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Interaction of estradiol and 2-hydroxy-estradiol with histamine receptors at hypothalamic level
216
Brain Research, 187 (1980) 216 220 :(') Elsevier/North-Holland Biomedical Press
Interaction of estradiol and 2-hydroxy-estradiol with histamine receptors at hypothalamic level
PAOLO PORTALEONE, ENRICO GENAZZANI, GIUSEPPE PAGNINI, ANTONIO CR1SPINO and FRANCESCO DI CARLO Institute of Pharmacology, University of Turin, School of Medicine, Corso Raffaello 30, 10125 Turin (Italy)
(Accepted December 6th, 1979) Key words: estradiol - - histamine receptors -- hypothalamus - - 2-hydroxy-estradiol
On the basis of increasing biochemical, physiological and pharmacological evidence, many investigators tended to consider histamine as a putative neurotransmitter of the mammalian central nervous system 1,19,20. Recently histamine has been found to be a powerful stimulant of cAMP synthesis in the central nervous system, and develops its activity by interacting with two types of receptors, the so-called H1 and H2 receptors 2,s,13,19. Our group has also found a histamine-sensitive adenylate cyclase in homogenates of rat hypothalamus 18, where a mixed population of H1 and H2 receptors is present with a prevalence of H2 receptors. The stimulating effect of histamine was found to be greatest in hypothalamus from male rats, while a very modest stimulation of adenylate cyclase was observed in female rats. Other investigators have recently found that histamine interferes with the control of prolactin, vasopressin and gonadotrophin release a-5,l°. These and our own results strongly suggest the presence of some mutual correlations between histamine and hormones in the central nervous system. In order to verify whether the difference between the two sexes in the sensitivity of the hypothalamic adenylate cyclase was to be attributed to the hormonal make-up of the animals we evaluated the adenylate cyclase activity in hypothalamic membrane preparations of immature (30-day-old) and adult (at least 6 l-day-old) male and female rats in different hormonal conditions. Sprague-Dawley rats were killed by decapitation and the hypothalami were quickly removed according to Glowinski and Iversen 7. Hypothalamic membrane preparations and determinations of adenylate cyclase activity were performed according to the method of Krishna et alP, modified as described by Portaleone et al. is. The protein concentration was determined according to the method of Lowry et al.lL Incubations were carried out at 35 °C for 30 rain. The final volume was 1.2 ml in 40 mM Tris.HC1, pH 7.3, 3.3 mM MgSO4, 0.2 mM EGTA
217 2 mM theophylline, and contained 2 mg of protein and ATP at a concentration of 2 mM ([aH]ATP, 0.33 #Ci/ml). The reaction was stopped by addition of ZnSO4-Ba (OH)~. Cyclic AMP was purified by column chromatography on Dowex AG 50 W x 4,200-400 mesh, H + form. The radioactivity of Jail]cAMP was determined in the eluate with a LKB Wallac liquid scintillation counter. Table I shows that histamine cannot stimulate the hypothalamic adenylate cyclase of immature rats, whether male or female. This discrepancy between immature and adult male rats suggests that immature rats lack the substratum on which histamine acts in adult animals. In rats castrated when immature and sacrificed when adults (i.e. 31 days after the operation), histamine induces a powerful stimulating effect on the adenylate cyclase hypothalamic activity of both male and female rats. This result suggests that when ovarian hormones are removed histamine also acts in female rats. Taking account of these observations, we evaluated the sensitivity of hypothalamic adenylate cyclase of male rats castrated when immature and treated (since the twenty-first day after castration) with estradiol-17fl, 10 #g/kg/day for 10 days, and female rats ovariectomized when immature and treated (since the twenty-first day after ovariectomy) with methyl-testosterone-17a, 100/~g/kg/day for 10 days. The treatment with estradiol-17fl completely inhibits the histamine-induced stimulation of hypothalamic adenylate cyclase of castrated male rats, while the treatments with methyl-testosterone-17a cannot inhibit the histamine stimulating effect on hypothalamic preparations of ovariectomized female rats (Table I). TABLE I
Effect of histamine on the hypothalamic adenylate cyclase activity of rats Values represent a mean of 6 determinations 4- S.E.
Concentration of histamine (mol/litre) Adults 10-7 10-6 10-5 Immatures 10-6 10-5 Adults castrated when immature 10-6 10-5 Castrated + estradiol 10-5 Ovariectomized + methyltestosterone 10-5 * P < 0.01 in respect to basal values.
nmoles cAMP/mgprotein/30 min Male
Female
0.92 1.84 2.98 3.02 0.78 0.84 0.71 0.91 2.23 3.16 0.93 1.05
1.09 0.94 1.11 1.42 0.85 0.94 0.91 0.98 2.87 2.78
4- 0.13 i 0.21" ± 0.33* 4- 0.27* 4- 0.08 4- 0.13 4- 0.08 4- 0.09 4- 0.24* 4- 0.27* 4- 0.14 4- 0.19
4- 0.09 + 0.12 4- 0.15 4- 0.19 4- 0.12 4- 0.15 -4- 0.11 4- 0.13 4- 0.21 * 4- 0.19"
0.89 -4- 0.11 2.94 4- 0.33*
218
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Fig. 1. A: in vitro action of 2-hydroxy-estradiol (O-----@), estradioi-17fl (O ©), progesterone (A A) or methyl-testosterone 17-a (A A) on hypothalamic adenylate cyclase activity of female ovariectomized rats. Dotted area = basal values ± S.E. B : in vitro action of 2-hydroxy-estradiol. (0 @), estradiol-17fl (O O), progesterone (A A) or methyl-testosterone 17-a (A £) on hypothalamic adenytate cyclase activity of female ovariectomized rats stimulated by histamine. The dotted area on the top represents the basal hypothalamic adenylate cyclase activity stimulated by histamine 1 x 10 5 M. Each value represents a mean of 5 determinations ~z S.E. These results further support the conclusion that estrogens play an inhibiting role in the development of the histamine-sensitive adenylate cyclase. They also seem to confirm a possible interaction between estrogens and histaminergic receptors in central nervous system. In recent years, there has been increasing evidence of the leading role of the hydroxylated derivatives of estrogens (so-called catechol estrogens) 6,15,17, especially in relation to the control of gonadotrophin release at hypothalamic level6,12,14. One is led to speculate that estrogens can also act on the hypothalamic histaminergic system after metabolization to catechol estrogens. Consequently, we compared the effects in vitro of estradiol, 2-hydroxy-estradiol and other hormonal compounds on hypothalamic adenylate cyclase obtained from adult female rats ovariectomized when immature. Fig. I shows the strong stimulation of hypothalamic adenylate cyclase produced by estradiol and 2-hydroxy-estradiol; no significant variation is produced by testosterone and progesterone. Fig. 1 also shows that both the catechol estrogen and estradiol inhibit the histamine-induced stimulation, while the catechol estrogen produces a stronger effect. These results indicate that the inhibiting effect of estrogens on the hypothalamic histamine-sensitive adenylate cyclase is undoubtedly due to a direct activity.
219 D o n o s o et al.4, 5 observed a h i s t a m i n e - i n d u c e d s t i m u l a t i o n o f luteinizing h o r m o n e ( L H ) release o n b o t h p r o e s t r o u s a n d o v a r i e c t o m i z e d e s t r a d i o l - p r o g e s t e r o n e p r i m e d rats, b u t n o t in ovariectomized female rats n o r in intact or c a s t r a t e d e s t r o g e n - p r o g e s t e r o n e p r i m e d male rats. O u r results show an opposite p a t t e r n in c o m p a r i s o n with those o f D o n o s o et al.4, 5. I n fact when D o n o s o et al. 4,5 observed a histamine s t i m u l a t o r y a c t i o n o n release o f L H , we saw an inactivity o f a d e n y l a t e cyclase, a n d when they showed a failure o f the s t i m u l a t o r y effect o f histamine on L H release, we f o u n d a s t i m u l a t i o n o f adenylate cyclase. Therefore we m a y r e a s o n a b l y assume t h a t histamine is involved in the regulation o f g o n a d o t r o p h i n s . O n the other hand, the estrogens, p a r t i c u l a r l y the catechol estrogens, seem to interfere with the histamine receptors at h y p o t h a l a m i c level in the c o n t r o l o f g o n a d o t r o p h i n secretion. The a u t h o r s t h a n k Dr. F. N e u m a n n , Schering A. G., Berlin, for his kind gift o f 2-hydroxy-estradiol.
1 Barchas, J. D., Akil, H., Elliott, G. R., Holman, R. B. and Watson, S. J., Behavioral neurochemistry: neuroregulatory and behavioral states, Science, 200 (1978) 964-973. 2 Dismukes, K., Rogers, M. and Daly, J. W., Cyclic adenosine 3',5'-monophosphate formation in guinea-pig brain slices: effect of H1- and H2-histaminergic agonists, J. Neurochem., 26 (1976) 785-790. 3 Dogterom, J., Van Wimersma Greidanus, Tj. B. and DeWied, D., Histamine as an extremely potent releaser of vasopressin in the rat, Experientia (Basel), 32 (1976) 659-660. 4 Donoso, A. O., Induction of prolactin and luteinizing hormone release by histamine in male and female rats and the influence of brain transmitter antagonists, J. Endocr., 76 (1978) 193-202. 5 Donoso, A. O. and Banzan, A. M., Failure of histamine to induce the release of luteinizing hormone in castrated rats primed with sex steroids, J. Endocr., 78 (1978) 447-448. 6 Fishman, J., The catechol estrogens, Neuroendocrinology, 22 (1976) 369-374. 7 Glowinski, I. and Iversen, L. L., Regional studies of catecholamines in the rat brain - - I, J. Neurochem., 13 (1966) 655-669. 8 Hegstrand, L. R., Kanof, P. D. and Greengard, P., Histamine-sensitive adenylate cyclase in mammalian brain, Nature (Lond.), 260 (1976) 163-165. 9 Krishna, G., Weiss, B. and Brodie, B. B., A simple, sensitive method for the assay of adenyl cyclase, J. Pharmacol. exp. Ther., 163 (1968) 379-385. I0 Libertum, C. and McCann, S. M., The possible role of histamine in the control of prolactin and gonadotropin release, Neuroendocrinology, 20 (1976) 110-120. 11 Lowry, O. H., Rosebrough, N. J., Farr, A. L. and Randall, R. J., Protein measurement with the Folin phenol reagent, J. biol. Chem. 193 0951) 265-275. 12 Naftolin, F., Morishita, H., Davies, I. J., Todd, R., Ryan, K. J. and Fishman, J., 2-Hydroxyestrone induced rise in serum luteinizing hormone in the immature male rats, Biochem. biophys. Res. Comm., 64 (1975) 905-910. 13 Nahorski, S. R., Rogers, K. J. and Smith, B. M., Stimulation of cyclic adenosine 3',5'-monophosphate in chick cerebral hemisphere slices: effects of H1 and H2 histaminergic agonists and antagonists, Brain Research, 126 (1977) 387-390. 14 Parvizi, N. and Ellendorf, F., 2-hydroxy-oestradiol-17fl as a possible link in steroid brain interaction, Nature (Lond.), 256 (1975) 59-60. 15 Paul, S. M. and Axelrod, J., Catechol estrogens : presence in brain and endocrine tissues, Science, 197 (1977) 657-659. 16 Paul, S. M. and Axelrod, J., Catechol estrogens: localization, formation and actions in brain and other estrogen sensitive tissues. In, E. Genazzani, P. J. W. Mainwaring and F. Di Carlo (Eds.), Pharmacological Modulation of Steroid Action, Raven Press, New York, 1980, in press.
220 17 Paul, S. M. and Skolnick, P., Catechol oestrogens inhibit oestrogen elicited accumulation of hypothalamic cyclic AMP suggesting role as endogenous antioestrogens, Nature (Lond.), 266 (1977) 559-561. 18 Portaleone, P., Pagnini, G., Crispino, A. and Genazzani, E., Histamine-sensitive adenylate cyclase in hypothalamus of rat brain: H1 and H2 receptors, J. Neurochem., 31 (1978) 1371-1374. 19 Schwartz, J. C., Histaminergic mechanism in brain, Ann. Rev. Pharmacol. Toxicol., 17 (1977) 325-339. 20 Taylor, K. M., Brain histamine. In L. L. Iversen, S. D. Iversen and S. H. Snyder (Eds.), Handbook ofPsyehopharmacology, Vol. 3, Plenum Press, New York, 1975, pp. 327-379.
Brain Research, 187 (1980) 216 220 :(') Elsevier/North-Holland Biomedical Press
Interaction of estradiol and 2-hydroxy-estradiol with histamine receptors at hypothalamic level
PAOLO PORTALEONE, ENRICO GENAZZANI, GIUSEPPE PAGNINI, ANTONIO CR1SPINO and FRANCESCO DI CARLO Institute of Pharmacology, University of Turin, School of Medicine, Corso Raffaello 30, 10125 Turin (Italy)
(Accepted December 6th, 1979) Key words: estradiol - - histamine receptors -- hypothalamus - - 2-hydroxy-estradiol
On the basis of increasing biochemical, physiological and pharmacological evidence, many investigators tended to consider histamine as a putative neurotransmitter of the mammalian central nervous system 1,19,20. Recently histamine has been found to be a powerful stimulant of cAMP synthesis in the central nervous system, and develops its activity by interacting with two types of receptors, the so-called H1 and H2 receptors 2,s,13,19. Our group has also found a histamine-sensitive adenylate cyclase in homogenates of rat hypothalamus 18, where a mixed population of H1 and H2 receptors is present with a prevalence of H2 receptors. The stimulating effect of histamine was found to be greatest in hypothalamus from male rats, while a very modest stimulation of adenylate cyclase was observed in female rats. Other investigators have recently found that histamine interferes with the control of prolactin, vasopressin and gonadotrophin release a-5,l°. These and our own results strongly suggest the presence of some mutual correlations between histamine and hormones in the central nervous system. In order to verify whether the difference between the two sexes in the sensitivity of the hypothalamic adenylate cyclase was to be attributed to the hormonal make-up of the animals we evaluated the adenylate cyclase activity in hypothalamic membrane preparations of immature (30-day-old) and adult (at least 6 l-day-old) male and female rats in different hormonal conditions. Sprague-Dawley rats were killed by decapitation and the hypothalami were quickly removed according to Glowinski and Iversen 7. Hypothalamic membrane preparations and determinations of adenylate cyclase activity were performed according to the method of Krishna et alP, modified as described by Portaleone et al. is. The protein concentration was determined according to the method of Lowry et al.lL Incubations were carried out at 35 °C for 30 rain. The final volume was 1.2 ml in 40 mM Tris.HC1, pH 7.3, 3.3 mM MgSO4, 0.2 mM EGTA
217 2 mM theophylline, and contained 2 mg of protein and ATP at a concentration of 2 mM ([aH]ATP, 0.33 #Ci/ml). The reaction was stopped by addition of ZnSO4-Ba (OH)~. Cyclic AMP was purified by column chromatography on Dowex AG 50 W x 4,200-400 mesh, H + form. The radioactivity of Jail]cAMP was determined in the eluate with a LKB Wallac liquid scintillation counter. Table I shows that histamine cannot stimulate the hypothalamic adenylate cyclase of immature rats, whether male or female. This discrepancy between immature and adult male rats suggests that immature rats lack the substratum on which histamine acts in adult animals. In rats castrated when immature and sacrificed when adults (i.e. 31 days after the operation), histamine induces a powerful stimulating effect on the adenylate cyclase hypothalamic activity of both male and female rats. This result suggests that when ovarian hormones are removed histamine also acts in female rats. Taking account of these observations, we evaluated the sensitivity of hypothalamic adenylate cyclase of male rats castrated when immature and treated (since the twenty-first day after castration) with estradiol-17fl, 10 #g/kg/day for 10 days, and female rats ovariectomized when immature and treated (since the twenty-first day after ovariectomy) with methyl-testosterone-17a, 100/~g/kg/day for 10 days. The treatment with estradiol-17fl completely inhibits the histamine-induced stimulation of hypothalamic adenylate cyclase of castrated male rats, while the treatments with methyl-testosterone-17a cannot inhibit the histamine stimulating effect on hypothalamic preparations of ovariectomized female rats (Table I). TABLE I
Effect of histamine on the hypothalamic adenylate cyclase activity of rats Values represent a mean of 6 determinations 4- S.E.
Concentration of histamine (mol/litre) Adults 10-7 10-6 10-5 Immatures 10-6 10-5 Adults castrated when immature 10-6 10-5 Castrated + estradiol 10-5 Ovariectomized + methyltestosterone 10-5 * P < 0.01 in respect to basal values.
nmoles cAMP/mgprotein/30 min Male
Female
0.92 1.84 2.98 3.02 0.78 0.84 0.71 0.91 2.23 3.16 0.93 1.05
1.09 0.94 1.11 1.42 0.85 0.94 0.91 0.98 2.87 2.78
4- 0.13 i 0.21" ± 0.33* 4- 0.27* 4- 0.08 4- 0.13 4- 0.08 4- 0.09 4- 0.24* 4- 0.27* 4- 0.14 4- 0.19
4- 0.09 + 0.12 4- 0.15 4- 0.19 4- 0.12 4- 0.15 -4- 0.11 4- 0.13 4- 0.21 * 4- 0.19"
0.89 -4- 0.11 2.94 4- 0.33*
218
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.~ 24J 0 O~ ~D E
< D
-.-.-. -.-.-.-.-.-.-.-.-.~ -.-.%-.-.-.-.-.-.-.-.-. •.°°° .o.°°%°°o°O°.o°...o°° ,°°O.°o..°o.°°°°.°o°.Oo
I.I.:-:.:.:.:.:.:.:.:.:-:-:-:-:-:-:.:.X.I.:.:-2.
m
0 E
O_
A
8 I
I
~
I
~
I
~
,
~
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log M/I
Fig. 1. A: in vitro action of 2-hydroxy-estradiol (O-----@), estradioi-17fl (O ©), progesterone (A A) or methyl-testosterone 17-a (A A) on hypothalamic adenylate cyclase activity of female ovariectomized rats. Dotted area = basal values ± S.E. B : in vitro action of 2-hydroxy-estradiol. (0 @), estradiol-17fl (O O), progesterone (A A) or methyl-testosterone 17-a (A £) on hypothalamic adenytate cyclase activity of female ovariectomized rats stimulated by histamine. The dotted area on the top represents the basal hypothalamic adenylate cyclase activity stimulated by histamine 1 x 10 5 M. Each value represents a mean of 5 determinations ~z S.E. These results further support the conclusion that estrogens play an inhibiting role in the development of the histamine-sensitive adenylate cyclase. They also seem to confirm a possible interaction between estrogens and histaminergic receptors in central nervous system. In recent years, there has been increasing evidence of the leading role of the hydroxylated derivatives of estrogens (so-called catechol estrogens) 6,15,17, especially in relation to the control of gonadotrophin release at hypothalamic level6,12,14. One is led to speculate that estrogens can also act on the hypothalamic histaminergic system after metabolization to catechol estrogens. Consequently, we compared the effects in vitro of estradiol, 2-hydroxy-estradiol and other hormonal compounds on hypothalamic adenylate cyclase obtained from adult female rats ovariectomized when immature. Fig. I shows the strong stimulation of hypothalamic adenylate cyclase produced by estradiol and 2-hydroxy-estradiol; no significant variation is produced by testosterone and progesterone. Fig. 1 also shows that both the catechol estrogen and estradiol inhibit the histamine-induced stimulation, while the catechol estrogen produces a stronger effect. These results indicate that the inhibiting effect of estrogens on the hypothalamic histamine-sensitive adenylate cyclase is undoubtedly due to a direct activity.
219 D o n o s o et al.4, 5 observed a h i s t a m i n e - i n d u c e d s t i m u l a t i o n o f luteinizing h o r m o n e ( L H ) release o n b o t h p r o e s t r o u s a n d o v a r i e c t o m i z e d e s t r a d i o l - p r o g e s t e r o n e p r i m e d rats, b u t n o t in ovariectomized female rats n o r in intact or c a s t r a t e d e s t r o g e n - p r o g e s t e r o n e p r i m e d male rats. O u r results show an opposite p a t t e r n in c o m p a r i s o n with those o f D o n o s o et al.4, 5. I n fact when D o n o s o et al. 4,5 observed a histamine s t i m u l a t o r y a c t i o n o n release o f L H , we saw an inactivity o f a d e n y l a t e cyclase, a n d when they showed a failure o f the s t i m u l a t o r y effect o f histamine on L H release, we f o u n d a s t i m u l a t i o n o f adenylate cyclase. Therefore we m a y r e a s o n a b l y assume t h a t histamine is involved in the regulation o f g o n a d o t r o p h i n s . O n the other hand, the estrogens, p a r t i c u l a r l y the catechol estrogens, seem to interfere with the histamine receptors at h y p o t h a l a m i c level in the c o n t r o l o f g o n a d o t r o p h i n secretion. The a u t h o r s t h a n k Dr. F. N e u m a n n , Schering A. G., Berlin, for his kind gift o f 2-hydroxy-estradiol.
1 Barchas, J. D., Akil, H., Elliott, G. R., Holman, R. B. and Watson, S. J., Behavioral neurochemistry: neuroregulatory and behavioral states, Science, 200 (1978) 964-973. 2 Dismukes, K., Rogers, M. and Daly, J. W., Cyclic adenosine 3',5'-monophosphate formation in guinea-pig brain slices: effect of H1- and H2-histaminergic agonists, J. Neurochem., 26 (1976) 785-790. 3 Dogterom, J., Van Wimersma Greidanus, Tj. B. and DeWied, D., Histamine as an extremely potent releaser of vasopressin in the rat, Experientia (Basel), 32 (1976) 659-660. 4 Donoso, A. O., Induction of prolactin and luteinizing hormone release by histamine in male and female rats and the influence of brain transmitter antagonists, J. Endocr., 76 (1978) 193-202. 5 Donoso, A. O. and Banzan, A. M., Failure of histamine to induce the release of luteinizing hormone in castrated rats primed with sex steroids, J. Endocr., 78 (1978) 447-448. 6 Fishman, J., The catechol estrogens, Neuroendocrinology, 22 (1976) 369-374. 7 Glowinski, I. and Iversen, L. L., Regional studies of catecholamines in the rat brain - - I, J. Neurochem., 13 (1966) 655-669. 8 Hegstrand, L. R., Kanof, P. D. and Greengard, P., Histamine-sensitive adenylate cyclase in mammalian brain, Nature (Lond.), 260 (1976) 163-165. 9 Krishna, G., Weiss, B. and Brodie, B. B., A simple, sensitive method for the assay of adenyl cyclase, J. Pharmacol. exp. Ther., 163 (1968) 379-385. I0 Libertum, C. and McCann, S. M., The possible role of histamine in the control of prolactin and gonadotropin release, Neuroendocrinology, 20 (1976) 110-120. 11 Lowry, O. H., Rosebrough, N. J., Farr, A. L. and Randall, R. J., Protein measurement with the Folin phenol reagent, J. biol. Chem. 193 0951) 265-275. 12 Naftolin, F., Morishita, H., Davies, I. J., Todd, R., Ryan, K. J. and Fishman, J., 2-Hydroxyestrone induced rise in serum luteinizing hormone in the immature male rats, Biochem. biophys. Res. Comm., 64 (1975) 905-910. 13 Nahorski, S. R., Rogers, K. J. and Smith, B. M., Stimulation of cyclic adenosine 3',5'-monophosphate in chick cerebral hemisphere slices: effects of H1 and H2 histaminergic agonists and antagonists, Brain Research, 126 (1977) 387-390. 14 Parvizi, N. and Ellendorf, F., 2-hydroxy-oestradiol-17fl as a possible link in steroid brain interaction, Nature (Lond.), 256 (1975) 59-60. 15 Paul, S. M. and Axelrod, J., Catechol estrogens : presence in brain and endocrine tissues, Science, 197 (1977) 657-659. 16 Paul, S. M. and Axelrod, J., Catechol estrogens: localization, formation and actions in brain and other estrogen sensitive tissues. In, E. Genazzani, P. J. W. Mainwaring and F. Di Carlo (Eds.), Pharmacological Modulation of Steroid Action, Raven Press, New York, 1980, in press.
220 17 Paul, S. M. and Skolnick, P., Catechol oestrogens inhibit oestrogen elicited accumulation of hypothalamic cyclic AMP suggesting role as endogenous antioestrogens, Nature (Lond.), 266 (1977) 559-561. 18 Portaleone, P., Pagnini, G., Crispino, A. and Genazzani, E., Histamine-sensitive adenylate cyclase in hypothalamus of rat brain: H1 and H2 receptors, J. Neurochem., 31 (1978) 1371-1374. 19 Schwartz, J. C., Histaminergic mechanism in brain, Ann. Rev. Pharmacol. Toxicol., 17 (1977) 325-339. 20 Taylor, K. M., Brain histamine. In L. L. Iversen, S. D. Iversen and S. H. Snyder (Eds.), Handbook ofPsyehopharmacology, Vol. 3, Plenum Press, New York, 1975, pp. 327-379.