22. 23. 24. 25.
V . G . Baranov, A. L. Polenov, M. V. Proni, et al., Fiziol. Zh. SSSR, No. I I , 1626 (1971). I. Barry, M. Dubois, and B. Carette, Endocrinology, 95, 1416 (1974). M . H . Meyer, J. E. Masken, T. M. Nett, et al., Neuroendocrinology, 1.55,32 (1974). A . O . Donoso and J. O. Cukier, Nature, 218, 969 (1968).
EFFECT
OF L - D O P A
ON PITUITARY
GONADOTROPIC
FUNCTION UDC 612.433.62.018.014.46 : 615 3 1 : 547.583.5
~. P . B e k h t e r e v a
The role of the brain catecholamines in the regulation of pituitary gonadotropic function has been widely discussed in the recent literature. In their earlier publications, Sawyer et al. [1] reported that the adrenoblocking drug dibenamine can prevent ovulation. Later, Barraclough and Sawyer [2, 3] showed that reserpine, which can exhaust the reserves of catecholamines and serotonin in the brain, blocked spontaneous ovulation and induced pseudopregnancy. Many investigations have confirmed the presence of noradrenalin and dopamine in the hypothalamus and, as has now been shown, their level varies under different physiological conditions connected with changes in gonadotropic secretion [4]. For instance, the concentration of noradrenalin in the hypothalamus and its secretion increase immediately after ovariectomy [5] and in the phase of proestrus [6]. Analysis of the mechanisms whereby catecholamines stimulate gonadotropin secretion has shown that noradrenalin and dopamine, as synaptic transmitters, activate the secretion of hypothalamic releasing factors, stimulating the secretion of gonadotropins: LH-RF and FSH-RF [7, 8]. Inview of the possible role of adrenergic mediation in gonadotropic secretion it is interesting to study the pharmacological agents influencing catecholamine reserves in the brain. This paper describes the study of the effect of the noradrenalin precursor L-dopa (L-3,4-dihydroxyphenylalanine) on the pituitary gonadotropic function of sexually immature female rats, young sexually mature rats with a normal sex cycle, and rats with spontaneous disturbances of the sex cycle and of ovulation. MATERIALS
AND
METHODS
In the experiments of series I sexually immature female rats were used; from the 19th to the 30th day of life they received daily subcutaneous injections of L-dopa in doses of 20 and I00 mg/kg. The time of vaginal opening was investigated in all rats. On the day of vaginal opening the rats were killed, and the bodyweight and the weight of the reproductive organs and the presence of ovulation were recorded. The brain was removed, the region of the median eminence and adjacent areas was excised, and the catecholamine content in it was determined by the method described by Anton and Sayre [9] and by Matlina and Rakhmanova [10].
In the experiments of series H administration of L-dopa in a dose of 20 mg/kg to sexually immature female rats weighing 80 g began about 12 days before sexual maturation and the compound continued to be given daily to the sexually mature young female rats for some time (total duration of administration 3-4 weeks). The time of vaginal opening, the dynamics of the sex cycle, and the level of luteinizing hormone (LH) in the pituitary gland was determined by Parlow's method [11]. Department of Pharmacol0gy, Institute of Experimental Medicine, Academy of Medical sciences of the USSR, Leningrad. Translated from Problemy ~ndokrinologii, Vol. 22, No. 5, pp. 50-54, July-August, 1976.
I This material is protected by copyright registered in the name of Plenum Publishing Corporation, 227 West 17th Street, New York, N.Y. 10011. No part'i of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, [ microfilming recording or otherwise without written permission o f the publisher. A copy of this article is available from the publisher for $ Z 50. I
211
TABLE 1. E f f e c t of L - d o p a on Body Weight, Weight of Reproductive Organs, T i m e of Sexual Maturation, and Catecholamine Level in Hypothalamus of Sexually I m m a t u r e F e m a l e Rats M s i n ) Time of = ~ = ~ IBodyweight (in g)lOrganweight (mg/lO0 g)] Catecholamines opening of 1 , ,,, (in, o'~ o ~ ! adrenalin ]noradrenai'in vagina and Prepa,ration img/kg) "~ ~'~ "~ ~ I initial final I ovary uterus [ Nofu mrats b e r of~)vulatio (in days) r
PhyMologicatsaline L-dopa P Physiological saline P L-dopa
IDose
130 136
12 IO0
12
40
131
12
40
122
87,0_+2,1 35,0_.+1,9 >0,05 33,0+ 1,2 >0,05 29_+1.4 >0,05
132,0_+11,0 123,0_+ 8,0 >0,05 t00• 5,0
20 t8
90• IO,O >0,05
10
45• 1.6 38• 1,5 0,05
0,2--+0,01 0,06• 0,007
LOS 25_+1,2 230_+12,0
8
201
32_+1,3
12
220
7
210
0,05
80 (11) 75-+3,2 90 (12,5)
4--5 4--5
29 16
68 79,8
3 4,2
isc t
45
5o
5
ISCz
35
59
6
50 (9)
--
80
15
5
0
4--5
32
64
4
0
1,66-+0.3
120-+ 10,0 0,5-- 0,08
V . G . Baranov, A. L. Polenov, M. V. Proni, et al., Fiziol. Zh. SSSR, No. I I , 1626 (1971). I. Barry, M. Dubois, and B. Carette, Endocrinology, 95, 1416 (1974). M . H . Meyer, J. E. Masken, T. M. Nett, et al., Neuroendocrinology, 1.55,32 (1974). A . O . Donoso and J. O. Cukier, Nature, 218, 969 (1968).
EFFECT
OF L - D O P A
ON PITUITARY
GONADOTROPIC
FUNCTION UDC 612.433.62.018.014.46 : 615 3 1 : 547.583.5
~. P . B e k h t e r e v a
The role of the brain catecholamines in the regulation of pituitary gonadotropic function has been widely discussed in the recent literature. In their earlier publications, Sawyer et al. [1] reported that the adrenoblocking drug dibenamine can prevent ovulation. Later, Barraclough and Sawyer [2, 3] showed that reserpine, which can exhaust the reserves of catecholamines and serotonin in the brain, blocked spontaneous ovulation and induced pseudopregnancy. Many investigations have confirmed the presence of noradrenalin and dopamine in the hypothalamus and, as has now been shown, their level varies under different physiological conditions connected with changes in gonadotropic secretion [4]. For instance, the concentration of noradrenalin in the hypothalamus and its secretion increase immediately after ovariectomy [5] and in the phase of proestrus [6]. Analysis of the mechanisms whereby catecholamines stimulate gonadotropin secretion has shown that noradrenalin and dopamine, as synaptic transmitters, activate the secretion of hypothalamic releasing factors, stimulating the secretion of gonadotropins: LH-RF and FSH-RF [7, 8]. Inview of the possible role of adrenergic mediation in gonadotropic secretion it is interesting to study the pharmacological agents influencing catecholamine reserves in the brain. This paper describes the study of the effect of the noradrenalin precursor L-dopa (L-3,4-dihydroxyphenylalanine) on the pituitary gonadotropic function of sexually immature female rats, young sexually mature rats with a normal sex cycle, and rats with spontaneous disturbances of the sex cycle and of ovulation. MATERIALS
AND
METHODS
In the experiments of series I sexually immature female rats were used; from the 19th to the 30th day of life they received daily subcutaneous injections of L-dopa in doses of 20 and I00 mg/kg. The time of vaginal opening was investigated in all rats. On the day of vaginal opening the rats were killed, and the bodyweight and the weight of the reproductive organs and the presence of ovulation were recorded. The brain was removed, the region of the median eminence and adjacent areas was excised, and the catecholamine content in it was determined by the method described by Anton and Sayre [9] and by Matlina and Rakhmanova [10].
In the experiments of series H administration of L-dopa in a dose of 20 mg/kg to sexually immature female rats weighing 80 g began about 12 days before sexual maturation and the compound continued to be given daily to the sexually mature young female rats for some time (total duration of administration 3-4 weeks). The time of vaginal opening, the dynamics of the sex cycle, and the level of luteinizing hormone (LH) in the pituitary gland was determined by Parlow's method [11]. Department of Pharmacol0gy, Institute of Experimental Medicine, Academy of Medical sciences of the USSR, Leningrad. Translated from Problemy ~ndokrinologii, Vol. 22, No. 5, pp. 50-54, July-August, 1976.
I This material is protected by copyright registered in the name of Plenum Publishing Corporation, 227 West 17th Street, New York, N.Y. 10011. No part'i of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, [ microfilming recording or otherwise without written permission o f the publisher. A copy of this article is available from the publisher for $ Z 50. I
211
TABLE 1. E f f e c t of L - d o p a on Body Weight, Weight of Reproductive Organs, T i m e of Sexual Maturation, and Catecholamine Level in Hypothalamus of Sexually I m m a t u r e F e m a l e Rats M s i n ) Time of = ~ = ~ IBodyweight (in g)lOrganweight (mg/lO0 g)] Catecholamines opening of 1 , ,,, (in, o'~ o ~ ! adrenalin ]noradrenai'in vagina and Prepa,ration img/kg) "~ ~'~ "~ ~ I initial final I ovary uterus [ Nofu mrats b e r of~)vulatio (in days) r
PhyMologicatsaline L-dopa P Physiological saline P L-dopa
IDose
130 136
12 IO0
12
40
131
12
40
122
87,0_+2,1 35,0_.+1,9 >0,05 33,0+ 1,2 >0,05 29_+1.4 >0,05
132,0_+11,0 123,0_+ 8,0 >0,05 t00• 5,0
20 t8
90• IO,O >0,05
10
45• 1.6 38• 1,5 0,05
0,2--+0,01 0,06• 0,007
LOS 25_+1,2 230_+12,0
8
201
32_+1,3
12
220
7
210
0,05
80 (11) 75-+3,2 90 (12,5)
4--5 4--5
29 16
68 79,8
3 4,2
isc t
45
5o
5
ISCz
35
59
6
50 (9)
--
80
15
5
0
4--5
32
64
4
0
1,66-+0.3
120-+ 10,0 0,5-- 0,08
