron system in the brain. HISTAMINE
rotransmitter
LOCATION AND MORPHOLOGY OF HISTAMINERGIC NEURONAL CELL BODIES IN THE RAT BRAIN
PATHWAYS AND DISTRIBUTION OF HISTAMINERGIC NERVE FIBERS IN THE RAT BRAIN
In the rat brain, cell bodies of the histaminergic neuron system are located in the ventral part of the posterior hypothalamus, constituting the tuberomammillary nucleus (37, 48, 53, 61). Recently, the tuberomammillary nucleus of the rat brain has been found to be composed of five subgroups (14,47). As listed in Table 1, these five subgroups have been named differently by different workers. For simplicity, we called the histaminergic neurons in these five subgroups groups El, E2, E3, E4 and E5 (Fig. 1) (23), by analogy with the nomenclature for other monoaminergic neuron systems: noradrenergic, Al-A7; dopaminergic, A8-A17; serotoninergic, Bl-B9; and adrenergic, Cl-C3 (10,18). The El and E2 groups are located in the lateral surface of the mammillary body, and caudally situated El group is separated from the rostral E2 group by the lateral mammillary nucleus. The E3 neuron group is located in the ventral surface of the
The histaminergic neurons project their efferent fibers widely and unevenly to various regions from the olfactory bulb to the spinal cord (21,38). The fibers are densest in the hypothalamic nuclei, and dense fiber networks are also present in the thalamic nuclei. The densities of fibers are moderate in the cerebral cortex, basal ganglia, amygdaloid complex and septum, and low in the olfactory bulb, hippocampus, brain stem, cerebellum spinal cord and posterior hypophysis. No fibers innervate the retina or intermediate and anterior lobes of the hypophysis. Most histaminergic fibers do not surround specific neuronal cell bodies but are diffusely scattered in the brain (21,38), and only a few of their varicosities form synaptic contacts with neuronal elements (17.51). However, in the mesencephalic trigeminal nucleus,
367
36X
WAOA
TABLE
ET AL..
I
COMPARISONOF THE NOMENCLATURES OF THE FIVESUBGROUPSOF THETUBEROMAMMILLARY NUCLEUSIN THE RAT BRAIN Tuberomammillary
El PCM TMVc Ps
E2 CMC TM TMVr LS
Nucleus
E3
TMMv vs
Reference
E4 TMC TMC TMMd TS
ES
TMdif Is
(23) (5) (40) (14) (47)
Abbreviations: CMC, caudal magnocellular nucleus; Is, interstitial subdivision; Ls, lateral subdivision; PCM, postmammillary caudal magnocellular nucleus; Ps, posterior subdivision; TM, tuberomammillary nucleus; TMC, tuberal magnocellular nucleus; TMdif, Diffuse part; TMMd, dorsal component of the medial part; TMMv, ventral component of the medial part, TMVc, caudal component of the ventral part; TMVr. rostral component of the ventral part; Vs. ventral part.
ous brain regions are bilateral with ipsilateral predominance, and groups El-E5 have similar efferent projection patterns to various regions in the brain (14, 23, 49, 53). AFFJZRENT FIBERCONNECTIONS TO HISTAMINERGIC SYSTEM
=jMR
Arc
Afferent fiber connections to the histaminergic neurons from the prefrontal cortex, medial preoptic nucleus, and septum-diagonal band complex have been demonstrated (63, 64, 65). Tamiya et al. showed that histaminergic neurons receive synaptic contacts from varicose fibers containing neuropeptide Y (54) and substance P (55). Ericson et al. reported the adrenergic, noradrenergic and serotoninergic afferents to the tuberomammillary nucleus originate from the ClZ3, Al-A2 and B5-B9 cell groups, respectively (15). HISTAMINERGIC SYSTEMIN OTHERSPECIES
FIG. 1. Subgroups of histaminergic neurons in the rat brain, Serial anterior and posterior sections (a-e) showing the distribution of histaminergic neurons and the subgroups El-E5. Abbreviations: 3V, third ventricle;
DA, dorsal hypothalamic area; DM, dorsomedial hypothalamic nucleus; LH, lateral hypothalamic nucleus; VMH, ventromedial hypothalamic nucleus; Arc, arcuate nucleus; MM, medial mammillary nucleus; MR. mammillary recess; PM, premammikuy nucleus; SUM, supramammillary nucleus; LM, lateral mammillary nucleus.
dense networks of the fibers surround the neuronal cell bodies, forming synaptic contacts to them (20). The main ascending fibers run in the medial forebrain bundle and ventral surface of the hypothalamus, and some of them cross the midline at the level of the retrochiasmatic area. The descending fibers run through the central gray of the mesencephalon to the dorsal part of the rhombencephalon and spinal cord (21,38). The projections from the tuberomammillary nucleus to the vari-
The central histaminergic system has also been demonstrated in the guinea pig (l), tree shrew (2) and human (38) brains and in the brains of nonmammalian vertebrates, such as turtle (24), frog (3), teleost (24a) and lamprey (7). The basic organization of the central histaminergic system is similar in all the vertebrates examined, with cell bodies in the posterior part of the ventral hypothalamus and extensive fiber projections. The only exception so far is the lamprey. In the brain of lamprey, another group of histamine-immunoreactive neuron has been found in the border area between the mesencephalon and rhombencephalon (7). Those cells may correspond to the histamine-immunoreactive neurons that appear transiently in the lower brain stem of the rat embryo during development (4). Thus, the principal morphological features of the histaminergic neuron system appear to be well conserved in vertebrates. POSSIBLEPHYSIOLOGICAL FUNCTIONSOF THE CENTRAL HISTAMINERGIC SYSTEM Information on the distribution of histaminergic fibers in the brain provides a better understanding of the physiological functions of the central histaminergic system. The widespread projection of efferent fibers suggests that histamine is related to diverse functions of the brain. Studies on the effects of intracerebral injection of histamine and antihistamines and administration of a-fluoromethylhistidine (FMH), a specific inhibitor of histamine synthesis (62), support this idea as described below. Intracerebroventricular injection of histamine depresses the
HISTAMINERGIC
369
SYSTEM IN BRAIN
feeding behavior (9,26), while microinjection of HI-antagonists into the ventromedial hypothalamus induces transient increase in feeding (43), suggesting that histamine may be a physiological anorectic that controls feeding. Intracerebral injection of histamine induces drinking behavior (34). Depletion of brain histamine depresses hormone-activated female copulatory responsiveness (13). Intracerebroventricular injection of histamine or an H,-histamine agonist causes arousal response (29,.56), and administration of FMH increases slow-wave sleep and decreases wakefulness (30,33), suggesting the essential role of histamine in the maintenance of wakefulness. Recently, Itowi et al. observed effects of FMH on circadian rhythms: namely, they found that administration of FMH attenuated the amplitude of the circadian change in plasma corticosterone level (27) and induced transient phase-shift of free-running locomotor and drinking activities (28). There are numerous reports about the effects of histamine on neuroendocrine hormones and autonomic activities. Results have
been somewhat discrepant, but suggest that central histamine may elevate the levels of adrenocorticotropin (ACTH) (8,45), luteinizing hormone (LH) (12), prolactin (12) and vasopressin (11,58), decrease those of growth hormone (35) and thyrotropin (57), and induces hypothermia (6), rise in blood pressure (16) and hyperglycemia (36). Thus, conceivably the histaminergic system regulates the activities of extensive regions of the central nervous system. Recent findings that central histamine acts not only on neurons, but also on astrocytes (22,25), are also suggestive in understanding the functions of central histamine. ACKNOWLEDGEMENTS
We would like to thank Prof. Takehiko Watanabe for great contributions to our studies on the central histaminergic system. The preparation of this review was supported by a Grant-in-Aid for Specially Promoted Research (#63065004) from the Ministry of Education, Science and Culture of Japan.
REFERENCES M. S.; Panula, P. The histaminergic system in the 1. Airaksinen, guinea pig central nervous system: immunocytochemical mapping study using an antiserum against histamine. J. Comp. Neural. 273: 163-186; 1988. 2. Airaksinen, M. S.; Fliigge, G.; Fuchs, E.; Panula, P. Histaminergic system in the tree shrew brain. J. Comp. Neurol. 286:289-310; 1989. 3. Airaksinen, M. S.; Panula, P. Comparative neuroanatomy of the histaminergic system in the brain of the frog Xenopus lavis. J. Comp. Neurol. 292:412423; 1990. 4. Auvinen, S.; Panula, P. Development of histamine-immunoreactive neurons in the rat brain J. Comp. Neurol. 276:289-303; 1988. 5. Bleier, R.; Cohn, 0.; Siggelcow, I. R. A cytoarchitectonic atlas of the rat hypothalamus and third ventricle of the rat. In: Morgan, P. J.; Panksepp, J., eds. Anatomy of the hypothalamus, handbook of the hypothalamus, vol. I. New York: Marcel Dekker; 1979:137-220. 6. Brezenoff, H. E.; Lomax, R. Temperature changes following microinjection of histamine into the thermoregulatory centers of the rat. Experientia 26:51-;1970. 7. Brodin, L.; HBkfelt, T.; Grillner, S.; Panula, P. Distribution of histaminergic neurons in the brain of the lamprey Lampetra fluviatilis as revealed by histamine-immunoreactivity. J. Comp. Neurol. 292: 43542; 1990. 8. Cacabelos, R.; Yamatodani, A.; Fukui, H.; Watanabe, T.; Hariguchi, S.; Nishimura, T.; Wada, H. Nature of histaminergic neuromodulation of the release of the corticotropinergic system. Biogenic Amines 3:9-19; 1985. 9. Clineschmidt, B. V.; Lotti, V. J. Histamine intraventricular injection suppresses ingestive behavior of cat. Arch. Int. Pharmacodyn. Ther. 206:228-298; 1973. 10. Dahlstrijm, A.; Fuxe, K. Evidence for the existence of monoaminecontaining neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Stand. 62:1-55; 1964. 11. Dogterom, J.; Van Wimersma Greidanus, Tj. B.; Dewied, D. Histamine as an extremely potent releaser of vasopressin in the rat. Experientia 32:659-660; 1976. 12. Donoso, A. 0. Induction of prolactin and luteinizing hormone release by histamine in male and female rats and the influence of brain transmitter antagonists. J. Endocrinol. 76: 193-202; 1978. 13. Donoso, A. 0.; Broitman, S. T. Effect of a histamine synthesis inhibitor and antihistamines on the sexual behavior of female rats. Psychopharmacology (Berlin) 66:25 l-256; 1979. 14. Ericson, H.; Watanabe, T.; Kbhler, C. Morphological analysis of the tuberomammillary nucleus of the rat brain: delineation of subgroups with antibody against L-histidine decarboxylase as a marker. J. Comp. Neural. 263:1-24; 1987. 15. Ericson, H.; Blomqvist, A.; Kiihler, C. Brainstem afferents to the tuberomammillary nucleus in the rat brain with special reference to
monoaminergic innervation. J. Comp. Neurol. 281:169-192; 1989. 16. Finch, L.; Hicks, P. E. The cardiovascular effects of intraventricularly administrated histamine in the anaesthetized rat. Naunyn Schiedebergs Arch. Pharmacol. 293:151-157; 1976. 17. Hayashi, H.; Takagi, H.; Takeda, N.; Kubota, Y.; Tohyama, M.; Watanabe, T.; Wada, H. Fine structure of histaminergic neurons in the caudal magnocellular nucleus of the rat as demonstrated by immunocytochemistry using histidine decarboxylase as a marker. J. Comp. Neurol. 229:233-241; 1984. 18. HGkfelt, T.; Fuxe, K.; Goldstein, M.; Johansson, 0. Immunohistochemical evidence for the existence of adrenaline neurons in the rat brain. Brain Res. 66:235-251; 1974. 19. Hough, L. B. Cellular localization and possible functions for brain histamine. hog. Neurobiol. 30:469-505; 1988. 20. Inagaki, N.; Yamatodani, A.; Shinoda, K.; Shiotani, Y.; Tohyama, M.; Watanabe, T. Wada, H. The histaminergic innervation of the mesencephalic nucleus of the trigeminal nerve in the rat brain: a light and electron microscopic study. Brain Res. 418:388-391; 1987. 21. Inagaki, N.; Yamatodani, A.; Ando-Yamamoto, M.; Tohyama, M.; Watanabe, T.; Wada, H. Organization of histaminergic fibers in the rat brain. J. Comp. Neurol. 273:283-300; 1988. 22. Inagaki, N.; Fukui, H.; Taguchi, Y.; Wang, N. P.; Yamatodani, A.; Wada, H. Characterization of histamine H,-receptors on astrocytes in primary culture: [3H]mepyramine binding studies. Eur. J. Pharmacol. 173:43-51; 1989. 23. Inagaki, N.; Toda, K.; Taniuchi, I.; Panula, P.; Yamatodani, A.; Tohyama, M.; Watanabe, T.; Wada, H. An analysis of histaminergic efferents of the tuberomammillary nucleus to the medial preoptic area and inferior colliculus of the rat. Exp. Brain Res. 80:374380; 1990. 24. Inagaki, N.; Panula, P.; Yamatodani, A.; Wada, H. Organization of the histaminergic system in the brain of the turtle. Chinemys reevesii. J. Comp. Neurol. 297:132-144; 1990. 24a Inagaki, N.; Panula, P.; Yamatodani, A.; Wada, H. Organization of histaminergic system in the brain of the teleost, Trachurus trachums. J. Comp. Neurol. 310:94-102; 1991. 25. Inagaki, N.; Fukui, H.; Ito, S.; Yamatodani, A.; Wada, H. Single type-2 astrocytes show independent sites of Ca*+ signaling in response to histamine. Proc. Natl. Acad. Sci. USA 88:42154219; 1991. 26. Itowi, N.; Nagai, K.; Nakagawa, H.; Watanabe, T.; Wada H. Changes in the feeding of rats elicited by histamine infusion. Physiol. Behav. 44:221-226; 1988. 27. Itowi, N.; Yamatodani, A.; Cacabelos, R.; Goto, M.; Wada, H. Effect of histamine depletion on circadian variation of corticotropin and corticosterone in rats. Neuroendocrinology 50:187-192; 1989. 28. Itowi, N.; Yamatodani, A.; Nagai, K.; Nakagawa, H.; Wada, H. Effects of histamine and a-fluoromethylhistidine injections on circadian phase of free-running rhythms. Physiol. Behav. 47:549-554; 1990.
370
29. Kalivas, P. W. Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. J. Pharmacol. Exp. Ther. 222:37-42: 1982. 30. Kiyono, S.; Seo, M. L.; Shibagaki, M.; Watanabe, T.; Maeyama, K.; Wada, H. Effects of a-fluoromethylhistidine on sleep-waking parameters in rats. Physiol. Behav. 34:615417; 1985, 31. Kiihler, C.; Swanson, L. W.; Haglund, L.; Wu, J.-Y. The cytoarchitecture, histochemistry, and projections of the tuberomammillary nucleus in the rat. Neuroscience 16:85-l 10; 1985. 32. Knhler, C.; Ericson, H.; Watanabe, T.; Polak, J.; Palay, S. L.; Palay, V.; Chan-Palay, V. Galanin immunoreactivity in hypothalamic histamine neurons: further evidence for multiple chemical messengers in the tuberomammillary nucleus. J. Comp. Neural. 250:5864; 1986. 33. Lin. J.-S.; Sakai, K.; Jouvet, M. Evidence for histaminergic arousal mechanism in the hypothalamus of cat. Neuropharmacology 27:11 l122: 1988. 34. Leibowitz, S. F. Histamine: a stimulatory effect on drinking behavior in the rat. Brain Res. 63:44043; 1973. 35. Netti. C.; Guidobono, F.; Olgiati, V. R.: Sibilia, V.; Pagani, F.; Pecil. A. Influence of brain histamine system on episodic growth hormone secretion in the rat. Neuroendocrinology 35:43117; 1982. 36. Nishibori, M.; Itoh, Y.; Oishi, R.; Saeki. K. Mechanism of the central hyperglycemic action of histamine in mice. J. Pharmacol. Exp. Ther. 241:582-586; 1987. 37. Panula, P.; Yang, H.-Y. T.; Costa, E. Histamine-containing neurons in the rat hypothalamus. Proc. Natl. Acad. Sci. USA 81:25722576; 1984. 38. Panula, P.; Pirvola, U.; Auvinen, S.; Airaksinen, M. S. Histamineimmunoreactive nerve fibers in the rat brain. Neuroscience 28:585610; 1989. 39. Panula, P.; Airaksinen, M. S.; Pirvola, U.; Kotilainen, E. A histamine-containing neuronal system in human brain. Neuroscience 34: 127-132; 1990. 40. Paxmos, G.; Watson, C. The rat brain in stereotaxic coordinates, 2nd ed. New York: Academic Press; 1986. 41. Prell. G. D.; Green, J. P. Histamine as a neuroregulator. Annu. Rev. Neurosci. 9:209-254; 1986. 42. Reiner. P. B.; Semba, K.; Fibiger, H. C.; McGeer, E. G. Ontogeny of histidine-decarboxylase-immunoreactive neurons in the tuberomammillary nucleus of the rat hypothalamus: time of origin and development of transmitter phenotype. J. Comp. Neurol. 276:304311; 1988. 43. Sakata. T.; Fukagawa, K.; Ookuma, K.; Fujimoto, K.; Yoshimatsu, H.; Yamatodani, A.; Wada, H. Modulation of neuronal histamine in control of food intake. Physiol. Behav. 44:539-547; 1988. 44. Schwartz, J.-C.; Garbarg, M.; Pollard, H. Histaminergic transmission in the brain. In: Mountcastle, V. B., ed. Handbook of physiology, the nervous system IV. Bethesda, MD: American Physiological Society; 1986:257-316. 45. Seltzer. A. M.; Donoso, A. 0. Involvement of specific receptors in the histamine stimulation of the pituitary-corticoadrenal system in the rat. Neuroendocrinol. Lett. 4:299-304: 1982. 46. Senba, E.; Daddona, P. E.; Watanabe, T.; Wu, J.-Y .; Nagy, J. I. Coexistence of adenosine deaminase, histidine decarboxylase, and glutamate decarboxylase in hypothalamic neurons of the rat. J. Neurosci. 5:3393-3420; 1985. 47. Staines, W. A.; Daddona, P. E.; Nagy, J. I. The organization and hypothalamic projections of the tuberomammillary nucleus in the rat: an imrnunocytochemical study of adenosine deaminase positive neurons and fibers. Neuroscience 23:.571-596; 1987. 48. Steinbusch. H. W. M.; Mulder, A. H. Immunohistochemical localization of histamine in neurons and mast cells in the rat brain. In: Bjarklund, A.; HBkfelt, T.; Kuhar, M. J., eds. Classical transmitters and transmitter receptors in the CNS, Part II, handbook of chemical neuroanatomy. Amsterdam: Elsevier; 1984: 126-140. 49. Steinbusch, H. W. M.; Sauren, Y.; Groenwegen, H.; Watanabe, T.; Mulder, A. H. Histaminergic projections from the premammillary and posterior hypothalamus region to the caudate putamen complex in the rat. Brain Res. 368:389-393; 1986. 50. Taguchi, Y.; Watanabe, T.; Kubota, H.; Hayashi, H.; Wada, HPurification of histidine decarboxylase from the liver of fetal rats and its immunochemical and immunohistochemical characterization. J.
WADA
E?’ AL.
Biol. Chem. 259:5214-5221; 1984. 51. Takagi, H.; Morishima, Y.; Matsuyama, T.; Hayaslu, H.; Watanabe. T.: Wada. H. Histaminergic axons in the neostriatum and cerebral cortex of the rat: a correlated light and electron microscope unrnunocytochemical study using histidine decarboxylase as a marker. Brain Res. 364:114-123: 1986. 52. Takeda. N.; lnagaki, S.; Shiosaka, S.; Taguchi, Y.; Oertel, W. H.; Tohyama. M.: Watanabe. T.: Wada, H. Immunocytochemical evidence for the coexistence of histidine decarboxylase-like and gluamate decarboxylase-like immunoreactivities in nerve cells of the posterior magnocellular nucleus of the hypothalamus of rats. Proc. Natl. Acad. Sci. USA 81:7647-7650; 1984. 53. Takeda. N.; Inagaki, S.; Taguchi. Y.; Tohyama, M.; Watanabe, T.; Wada, H. Origins of histamine containing fibers in the cerebral cortex of rats studied by immunohistochemistry with histidine decarboxylase as a marker and transection. Brain Res. 323:55-63: 1984, 54. Tamiya, R.; Hanada, M.; Narita, N.; Kawai, Y.: Tohyama, M.; Takagi. H. Neuropeptide Y afferents have synaptic intereactions with histaminergic (histidine decarboxylase-immunoreactive) neurons in the rat brain. Neurosci. Lett. 99:241-245; 1989. 55. Tamiya, R.; Hanada. M.; Kawai. Y.; Narita, N.; lnagaki, S.; Tohyama, M.; Takagi. H. Histaminergic neurons receive substance P-ergic inputs in the posterior hypothalamus. Esp. Brain Res. 79: 261-265; 1990. 56. Tasaka, K.; Chung, Y. H.; Sawada, K.; Mio, M. Excitatory effect of histamine on the arousal system and its inhibition by H, blockers. Brain Res. Bull. 22:271-275; 1989. 57. Tuominen, R. K.; Mattila, J.: MlnnistG, P. T. Inhibition of the TSH secretion by histamine in male rats. Acta Endocrinol. (Copenh.) 103:88-94; 1983. 58. Toumisto. L.; Eriksson, L.; Fyhrquist, F. Vasopressin release by histamine in the conscious goat. Eur. J. Pharmacol. 63: 15-24; 1980. 59. Wada, H.; Watanabe, T.: Yamatodani, A.; Maeyama, K.; Itoi, N.; Cacabelos, R.: Seo, M.; Kiyino, S.; Nagai, K.; Nakagawa, H. Physiological functions of histamine in the rat brain. In: Ganellin. C. R.: Schwartz. J. C., eds. Frontiers in histamine research. Advance in the biosciences. vol. 51, Oxford: Pergamon; 1985:225235. 60. Watanabe, T.; Taguchi, Y .; Hayashi, H.; Tanaka, J,; Shiosaka, S.: Tohyama, M.; Kubota, H.; Terano, T.; Wada, H. Evidence for the presence of a histaminergic neuron system in the rat brain: an immunocytochemical analysis. Neurosci. Lett. 39:249-254; 1983. 61. Watanabe, T.; Taguchi, Y.; Shiosaka, S.; Tanaka, J.; Kubota, H.; Terano, Y.; Tohyama, M.; Wada, H. Distribution of the histaminergic neuron system in the central nervous system of rats: a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res. 295:13-25: 1984. 62. Watanabe, T.; Yamatodani, A.; Maeyama, K.; Wada, H. Pharmacology of a-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol. Sci. 11:363-367; 1990. 63. Wouterlood. F. G.; Steinbusch, H. W. M.; Luiten, P. G. M.: Bol, J. G. J. M. Projection from the prefrontal cortex to histaminergic cell groups in the posterior hypothalamic region of the rat. Anterograde tracing with Phaseolus vulgaris-leucoagglutinin (PHA-LJ combined with immunocytochemistry of histidine decarboxylase. Brain Res. 406:330-336; 1987. 64. Wouterlood, F. G.; Gaykema, R. P. A. Innervation of histaminergic neurons in the posterior hypothalamic region by medial prooptic nucleus: Anterograde tracing with Phaseolus vulgaris-leucoagglutinin combined with immunocytochemistry of histidine decarboxylase in the rat. Brain Res. 455:170-176; 1988. 65. Wouterlood, F. G.; Gaykema, R. P. A.; Steinbusch, H. W. M.; Watanabe, T.; Wada, H. The connections between the septum-diagonal band complex and histaminergic neurons in the posterior hypothalamus of the rat. Anterograde tracing with Phaseolus vulgarisleucoagglutinin combined with immunocytochemistry of histidine decarboxylase. Neuroscience 26:827-845; 1988. 66. Yamatodani, A.; Inagaki, N.; Panula, P.; Itowi, N.; Watanabe, T.; Wada, H. Structure and functions of the histaminergic neuron system. In: Uvnls, B., ed. Histamine and histamine antagonist, handbook of experimental pharmacology, vol. 97. Berlin: SpringerVerlag; 1991:243-283.
Research
Bulletin,
0361-9230191 $3.00 + .CUI
Vol. 27, PP. 367-370. 0 Pergamon Press plc, 1991. Printed in the U.S.A
Histaminergic Neuron System in the Brain: Distribution and Possible Functions HIROSHI WADA,
NAOYUKI
INAGAKI,
NOBUKO
ITOWI AND ATSUSHI
YAMATODANI
Department of Pharmacology II, Osaka University Faculty of Medicine Yamadaoka 2-2, Suita 565, Japan
WADA, H., N. INAGAKI, N. ITOWI AND A. YAMATODANI. Histaminergic neuron system in the brain: Distribution and possible functions. BRAIN RES BULL 27(3/4) 367-370, 1991.-Recent immunocytochemical studies have identified the histaminergic neuron system in the brain. In the rat brain, histaminergic neuronal cell bodies are located in the tuberomammillary nucleus in the posterior hypothalamus, while histaminergic fibers are distributed in almost all regions of the brain. Similar distributions of histaminergic neuronal cell bodies and fibers have been reported in the brains of other mammals and nonmammalian vertebrates. As expected from the widespread distributions of the efferent fibers, the central histaminergic neuron system seems to be involved in multiple functions in the brain. The results of intracerebral injection of histamine and administration of a-fluoromethylhistidine (FMH), which depletes brain histamine level, suggest that the central histaminergic system may modulate feeding, drinking and sexual behaviors, sleep-wakefulness and circadian rhythm, neuroendocrine and cardiovascular controls and thennoregulation. Histaminergic
system
Tuberomammillary
nucleus
E groups
a-Fluoromethylhistidine
mammillary body. The E4 group is the neuron clusters on the dorsolateral side of the mammillary recess. The E.5 group is the neurons scattered between the E2 and E4 groups. The histaminergic neurons have 2-4 well-developed dendrites with a few dendritic spines, and some of their cell bodies or dendrites seem to contact with cerebrospinal fluid (14, 17, 61). Like many other neuron systems, the histaminergic neuron system contains other neuroactive substances and related enzymes, such as glutamate decarboxylase (46,52), adenosine deaminase (46), Met-Enkephalin-Arg-Phe (31), substance P (31), and galanin (32). In the developing brain, the histaminergic neurons undergo their final mitotic division between the embryonic days 13-18 and begin to express HDC and histamine-immunoreactivities on the embryonic days 16 and 20, respectively (4,42).
has been shown to act as a neuroregulator or neuin the mammalian central nervous system (19, 4 1, 44, 59, 66). The central histaminergic neuron system has been identified by morphological studies with antibodies against histidine decarboxylase (HDC) (50, 60, 61) or histamine (37,48) as markers. Efferent fibers of the histaminergic system are distributed in almost all regions of the brain. Consistent with this morphological feature, accumulating evidence indicates that the histaminergic system is involved in diverse functions of the brain. In this brief review, we report recent studies on the distribution and possible functions of the histaminergic neuron system in the brain. HISTAMINE
rotransmitter
LOCATION AND MORPHOLOGY OF HISTAMINERGIC NEURONAL CELL BODIES IN THE RAT BRAIN
PATHWAYS AND DISTRIBUTION OF HISTAMINERGIC NERVE FIBERS IN THE RAT BRAIN
In the rat brain, cell bodies of the histaminergic neuron system are located in the ventral part of the posterior hypothalamus, constituting the tuberomammillary nucleus (37, 48, 53, 61). Recently, the tuberomammillary nucleus of the rat brain has been found to be composed of five subgroups (14,47). As listed in Table 1, these five subgroups have been named differently by different workers. For simplicity, we called the histaminergic neurons in these five subgroups groups El, E2, E3, E4 and E5 (Fig. 1) (23), by analogy with the nomenclature for other monoaminergic neuron systems: noradrenergic, Al-A7; dopaminergic, A8-A17; serotoninergic, Bl-B9; and adrenergic, Cl-C3 (10,18). The El and E2 groups are located in the lateral surface of the mammillary body, and caudally situated El group is separated from the rostral E2 group by the lateral mammillary nucleus. The E3 neuron group is located in the ventral surface of the
The histaminergic neurons project their efferent fibers widely and unevenly to various regions from the olfactory bulb to the spinal cord (21,38). The fibers are densest in the hypothalamic nuclei, and dense fiber networks are also present in the thalamic nuclei. The densities of fibers are moderate in the cerebral cortex, basal ganglia, amygdaloid complex and septum, and low in the olfactory bulb, hippocampus, brain stem, cerebellum spinal cord and posterior hypophysis. No fibers innervate the retina or intermediate and anterior lobes of the hypophysis. Most histaminergic fibers do not surround specific neuronal cell bodies but are diffusely scattered in the brain (21,38), and only a few of their varicosities form synaptic contacts with neuronal elements (17.51). However, in the mesencephalic trigeminal nucleus,
367
36X
WAOA
TABLE
ET AL..
I
COMPARISONOF THE NOMENCLATURES OF THE FIVESUBGROUPSOF THETUBEROMAMMILLARY NUCLEUSIN THE RAT BRAIN Tuberomammillary
El PCM TMVc Ps
E2 CMC TM TMVr LS
Nucleus
E3
TMMv vs
Reference
E4 TMC TMC TMMd TS
ES
TMdif Is
(23) (5) (40) (14) (47)
Abbreviations: CMC, caudal magnocellular nucleus; Is, interstitial subdivision; Ls, lateral subdivision; PCM, postmammillary caudal magnocellular nucleus; Ps, posterior subdivision; TM, tuberomammillary nucleus; TMC, tuberal magnocellular nucleus; TMdif, Diffuse part; TMMd, dorsal component of the medial part; TMMv, ventral component of the medial part, TMVc, caudal component of the ventral part; TMVr. rostral component of the ventral part; Vs. ventral part.
ous brain regions are bilateral with ipsilateral predominance, and groups El-E5 have similar efferent projection patterns to various regions in the brain (14, 23, 49, 53). AFFJZRENT FIBERCONNECTIONS TO HISTAMINERGIC SYSTEM
=jMR
Arc
Afferent fiber connections to the histaminergic neurons from the prefrontal cortex, medial preoptic nucleus, and septum-diagonal band complex have been demonstrated (63, 64, 65). Tamiya et al. showed that histaminergic neurons receive synaptic contacts from varicose fibers containing neuropeptide Y (54) and substance P (55). Ericson et al. reported the adrenergic, noradrenergic and serotoninergic afferents to the tuberomammillary nucleus originate from the ClZ3, Al-A2 and B5-B9 cell groups, respectively (15). HISTAMINERGIC SYSTEMIN OTHERSPECIES
FIG. 1. Subgroups of histaminergic neurons in the rat brain, Serial anterior and posterior sections (a-e) showing the distribution of histaminergic neurons and the subgroups El-E5. Abbreviations: 3V, third ventricle;
DA, dorsal hypothalamic area; DM, dorsomedial hypothalamic nucleus; LH, lateral hypothalamic nucleus; VMH, ventromedial hypothalamic nucleus; Arc, arcuate nucleus; MM, medial mammillary nucleus; MR. mammillary recess; PM, premammikuy nucleus; SUM, supramammillary nucleus; LM, lateral mammillary nucleus.
dense networks of the fibers surround the neuronal cell bodies, forming synaptic contacts to them (20). The main ascending fibers run in the medial forebrain bundle and ventral surface of the hypothalamus, and some of them cross the midline at the level of the retrochiasmatic area. The descending fibers run through the central gray of the mesencephalon to the dorsal part of the rhombencephalon and spinal cord (21,38). The projections from the tuberomammillary nucleus to the vari-
The central histaminergic system has also been demonstrated in the guinea pig (l), tree shrew (2) and human (38) brains and in the brains of nonmammalian vertebrates, such as turtle (24), frog (3), teleost (24a) and lamprey (7). The basic organization of the central histaminergic system is similar in all the vertebrates examined, with cell bodies in the posterior part of the ventral hypothalamus and extensive fiber projections. The only exception so far is the lamprey. In the brain of lamprey, another group of histamine-immunoreactive neuron has been found in the border area between the mesencephalon and rhombencephalon (7). Those cells may correspond to the histamine-immunoreactive neurons that appear transiently in the lower brain stem of the rat embryo during development (4). Thus, the principal morphological features of the histaminergic neuron system appear to be well conserved in vertebrates. POSSIBLEPHYSIOLOGICAL FUNCTIONSOF THE CENTRAL HISTAMINERGIC SYSTEM Information on the distribution of histaminergic fibers in the brain provides a better understanding of the physiological functions of the central histaminergic system. The widespread projection of efferent fibers suggests that histamine is related to diverse functions of the brain. Studies on the effects of intracerebral injection of histamine and antihistamines and administration of a-fluoromethylhistidine (FMH), a specific inhibitor of histamine synthesis (62), support this idea as described below. Intracerebroventricular injection of histamine depresses the
HISTAMINERGIC
369
SYSTEM IN BRAIN
feeding behavior (9,26), while microinjection of HI-antagonists into the ventromedial hypothalamus induces transient increase in feeding (43), suggesting that histamine may be a physiological anorectic that controls feeding. Intracerebral injection of histamine induces drinking behavior (34). Depletion of brain histamine depresses hormone-activated female copulatory responsiveness (13). Intracerebroventricular injection of histamine or an H,-histamine agonist causes arousal response (29,.56), and administration of FMH increases slow-wave sleep and decreases wakefulness (30,33), suggesting the essential role of histamine in the maintenance of wakefulness. Recently, Itowi et al. observed effects of FMH on circadian rhythms: namely, they found that administration of FMH attenuated the amplitude of the circadian change in plasma corticosterone level (27) and induced transient phase-shift of free-running locomotor and drinking activities (28). There are numerous reports about the effects of histamine on neuroendocrine hormones and autonomic activities. Results have
been somewhat discrepant, but suggest that central histamine may elevate the levels of adrenocorticotropin (ACTH) (8,45), luteinizing hormone (LH) (12), prolactin (12) and vasopressin (11,58), decrease those of growth hormone (35) and thyrotropin (57), and induces hypothermia (6), rise in blood pressure (16) and hyperglycemia (36). Thus, conceivably the histaminergic system regulates the activities of extensive regions of the central nervous system. Recent findings that central histamine acts not only on neurons, but also on astrocytes (22,25), are also suggestive in understanding the functions of central histamine. ACKNOWLEDGEMENTS
We would like to thank Prof. Takehiko Watanabe for great contributions to our studies on the central histaminergic system. The preparation of this review was supported by a Grant-in-Aid for Specially Promoted Research (#63065004) from the Ministry of Education, Science and Culture of Japan.
REFERENCES M. S.; Panula, P. The histaminergic system in the 1. Airaksinen, guinea pig central nervous system: immunocytochemical mapping study using an antiserum against histamine. J. Comp. Neural. 273: 163-186; 1988. 2. Airaksinen, M. S.; Fliigge, G.; Fuchs, E.; Panula, P. Histaminergic system in the tree shrew brain. J. Comp. Neurol. 286:289-310; 1989. 3. Airaksinen, M. S.; Panula, P. Comparative neuroanatomy of the histaminergic system in the brain of the frog Xenopus lavis. J. Comp. Neurol. 292:412423; 1990. 4. Auvinen, S.; Panula, P. Development of histamine-immunoreactive neurons in the rat brain J. Comp. Neurol. 276:289-303; 1988. 5. Bleier, R.; Cohn, 0.; Siggelcow, I. R. A cytoarchitectonic atlas of the rat hypothalamus and third ventricle of the rat. In: Morgan, P. J.; Panksepp, J., eds. Anatomy of the hypothalamus, handbook of the hypothalamus, vol. I. New York: Marcel Dekker; 1979:137-220. 6. Brezenoff, H. E.; Lomax, R. Temperature changes following microinjection of histamine into the thermoregulatory centers of the rat. Experientia 26:51-;1970. 7. Brodin, L.; HBkfelt, T.; Grillner, S.; Panula, P. Distribution of histaminergic neurons in the brain of the lamprey Lampetra fluviatilis as revealed by histamine-immunoreactivity. J. Comp. Neurol. 292: 43542; 1990. 8. Cacabelos, R.; Yamatodani, A.; Fukui, H.; Watanabe, T.; Hariguchi, S.; Nishimura, T.; Wada, H. Nature of histaminergic neuromodulation of the release of the corticotropinergic system. Biogenic Amines 3:9-19; 1985. 9. Clineschmidt, B. V.; Lotti, V. J. Histamine intraventricular injection suppresses ingestive behavior of cat. Arch. Int. Pharmacodyn. Ther. 206:228-298; 1973. 10. Dahlstrijm, A.; Fuxe, K. Evidence for the existence of monoaminecontaining neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Stand. 62:1-55; 1964. 11. Dogterom, J.; Van Wimersma Greidanus, Tj. B.; Dewied, D. Histamine as an extremely potent releaser of vasopressin in the rat. Experientia 32:659-660; 1976. 12. Donoso, A. 0. Induction of prolactin and luteinizing hormone release by histamine in male and female rats and the influence of brain transmitter antagonists. J. Endocrinol. 76: 193-202; 1978. 13. Donoso, A. 0.; Broitman, S. T. Effect of a histamine synthesis inhibitor and antihistamines on the sexual behavior of female rats. Psychopharmacology (Berlin) 66:25 l-256; 1979. 14. Ericson, H.; Watanabe, T.; Kbhler, C. Morphological analysis of the tuberomammillary nucleus of the rat brain: delineation of subgroups with antibody against L-histidine decarboxylase as a marker. J. Comp. Neural. 263:1-24; 1987. 15. Ericson, H.; Blomqvist, A.; Kiihler, C. Brainstem afferents to the tuberomammillary nucleus in the rat brain with special reference to
monoaminergic innervation. J. Comp. Neurol. 281:169-192; 1989. 16. Finch, L.; Hicks, P. E. The cardiovascular effects of intraventricularly administrated histamine in the anaesthetized rat. Naunyn Schiedebergs Arch. Pharmacol. 293:151-157; 1976. 17. Hayashi, H.; Takagi, H.; Takeda, N.; Kubota, Y.; Tohyama, M.; Watanabe, T.; Wada, H. Fine structure of histaminergic neurons in the caudal magnocellular nucleus of the rat as demonstrated by immunocytochemistry using histidine decarboxylase as a marker. J. Comp. Neurol. 229:233-241; 1984. 18. HGkfelt, T.; Fuxe, K.; Goldstein, M.; Johansson, 0. Immunohistochemical evidence for the existence of adrenaline neurons in the rat brain. Brain Res. 66:235-251; 1974. 19. Hough, L. B. Cellular localization and possible functions for brain histamine. hog. Neurobiol. 30:469-505; 1988. 20. Inagaki, N.; Yamatodani, A.; Shinoda, K.; Shiotani, Y.; Tohyama, M.; Watanabe, T. Wada, H. The histaminergic innervation of the mesencephalic nucleus of the trigeminal nerve in the rat brain: a light and electron microscopic study. Brain Res. 418:388-391; 1987. 21. Inagaki, N.; Yamatodani, A.; Ando-Yamamoto, M.; Tohyama, M.; Watanabe, T.; Wada, H. Organization of histaminergic fibers in the rat brain. J. Comp. Neurol. 273:283-300; 1988. 22. Inagaki, N.; Fukui, H.; Taguchi, Y.; Wang, N. P.; Yamatodani, A.; Wada, H. Characterization of histamine H,-receptors on astrocytes in primary culture: [3H]mepyramine binding studies. Eur. J. Pharmacol. 173:43-51; 1989. 23. Inagaki, N.; Toda, K.; Taniuchi, I.; Panula, P.; Yamatodani, A.; Tohyama, M.; Watanabe, T.; Wada, H. An analysis of histaminergic efferents of the tuberomammillary nucleus to the medial preoptic area and inferior colliculus of the rat. Exp. Brain Res. 80:374380; 1990. 24. Inagaki, N.; Panula, P.; Yamatodani, A.; Wada, H. Organization of the histaminergic system in the brain of the turtle. Chinemys reevesii. J. Comp. Neurol. 297:132-144; 1990. 24a Inagaki, N.; Panula, P.; Yamatodani, A.; Wada, H. Organization of histaminergic system in the brain of the teleost, Trachurus trachums. J. Comp. Neurol. 310:94-102; 1991. 25. Inagaki, N.; Fukui, H.; Ito, S.; Yamatodani, A.; Wada, H. Single type-2 astrocytes show independent sites of Ca*+ signaling in response to histamine. Proc. Natl. Acad. Sci. USA 88:42154219; 1991. 26. Itowi, N.; Nagai, K.; Nakagawa, H.; Watanabe, T.; Wada H. Changes in the feeding of rats elicited by histamine infusion. Physiol. Behav. 44:221-226; 1988. 27. Itowi, N.; Yamatodani, A.; Cacabelos, R.; Goto, M.; Wada, H. Effect of histamine depletion on circadian variation of corticotropin and corticosterone in rats. Neuroendocrinology 50:187-192; 1989. 28. Itowi, N.; Yamatodani, A.; Nagai, K.; Nakagawa, H.; Wada, H. Effects of histamine and a-fluoromethylhistidine injections on circadian phase of free-running rhythms. Physiol. Behav. 47:549-554; 1990.
370
29. Kalivas, P. W. Histamine-induced arousal in the conscious and pentobarbital-pretreated rat. J. Pharmacol. Exp. Ther. 222:37-42: 1982. 30. Kiyono, S.; Seo, M. L.; Shibagaki, M.; Watanabe, T.; Maeyama, K.; Wada, H. Effects of a-fluoromethylhistidine on sleep-waking parameters in rats. Physiol. Behav. 34:615417; 1985, 31. Kiihler, C.; Swanson, L. W.; Haglund, L.; Wu, J.-Y. The cytoarchitecture, histochemistry, and projections of the tuberomammillary nucleus in the rat. Neuroscience 16:85-l 10; 1985. 32. Knhler, C.; Ericson, H.; Watanabe, T.; Polak, J.; Palay, S. L.; Palay, V.; Chan-Palay, V. Galanin immunoreactivity in hypothalamic histamine neurons: further evidence for multiple chemical messengers in the tuberomammillary nucleus. J. Comp. Neural. 250:5864; 1986. 33. Lin. J.-S.; Sakai, K.; Jouvet, M. Evidence for histaminergic arousal mechanism in the hypothalamus of cat. Neuropharmacology 27:11 l122: 1988. 34. Leibowitz, S. F. Histamine: a stimulatory effect on drinking behavior in the rat. Brain Res. 63:44043; 1973. 35. Netti. C.; Guidobono, F.; Olgiati, V. R.: Sibilia, V.; Pagani, F.; Pecil. A. Influence of brain histamine system on episodic growth hormone secretion in the rat. Neuroendocrinology 35:43117; 1982. 36. Nishibori, M.; Itoh, Y.; Oishi, R.; Saeki. K. Mechanism of the central hyperglycemic action of histamine in mice. J. Pharmacol. Exp. Ther. 241:582-586; 1987. 37. Panula, P.; Yang, H.-Y. T.; Costa, E. Histamine-containing neurons in the rat hypothalamus. Proc. Natl. Acad. Sci. USA 81:25722576; 1984. 38. Panula, P.; Pirvola, U.; Auvinen, S.; Airaksinen, M. S. Histamineimmunoreactive nerve fibers in the rat brain. Neuroscience 28:585610; 1989. 39. Panula, P.; Airaksinen, M. S.; Pirvola, U.; Kotilainen, E. A histamine-containing neuronal system in human brain. Neuroscience 34: 127-132; 1990. 40. Paxmos, G.; Watson, C. The rat brain in stereotaxic coordinates, 2nd ed. New York: Academic Press; 1986. 41. Prell. G. D.; Green, J. P. Histamine as a neuroregulator. Annu. Rev. Neurosci. 9:209-254; 1986. 42. Reiner. P. B.; Semba, K.; Fibiger, H. C.; McGeer, E. G. Ontogeny of histidine-decarboxylase-immunoreactive neurons in the tuberomammillary nucleus of the rat hypothalamus: time of origin and development of transmitter phenotype. J. Comp. Neurol. 276:304311; 1988. 43. Sakata. T.; Fukagawa, K.; Ookuma, K.; Fujimoto, K.; Yoshimatsu, H.; Yamatodani, A.; Wada, H. Modulation of neuronal histamine in control of food intake. Physiol. Behav. 44:539-547; 1988. 44. Schwartz, J.-C.; Garbarg, M.; Pollard, H. Histaminergic transmission in the brain. In: Mountcastle, V. B., ed. Handbook of physiology, the nervous system IV. Bethesda, MD: American Physiological Society; 1986:257-316. 45. Seltzer. A. M.; Donoso, A. 0. Involvement of specific receptors in the histamine stimulation of the pituitary-corticoadrenal system in the rat. Neuroendocrinol. Lett. 4:299-304: 1982. 46. Senba, E.; Daddona, P. E.; Watanabe, T.; Wu, J.-Y .; Nagy, J. I. Coexistence of adenosine deaminase, histidine decarboxylase, and glutamate decarboxylase in hypothalamic neurons of the rat. J. Neurosci. 5:3393-3420; 1985. 47. Staines, W. A.; Daddona, P. E.; Nagy, J. I. The organization and hypothalamic projections of the tuberomammillary nucleus in the rat: an imrnunocytochemical study of adenosine deaminase positive neurons and fibers. Neuroscience 23:.571-596; 1987. 48. Steinbusch. H. W. M.; Mulder, A. H. Immunohistochemical localization of histamine in neurons and mast cells in the rat brain. In: Bjarklund, A.; HBkfelt, T.; Kuhar, M. J., eds. Classical transmitters and transmitter receptors in the CNS, Part II, handbook of chemical neuroanatomy. Amsterdam: Elsevier; 1984: 126-140. 49. Steinbusch, H. W. M.; Sauren, Y.; Groenwegen, H.; Watanabe, T.; Mulder, A. H. Histaminergic projections from the premammillary and posterior hypothalamus region to the caudate putamen complex in the rat. Brain Res. 368:389-393; 1986. 50. Taguchi, Y.; Watanabe, T.; Kubota, H.; Hayashi, H.; Wada, HPurification of histidine decarboxylase from the liver of fetal rats and its immunochemical and immunohistochemical characterization. J.
WADA
E?’ AL.
Biol. Chem. 259:5214-5221; 1984. 51. Takagi, H.; Morishima, Y.; Matsuyama, T.; Hayaslu, H.; Watanabe. T.: Wada. H. Histaminergic axons in the neostriatum and cerebral cortex of the rat: a correlated light and electron microscope unrnunocytochemical study using histidine decarboxylase as a marker. Brain Res. 364:114-123: 1986. 52. Takeda. N.; lnagaki, S.; Shiosaka, S.; Taguchi, Y.; Oertel, W. H.; Tohyama. M.: Watanabe. T.: Wada, H. Immunocytochemical evidence for the coexistence of histidine decarboxylase-like and gluamate decarboxylase-like immunoreactivities in nerve cells of the posterior magnocellular nucleus of the hypothalamus of rats. Proc. Natl. Acad. Sci. USA 81:7647-7650; 1984. 53. Takeda. N.; Inagaki, S.; Taguchi. Y.; Tohyama, M.; Watanabe, T.; Wada, H. Origins of histamine containing fibers in the cerebral cortex of rats studied by immunohistochemistry with histidine decarboxylase as a marker and transection. Brain Res. 323:55-63: 1984, 54. Tamiya, R.; Hanada, M.; Narita, N.; Kawai, Y.: Tohyama, M.; Takagi. H. Neuropeptide Y afferents have synaptic intereactions with histaminergic (histidine decarboxylase-immunoreactive) neurons in the rat brain. Neurosci. Lett. 99:241-245; 1989. 55. Tamiya, R.; Hanada. M.; Kawai. Y.; Narita, N.; lnagaki, S.; Tohyama, M.; Takagi. H. Histaminergic neurons receive substance P-ergic inputs in the posterior hypothalamus. Esp. Brain Res. 79: 261-265; 1990. 56. Tasaka, K.; Chung, Y. H.; Sawada, K.; Mio, M. Excitatory effect of histamine on the arousal system and its inhibition by H, blockers. Brain Res. Bull. 22:271-275; 1989. 57. Tuominen, R. K.; Mattila, J.: MlnnistG, P. T. Inhibition of the TSH secretion by histamine in male rats. Acta Endocrinol. (Copenh.) 103:88-94; 1983. 58. Toumisto. L.; Eriksson, L.; Fyhrquist, F. Vasopressin release by histamine in the conscious goat. Eur. J. Pharmacol. 63: 15-24; 1980. 59. Wada, H.; Watanabe, T.: Yamatodani, A.; Maeyama, K.; Itoi, N.; Cacabelos, R.: Seo, M.; Kiyino, S.; Nagai, K.; Nakagawa, H. Physiological functions of histamine in the rat brain. In: Ganellin. C. R.: Schwartz. J. C., eds. Frontiers in histamine research. Advance in the biosciences. vol. 51, Oxford: Pergamon; 1985:225235. 60. Watanabe, T.; Taguchi, Y .; Hayashi, H.; Tanaka, J,; Shiosaka, S.: Tohyama, M.; Kubota, H.; Terano, T.; Wada, H. Evidence for the presence of a histaminergic neuron system in the rat brain: an immunocytochemical analysis. Neurosci. Lett. 39:249-254; 1983. 61. Watanabe, T.; Taguchi, Y.; Shiosaka, S.; Tanaka, J.; Kubota, H.; Terano, Y.; Tohyama, M.; Wada, H. Distribution of the histaminergic neuron system in the central nervous system of rats: a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Res. 295:13-25: 1984. 62. Watanabe, T.; Yamatodani, A.; Maeyama, K.; Wada, H. Pharmacology of a-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. Trends Pharmacol. Sci. 11:363-367; 1990. 63. Wouterlood. F. G.; Steinbusch, H. W. M.; Luiten, P. G. M.: Bol, J. G. J. M. Projection from the prefrontal cortex to histaminergic cell groups in the posterior hypothalamic region of the rat. Anterograde tracing with Phaseolus vulgaris-leucoagglutinin (PHA-LJ combined with immunocytochemistry of histidine decarboxylase. Brain Res. 406:330-336; 1987. 64. Wouterlood, F. G.; Gaykema, R. P. A. Innervation of histaminergic neurons in the posterior hypothalamic region by medial prooptic nucleus: Anterograde tracing with Phaseolus vulgaris-leucoagglutinin combined with immunocytochemistry of histidine decarboxylase in the rat. Brain Res. 455:170-176; 1988. 65. Wouterlood, F. G.; Gaykema, R. P. A.; Steinbusch, H. W. M.; Watanabe, T.; Wada, H. The connections between the septum-diagonal band complex and histaminergic neurons in the posterior hypothalamus of the rat. Anterograde tracing with Phaseolus vulgarisleucoagglutinin combined with immunocytochemistry of histidine decarboxylase. Neuroscience 26:827-845; 1988. 66. Yamatodani, A.; Inagaki, N.; Panula, P.; Itowi, N.; Watanabe, T.; Wada, H. Structure and functions of the histaminergic neuron system. In: Uvnls, B., ed. Histamine and histamine antagonist, handbook of experimental pharmacology, vol. 97. Berlin: SpringerVerlag; 1991:243-283.