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Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats
Neuropharmacology vol. 19, pp. 923
to 926 Printed in Great Britain Pergamon Press Ltd 1980.
CHA~CTERIZATION OF THE STRIATAL SUPERSENSITIVITY PRODUCED BY ESTROGEN
Robert
E. Hruska,
Lynn M. Ludmer,
DOPAMINE RECEPTOR TREATMENT OF MALE RATS
and Ellen K. Silbergeld
Neurotoxicology Section NINCDS, NIH Building 36, Room 4A22 Bethesda, MD 20205
(Accep.&d
20 June
19801
SUMMARY Estrogen treatment of male rats produced an increase in the number of striatal dopamine receptors, without altering their This effect only occurs in vivo and has a slow onset. affinity. Only the 6-diastereomer of 17-estradiol was active. Other striatal receptors appeared to be unchanged as was the presynaptic uptake of dopamine. Hypophysectomy completely blocked the response to estrogen as measured on striatal dopamine receptors and on stereotypy, a behavior associated with striatal dopamine receptor stimuThese results are relevant to the clinical observations lation. of chorea associated with the use of oral contraceptives or with pregnancy. INTRODUCTIONS There is mounting evidence that hormones of pituitary and gonadal origin have effects on non-hypothalamic areas of the central nervous system. The sex hormones have been of particular interest because of the identification of nuclear and cytoplasmic cellular receptors in other areas of the brain, and because many chemicals have estrogenic properties Recently, we reported that estrogen treatment of male rats resulted in an increase in the number of striatal dopamine (DA) receptors and in an increase of two behaviors associated with striatal DA receptor stimulation -- stereotypy, and rotation after unilateral nigrostriatal lesions (Hruska and Silbergeld, 1980a, b). These results are consistent with other reports that ovariectomy of guinea pigs decreased stereotypy (Nausieda, Koller, Weiner, and Klawans, 1979a), and ovariectomy of rats decreased DA-stimulated adenylate cyclase activity (Kumakura, Hoffman, Cocchi, Trabucchi, Spano, and Muller, 1979). Administration of estrogen reversed both of these decreases. Stereotypy has also been reported to be increased after estrogen treatment of ovariectomized rats (La1 and Sourkes, 1972; Chiodo, Caggiula, and Saller, 1979). These results have potentially important implications for clinical applications. There are unusual but significant findings of chorea associated with pregnancy or the use of oral contraceptives (Nausieda, Koller, Weiner, and Klawans, 1979b; ~naldson, 1978; Bickerstaff, 1975). This report further explores and characterizes the DA receptor supersensitivity produced by estrogen treatment of male rats. METHODS Male, Sprague-Dawley rats (250-300 g) were purchased from Taconic Farms. The rats were injected subcutaneously (0.1 ml) in the neck with 125 vg of 17B-estradiol valerate in sesame oil, or 125 pg of 17u-estradiol in sesame oil. Hypophysectomized male, SpragueDawley rats (250-300 g) were purchased from Taconic Farms and Charles River. These rats were given drinking water which contained 5% dextrose and an electrolyte mixture of 203 mg% NaCl, 8.3 mg% KCl, 3.5 mg% CaClz, and 1.7 mg% MgClz, Four to five days after hypophysectomy, the rats were injected with estrogen as described above. At the conclusion of the experiments, the skulls of the hypophysectomized rats were visually inspected to insure removal of the pituitary. A17 experiments, other than the time course, were performed 6 days after estrogen treatment. Stereotypy and striatal DA receptor analyses were performed as previously described (Hruska and Silbergeld, 1980a). Muscarinic cholinergic receptor analyses were performed using C3H1-IIquinuclidinyl benzilate (C3HI-l_-QNB), benzodiazepine receptor analyses were performed using ["HI-flunitrazepam, and cc-noradrenergic receptor analyses were performed using [3~1-~~.4101.
923
924
Preliminary Notes
For in vitro experiments, 178-estradiol was dissolved In ethanol and diluted in distilled water so that the final ethanol concentration in the incubation medium was less than 0.071, a level which does not alter [3H]-spiroperidol binding. Transport experiments were performed using a synaptosomal Pz suspension in a Kreb's-Ringer buffer. Sodium-deoendent transport was calculated by subtracting the transport in the absence of sodium from that in the presence of sodium. RESULTS The time course of the increase in striatal DA receptors after estrogen treatment is shown in Fig. 1. Not until three days after estrogen treatment was there a significant increase in the number of receptors. The maximum 20% increase was reached on day 4 and persisted through day 7. By day 11 the number of receptors had declined to levels not At no time point did the estrogen treatment alter significantly diferent from controls. the affinity of [3H]-spiroperidol for the DA receptor. The increase in the number of striatal DA receptors was only observed in vivo. The binding of [3H]-spiroperidol was not altered by the.in vitro addition of 17B-estradiol at concentrations from 1.0 nM to 3.3 PM. Also, the in vitro addition of 1.32 IIM 17sestradiol did not alter the inhibition of [3H]-spiroperidol binding produced by a agonist (DA) or an antagonist ((+)butaclamol). The specificity of the in vivo increase in striatal DA receptors was explored further. The injection of the CL and B-diastereomers of 17-estradiol showed that only the s-diastercomer produced an increase in the number of receptors (Table 1). Neither diastereomer altered the affinity of [3H]-spiroperidol for the receptor. Several other receptors in the striatum were measured after in vivo treatment with 170-estradiol to determine the specificity of the receptor increase. The numbers and the affinities of the muscarinic cholinergic ([3H]-l-Q~B), benzodiazepine ([3H]-flunitrazepam), and a-noradrenergic ([3H]-WB.4101) receptors were not changed by estrogen treatment (Table 1). The specificity of the effect on DA receptors was also analysed by measuring DA transThe high affinity uptake of DA at a port into synaptosomes prepared from the striatum. concentration of 0.388 UM was not altered by in vivo estrogen treatment. The role of the pituitary in the effect of estrogen was investigated. Hypophysectomy of male rats before estrogen treatment completely prevented an estrogen-induced increase in the number of striatal DA receptors (Table 1). Also, the stereotypy produced by DA agonist 4 mg/kg) was not altered in hypophysectomized male treatment (apomorphine hydrochloride, rats after estrogen treatment (Fig. 2). Therefore, neither the biochemical nor the behavioral effects of estrogen on striatal DA receptors occur after pituitary removal.
TIME IDAYSI
Fig. 1. Time course of the increase in the maximum [3H]-spiroperidol binding to striatal DA receptors after in viva injection of 17a-estradiol valerate. Each point is the mean f SEM of the oercent chanse in the maximum binding. Analyses were performed on tissue-from control and 17B-estradiol valerate treated rats at 10 concentrations of T3H]-soiroperidol and analvsed by linear regression analyses of_Scatchard‘plots. The shaded area represents the variation in the maximum binding averaged from the control values at each time point. *P < 0.05 by Student's time point.
5 test, compared
to the control
at that
925
Preliminary Notes
Time (mid
Fig. 2, Effect of apomorphine hydrochloride (4 mgfkg) on stereotypy scores of hypophysectomizedrats, without (CON) or with 17f+estradiol valerate (EDV) treatment. Each point is the mean f SEM of 11 CON or 13 EDV treated rats.
DISCUSSION .
The time course of the development and decline of the striatal DA receptor supersensltivity is slow. Normally, experiments were performed 6 days after treatment, a time at which the striatal DA receptors are maximally increased. The slow time course of the supersensitivity and the lack of affinity change argue against a conformational alteration or a change in the state of the receptors, and suggest that estrogen is activating synthesis of new receptors, which involves a genomic effect. The slow time course corresponds with the clinical observations of the chorea associated with oral contraceptives (Barber, Arnold, and Evans, t976). This chorea takes several days or weeks to develop after starting the medication and also takes several days or weeks to disappear after cessation of treatment. The increase in DA receptors is a specific in vivo response, as expected from a slow development of the supersensitivity. The in vitro addition of 17@-estradiol does not directly affect the binding of [3H]-spiroperidol,even at a high concentration of estrogen (3.3 uM). The [3H]-spiroperidolbinding was inhibited by an agonist and antagonist: the inhibition was equal in the presence or absence of 17@-estradiol. Therefore, 17B-estradioi does not have a specific modulatory function on the inhibition of binding by an agonist or an antagonist of the DA receptor.
TABLE 1 Specificity of Estrogen in vivo on Striatal Neurotransmitter Receptors in Male Rats Injected Six Days Previously Liqand
Treatment
!!
Kd (PM)
Bmax (fmole/mg protein)
[jH]-spiroperidol
Control 17cr-estradiol 17B-estradiol
6 :
16.5 + 1.3 16.6 i:1.4 17.3 + 2.4
427 i:18 428 + 18 508 i 30
___ +0.2 +19.0*
[3Hl-1-QNB
Control 17~-estradiol
Z
25.6 * 6.1 26.1 f 6.7
1372 +_106 1390 _+105
_-t1.3
[3H]-flunitrazepam
Control 17B-estradiol
3 3
1820 ?:230 1890 ? 300
691 + 44 683 ?:55
___ -1.2
r3H]-WB.410t
Control 176-estradiol
Z
109 t 9 98 ?:20
60.7 i 2.5 60.8 ?Z5.8
-__ +0.1
[3H]-spiroperidol
Hypophysectomy Hypophysectomy + 17g-estradiol
i:
19.2 + 4.0 18.6 t 4.2
412 i 23 17 395 rt:
--_ -4.2
* P < 0.05 by Student's $ test compared to the control group.
ABfIIax -&_I-
926
Preliminary Notes
The increase in the number of striatal DA receptors is a specific response to 176estradiol, since the a-diastereomer was inactive. The increase also appears to be specific to the DA receptors, as a survey of other receptors did not show any alteration in the binding for muscarinic cholinergic, benzodiazepine, or a-noradrenergic receptors. The effect of estrogen on DA neurotransmission appears to be primarily postsynaptic, since DA uptake, a presynaptic process, was not altered. Estrogen trea~ent of male rats not only increases the number of striatal DA receptors, but also increases stereotypy (Hruska and Silbergeid, 1980a), a behavior mediated by stimulation of striatal DA receptors. Hypophysectomy prevented both the increase in striatal DA receptors and the increase in stereotypy. This suggests that the effect of estrogen is either (a) indirect and mediated through the pituitary, or (b) relies upon the pituitary for a cofactor for its action. This mechanism is at present unknown. Therefore, estrogen treatment appears to selectively and specifically increase the number of DA receptors in the striatum, an area probably not associated directly with neuroendocr~ne function. This supersensitivity may be mediated by pituitary hormones, since hy~physectomized rats did not have the expected biochemical or behavioral responses. The effect of estrogen on striatal DA function has relevance for the unusual but significant findings of chorea associated with pregnancy or the use of oral contraceptives (Nausieda et al., 1979b; Donaldson, 1978; Bickerstaff, 1975). This chorea is thought to occur from an imbalance of neurotransmitters in the brain with a resultant overstimulation of the DA system. Such a response could result from the increase in the number of DA Further work is in progress receptors which we have found in vivo after estrogen treatment. to develop this model and assess its significance on striatal function in neurological diseases and animal models of these diseases.
ACKNOWLEDGEMENTS We thank Laura Tang for excellent technical assistance Teresa O'Brien for the preparation of this manuscript.
and Marguerite
Smiley
and
REFERENCES Barber, P.V., Arnold, A.G., and Evans, G. (1976). Recurrent hormone Effects of oestrogens and progestogens. Clinical Endocrinology Bickerstaff, E.R. (1975). Neurological Clarendon Press, Oxford.
Complications
of Oral Contraceptives
Chiodo, L.A., Caggiula, A.R., and Saller, C.F. (1979). behaviors. Sot. Neurosci. Abst. 5: 644. Donaldson,
J.O.
(1978).
Neurology
of Pregnancy,
dependent chorea: 5: 297-293.
Estrogen
pp. 74-87.
modulation
W.B. Saunders
Hruska, R.E. and Silbergeld, E.K. (198Oa). Estrogen trea~ent enhances sensitivity in the rat striatum. Eur. J. Pharmacol. 61: 397-400.
pp. 69-71.
of DA dependent
Co., Philadelphia.
dopamine
receptor
Demonstration of increased dopamine receptor Hruska, R.E. and Silbergeld, E.K. (1980b). sensitivity after estrogen treatment using the rat rotation model. Science (in press). Kumakura, K., Hoffman, M., Cocchi, D., Trabucchi, M., Spano, P.F., and Muller, E.E. (1979). Long-term effect of ovariectomy on dopamine-stimulated adenylate cyclase in rat striatum and nucleus accumbens. Psychopharmacology 61: 13-16. Potentiation Lal, S. and Sourkes, T.L. (1972). in rats by neuroleptics and other agents.
and inhibition of the amphetamine stereotypy Arch. int. Pharmacodyn. 199: 289-301.
Nausieda, P.A., Koller, W.C., Weiner, W.J., and Klawans, H.L. (1979a). of postsynaptic dopaminergic sensitivity by female sex hormones. 521-526. Nausieda, P.A., Koller, W.C., Weiner, W.J., and Klawans, Neurology 29: 1605-1609. oral contraceptives.
H.L.
(1979b).
Modification Life Sciences
Chorea
25:
induced
by
to 926 Printed in Great Britain Pergamon Press Ltd 1980.
CHA~CTERIZATION OF THE STRIATAL SUPERSENSITIVITY PRODUCED BY ESTROGEN
Robert
E. Hruska,
Lynn M. Ludmer,
DOPAMINE RECEPTOR TREATMENT OF MALE RATS
and Ellen K. Silbergeld
Neurotoxicology Section NINCDS, NIH Building 36, Room 4A22 Bethesda, MD 20205
(Accep.&d
20 June
19801
SUMMARY Estrogen treatment of male rats produced an increase in the number of striatal dopamine receptors, without altering their This effect only occurs in vivo and has a slow onset. affinity. Only the 6-diastereomer of 17-estradiol was active. Other striatal receptors appeared to be unchanged as was the presynaptic uptake of dopamine. Hypophysectomy completely blocked the response to estrogen as measured on striatal dopamine receptors and on stereotypy, a behavior associated with striatal dopamine receptor stimuThese results are relevant to the clinical observations lation. of chorea associated with the use of oral contraceptives or with pregnancy. INTRODUCTIONS There is mounting evidence that hormones of pituitary and gonadal origin have effects on non-hypothalamic areas of the central nervous system. The sex hormones have been of particular interest because of the identification of nuclear and cytoplasmic cellular receptors in other areas of the brain, and because many chemicals have estrogenic properties Recently, we reported that estrogen treatment of male rats resulted in an increase in the number of striatal dopamine (DA) receptors and in an increase of two behaviors associated with striatal DA receptor stimulation -- stereotypy, and rotation after unilateral nigrostriatal lesions (Hruska and Silbergeld, 1980a, b). These results are consistent with other reports that ovariectomy of guinea pigs decreased stereotypy (Nausieda, Koller, Weiner, and Klawans, 1979a), and ovariectomy of rats decreased DA-stimulated adenylate cyclase activity (Kumakura, Hoffman, Cocchi, Trabucchi, Spano, and Muller, 1979). Administration of estrogen reversed both of these decreases. Stereotypy has also been reported to be increased after estrogen treatment of ovariectomized rats (La1 and Sourkes, 1972; Chiodo, Caggiula, and Saller, 1979). These results have potentially important implications for clinical applications. There are unusual but significant findings of chorea associated with pregnancy or the use of oral contraceptives (Nausieda, Koller, Weiner, and Klawans, 1979b; ~naldson, 1978; Bickerstaff, 1975). This report further explores and characterizes the DA receptor supersensitivity produced by estrogen treatment of male rats. METHODS Male, Sprague-Dawley rats (250-300 g) were purchased from Taconic Farms. The rats were injected subcutaneously (0.1 ml) in the neck with 125 vg of 17B-estradiol valerate in sesame oil, or 125 pg of 17u-estradiol in sesame oil. Hypophysectomized male, SpragueDawley rats (250-300 g) were purchased from Taconic Farms and Charles River. These rats were given drinking water which contained 5% dextrose and an electrolyte mixture of 203 mg% NaCl, 8.3 mg% KCl, 3.5 mg% CaClz, and 1.7 mg% MgClz, Four to five days after hypophysectomy, the rats were injected with estrogen as described above. At the conclusion of the experiments, the skulls of the hypophysectomized rats were visually inspected to insure removal of the pituitary. A17 experiments, other than the time course, were performed 6 days after estrogen treatment. Stereotypy and striatal DA receptor analyses were performed as previously described (Hruska and Silbergeld, 1980a). Muscarinic cholinergic receptor analyses were performed using C3H1-IIquinuclidinyl benzilate (C3HI-l_-QNB), benzodiazepine receptor analyses were performed using ["HI-flunitrazepam, and cc-noradrenergic receptor analyses were performed using [3~1-~~.4101.
923
924
Preliminary Notes
For in vitro experiments, 178-estradiol was dissolved In ethanol and diluted in distilled water so that the final ethanol concentration in the incubation medium was less than 0.071, a level which does not alter [3H]-spiroperidol binding. Transport experiments were performed using a synaptosomal Pz suspension in a Kreb's-Ringer buffer. Sodium-deoendent transport was calculated by subtracting the transport in the absence of sodium from that in the presence of sodium. RESULTS The time course of the increase in striatal DA receptors after estrogen treatment is shown in Fig. 1. Not until three days after estrogen treatment was there a significant increase in the number of receptors. The maximum 20% increase was reached on day 4 and persisted through day 7. By day 11 the number of receptors had declined to levels not At no time point did the estrogen treatment alter significantly diferent from controls. the affinity of [3H]-spiroperidol for the DA receptor. The increase in the number of striatal DA receptors was only observed in vivo. The binding of [3H]-spiroperidol was not altered by the.in vitro addition of 17B-estradiol at concentrations from 1.0 nM to 3.3 PM. Also, the in vitro addition of 1.32 IIM 17sestradiol did not alter the inhibition of [3H]-spiroperidol binding produced by a agonist (DA) or an antagonist ((+)butaclamol). The specificity of the in vivo increase in striatal DA receptors was explored further. The injection of the CL and B-diastereomers of 17-estradiol showed that only the s-diastercomer produced an increase in the number of receptors (Table 1). Neither diastereomer altered the affinity of [3H]-spiroperidol for the receptor. Several other receptors in the striatum were measured after in vivo treatment with 170-estradiol to determine the specificity of the receptor increase. The numbers and the affinities of the muscarinic cholinergic ([3H]-l-Q~B), benzodiazepine ([3H]-flunitrazepam), and a-noradrenergic ([3H]-WB.4101) receptors were not changed by estrogen treatment (Table 1). The specificity of the effect on DA receptors was also analysed by measuring DA transThe high affinity uptake of DA at a port into synaptosomes prepared from the striatum. concentration of 0.388 UM was not altered by in vivo estrogen treatment. The role of the pituitary in the effect of estrogen was investigated. Hypophysectomy of male rats before estrogen treatment completely prevented an estrogen-induced increase in the number of striatal DA receptors (Table 1). Also, the stereotypy produced by DA agonist 4 mg/kg) was not altered in hypophysectomized male treatment (apomorphine hydrochloride, rats after estrogen treatment (Fig. 2). Therefore, neither the biochemical nor the behavioral effects of estrogen on striatal DA receptors occur after pituitary removal.
TIME IDAYSI
Fig. 1. Time course of the increase in the maximum [3H]-spiroperidol binding to striatal DA receptors after in viva injection of 17a-estradiol valerate. Each point is the mean f SEM of the oercent chanse in the maximum binding. Analyses were performed on tissue-from control and 17B-estradiol valerate treated rats at 10 concentrations of T3H]-soiroperidol and analvsed by linear regression analyses of_Scatchard‘plots. The shaded area represents the variation in the maximum binding averaged from the control values at each time point. *P < 0.05 by Student's time point.
5 test, compared
to the control
at that
925
Preliminary Notes
Time (mid
Fig. 2, Effect of apomorphine hydrochloride (4 mgfkg) on stereotypy scores of hypophysectomizedrats, without (CON) or with 17f+estradiol valerate (EDV) treatment. Each point is the mean f SEM of 11 CON or 13 EDV treated rats.
DISCUSSION .
The time course of the development and decline of the striatal DA receptor supersensltivity is slow. Normally, experiments were performed 6 days after treatment, a time at which the striatal DA receptors are maximally increased. The slow time course of the supersensitivity and the lack of affinity change argue against a conformational alteration or a change in the state of the receptors, and suggest that estrogen is activating synthesis of new receptors, which involves a genomic effect. The slow time course corresponds with the clinical observations of the chorea associated with oral contraceptives (Barber, Arnold, and Evans, t976). This chorea takes several days or weeks to develop after starting the medication and also takes several days or weeks to disappear after cessation of treatment. The increase in DA receptors is a specific in vivo response, as expected from a slow development of the supersensitivity. The in vitro addition of 17@-estradiol does not directly affect the binding of [3H]-spiroperidol,even at a high concentration of estrogen (3.3 uM). The [3H]-spiroperidolbinding was inhibited by an agonist and antagonist: the inhibition was equal in the presence or absence of 17@-estradiol. Therefore, 17B-estradioi does not have a specific modulatory function on the inhibition of binding by an agonist or an antagonist of the DA receptor.
TABLE 1 Specificity of Estrogen in vivo on Striatal Neurotransmitter Receptors in Male Rats Injected Six Days Previously Liqand
Treatment
!!
Kd (PM)
Bmax (fmole/mg protein)
[jH]-spiroperidol
Control 17cr-estradiol 17B-estradiol
6 :
16.5 + 1.3 16.6 i:1.4 17.3 + 2.4
427 i:18 428 + 18 508 i 30
___ +0.2 +19.0*
[3Hl-1-QNB
Control 17~-estradiol
Z
25.6 * 6.1 26.1 f 6.7
1372 +_106 1390 _+105
_-t1.3
[3H]-flunitrazepam
Control 17B-estradiol
3 3
1820 ?:230 1890 ? 300
691 + 44 683 ?:55
___ -1.2
r3H]-WB.410t
Control 176-estradiol
Z
109 t 9 98 ?:20
60.7 i 2.5 60.8 ?Z5.8
-__ +0.1
[3H]-spiroperidol
Hypophysectomy Hypophysectomy + 17g-estradiol
i:
19.2 + 4.0 18.6 t 4.2
412 i 23 17 395 rt:
--_ -4.2
* P < 0.05 by Student's $ test compared to the control group.
ABfIIax -&_I-
926
Preliminary Notes
The increase in the number of striatal DA receptors is a specific response to 176estradiol, since the a-diastereomer was inactive. The increase also appears to be specific to the DA receptors, as a survey of other receptors did not show any alteration in the binding for muscarinic cholinergic, benzodiazepine, or a-noradrenergic receptors. The effect of estrogen on DA neurotransmission appears to be primarily postsynaptic, since DA uptake, a presynaptic process, was not altered. Estrogen trea~ent of male rats not only increases the number of striatal DA receptors, but also increases stereotypy (Hruska and Silbergeid, 1980a), a behavior mediated by stimulation of striatal DA receptors. Hypophysectomy prevented both the increase in striatal DA receptors and the increase in stereotypy. This suggests that the effect of estrogen is either (a) indirect and mediated through the pituitary, or (b) relies upon the pituitary for a cofactor for its action. This mechanism is at present unknown. Therefore, estrogen treatment appears to selectively and specifically increase the number of DA receptors in the striatum, an area probably not associated directly with neuroendocr~ne function. This supersensitivity may be mediated by pituitary hormones, since hy~physectomized rats did not have the expected biochemical or behavioral responses. The effect of estrogen on striatal DA function has relevance for the unusual but significant findings of chorea associated with pregnancy or the use of oral contraceptives (Nausieda et al., 1979b; Donaldson, 1978; Bickerstaff, 1975). This chorea is thought to occur from an imbalance of neurotransmitters in the brain with a resultant overstimulation of the DA system. Such a response could result from the increase in the number of DA Further work is in progress receptors which we have found in vivo after estrogen treatment. to develop this model and assess its significance on striatal function in neurological diseases and animal models of these diseases.
ACKNOWLEDGEMENTS We thank Laura Tang for excellent technical assistance Teresa O'Brien for the preparation of this manuscript.
and Marguerite
Smiley
and
REFERENCES Barber, P.V., Arnold, A.G., and Evans, G. (1976). Recurrent hormone Effects of oestrogens and progestogens. Clinical Endocrinology Bickerstaff, E.R. (1975). Neurological Clarendon Press, Oxford.
Complications
of Oral Contraceptives
Chiodo, L.A., Caggiula, A.R., and Saller, C.F. (1979). behaviors. Sot. Neurosci. Abst. 5: 644. Donaldson,
J.O.
(1978).
Neurology
of Pregnancy,
dependent chorea: 5: 297-293.
Estrogen
pp. 74-87.
modulation
W.B. Saunders
Hruska, R.E. and Silbergeld, E.K. (198Oa). Estrogen trea~ent enhances sensitivity in the rat striatum. Eur. J. Pharmacol. 61: 397-400.
pp. 69-71.
of DA dependent
Co., Philadelphia.
dopamine
receptor
Demonstration of increased dopamine receptor Hruska, R.E. and Silbergeld, E.K. (1980b). sensitivity after estrogen treatment using the rat rotation model. Science (in press). Kumakura, K., Hoffman, M., Cocchi, D., Trabucchi, M., Spano, P.F., and Muller, E.E. (1979). Long-term effect of ovariectomy on dopamine-stimulated adenylate cyclase in rat striatum and nucleus accumbens. Psychopharmacology 61: 13-16. Potentiation Lal, S. and Sourkes, T.L. (1972). in rats by neuroleptics and other agents.
and inhibition of the amphetamine stereotypy Arch. int. Pharmacodyn. 199: 289-301.
Nausieda, P.A., Koller, W.C., Weiner, W.J., and Klawans, H.L. (1979a). of postsynaptic dopaminergic sensitivity by female sex hormones. 521-526. Nausieda, P.A., Koller, W.C., Weiner, W.J., and Klawans, Neurology 29: 1605-1609. oral contraceptives.
H.L.
(1979b).
Modification Life Sciences
Chorea
25:
induced
by