European Journal of Pharmacology, 122 (1986) 259-267 259

Elsevier

CHARACTERIZATION O F T H E H E P A T I C P R O L A C T I N R E C E P T O R S I N D U C E D BY C H R O N I C
I R O N DEFICIENCY AND N E U R O L E P T I C S

RONNIE J. BARKEY, TAMAR AMIT, DORIT BEN-SHACHAR and MOUSSA B.H. YOUDIM *
Department of Pharmacology, Faculty of Medicine and Rappaport Family Institute for Research in the Medical Sciences,
Technion-lsrael Institute of Technology, P.O.B. 9697, Haifa 31096, Israel

Received 1 July 1985, revised MS received 27 November 1985, accepted 17 December 1985

R.J. BARKEY, T. AMIT, D. BEN-SHACHAR and M.B.H. YOUDIM, Characterization of the hepatic prolactin
receptors induced by chronic iron deficiency and neuroleptics, European J. Pharmacol. 122 (1986) 259-267.
Nutritional iron deficiency (ID), like neuroleptic treatment, results in a reduction in dopaminergic activity and a
rise in serum prolactin (PRL). Since PRL has been shown to regulate its own receptors, we studied PRL binding sites
during the above treatments. ID induced in 21 day old male rats for 28 days, or treatment with either chlorpromazine
(10 mg/kg per day i.p.) or fluphenazine (5 mg/kg per day i.p.) for 21 days or haloperidol (5 mg/kg per day i.p.) for 9
days, caused significant increases (3- to 8-fold) in [1251]oPRL specific binding to the liver membranes. The combined
treatment with haloperidol and ID, as above, resulted in an additive effect on hepatic PRL receptors, suggesting that
the actions of neuroleptics and ID may be either submaximal or mediated by two different mechanisms. After 7 days
or recovery from ID, the induced PRL receptors were completely reduced to the control values. In vitro desaturation
of the induced PRL binding sites with MgCI z caused a further increase (1.57-fold) in PRL binding. Characterization of
the hepatic PRL binding sites induced by ID showed properties similar to those reported for the classical PRL
receptors, including specificity for the lactogenic hormones, a high affinity constant (2.38 × 101° M -1) and inhibition
of PRL binding to the induced receptors by an anti-PRL receptor antibody. The results of this study further support
the suggested role of endogenous PRL in inducing its own receptors.

Prolactin receptors Iron deficiency Chlorpromazine Fluphenazine Haloperidol Liver

1. Introduction although only to 20% of control level, while Manni

A n u m b e r of reports have provided evidence to
suggest that prolactin (PRL) directly stimulates its
own receptors. H y p o p h y s e c t o m y of female rats
causes a major reduction in hepatic binding of
PRL. Subsequent elevation of serum P R L by
pituitary transplants beneath the kidney capsule
(Posner et al., 1975; Posner, 1976) or by implanta-
tion of PRL-secreting pituitary tumors (Posner,
1976) results in complete restoration of P R L re-
ceptors in liver membranes. Costlow et al. (1975)
were able to restore hepatic P R L receptors in
hypophysectomized female rats by P R L injections,
• To whom all correspondence should be addressed.
et al. (1978) could completely restore P R L binding
by using polyvinylpyrrolidone (PVP) in order to
sustain P R L blood levels. Recently, we reported
that in adult male rats, whose basal P R L binding
is very low in the liver and not detectable in the
lung, P R L injected in PVP induces P R L binding
sites in both these organs (Barkey et al., 1981;
Amit et al., 1981; 1984; 1985; Ben-Harari et al.,
1983).
There is considerable evidence that the most
important inhibitor of P R L secretion is d o p a m i n e
( D A ) ( L a n c r a n j a n a n d Friesen, 1978). Drugs which
antagonize or deplete D A enhance P R L secretion,
while D A agonists or agents which enhance endog-
enous catecholamine levels inhibit P R L secretion
(Shaar and Clemens, 1974; Blake, 1976; M a c L e o d

0014-2999/86/$03.50 © 1986 Elsevier Science Publishers B.V.

260
and Lehmeyer, 1974). Brain irom concentrations
also affect dopaminergic activity: the distribution
of non-heme iron in rat brain is uneven, and there
is a highly localized concentration of the metal in
DA-rich brain regions (Hill and Switzer, 1984;
Youdim, 1985). Rats made iron deficient (ID)
have significantly lower brain iron content and
exhibit lower DA-dependent, amphetamine- and
apomorphine-induced behaviors (Youdim and
Green, 1977; Youdim et al., 1981; Ashkenazi et
al., 1982). DA-D2-receptor binding sites (Bmax)in
the caudate nucleus of ID rats have thus been
reported to be significantly reduced (Ashkenazi et
al., 1982). Since reduced dopaminergic activity
initiated by treatment with neuroleptics or by iron
deficiency (ID) results in elevated serum PRL
levels (Rupniak et al., 1983; Barkey et al., 1985),
the role of endogenous PRL in the induction of its
own receptors and the characteristics of the in-
duced receptors were investigated in male rats
following the above treatment,
2. Materials and methods
2.1. Hormones and other materials
Ovine PRL (oPRL) NIH-P-S15 (30,5 IU/mg),
human growth hormone (hGH) N I A M D D - h G H -
RP-1 (2.2 IU/mg), human placental lactogen
(hPL), rat PRL (rPRL) B3 (20 I U / m g ) and hu-
man follicle-stimulating hormone (hFSH) HS-1
were kindly supplied by the National Hormone
and Pituitary Program of the N I A D D K , National
Institutes of Health, Bethesda, MD, U.S.A. Hu-
man chorionic gonadotropin (hCG) was purchased
from NV Organon, Oss, The Netherlands. Anti-
PRL-receptor antiserum (No. 151), produced in
sheep against a partially purified rabbit mammary
gland PRL receptor, was kindly provided by Dr.
P.A. Kelly of the Molecular Endocrinology
Laboratory, Royal Victoria Hospital, Montreal,
Canada. Chlorpromazine hydrochloride was a gift
of Smith, Kline and French Laboratories, Phila-
delphia division of Smith Kline Corporation.
Fluphenazine 2HCI was donated by the Squibb
Institute for Medical Research (E.R. Squibb and
Sons, Inc., Princeton, N J, U.S.A.), and haloperidol
was donated by Janssen Pharmaceutica, N.V.,
Beerse, Belgium. Homoglobin kits and 2,4,6-tri-
pyridyl-S-triazine were purchased from Sigma
Chemical Co., St. Louis, MO, U.S.A.
All other reagents were of analytical grade and
were purchased from commercial sources. The rats
used were descendants of the Sprague-Dawley
strain.
2.2. Animals and treatments
Male rats, 21 days old at the start of the experi-
ment, were housed under standard conditions of
temperature (approximately 23°C) and light (12 h
light/12 h dark cycle). Animals received either
haloperidoi (5 m g / k g per day i.p.) for 9 days of
fluphenazine (5 m g / k g per day i.p.) or chlor-
promazine (10 m g / k g per day i.p.) for 21 days.
Control rats received an equivalent volume of 0.9%
saline i.p. After a 3 day treatment-free drug
washout period, the rats were killed by decapita-
tion and the liver excised and frozen in liquid N 2
and stored at - 8 0 ° C until determination of PRL
binding.
ID was induced in 21 day old male rats by
feeding them a semisynthetie diet low in iron
(McCall et al., 1962) and distilled water ad libitum
for 4 weeks. Control rats were given the same diet,
supplemented with ammonium ferrous sulfate (1.3
g / k g diet), although their food intake was re-
stricted to that of the ID group in order to main-
tain similar body weights in the 2 groups. In
recovery studies, iron repletion was achieved by
feeding the ID diet supplemented with iron to the
ID rats.
2.3. Hemoglobin and serum iron determinotion
Hemoglobin was measured weekly according to
a modification of the method described by Drab-
kin and Austin (1953), using a commercial kit.
Serum iron was determined using 2,4,6-tripyridyl-
S-triazine as an iron chelator (Caraway, 1963).
2.4. Assay of P R L binding to rat liver membranes
The liver from each rat was minced in 5 volumes
of ice-cold Tris buffer (Tris 0.01 M, sucrose 0.3 M,

KCI 0.001 M, MgC12 0.01 M, pH 7.6) then ho-
mogenized with four 15 s bursts of an Ystral
X10/20 laboratory disperser at speed 5. After
initial centrifugation at 1500 x g for 10 min at
4°C, the resultant supernatant was further centri-
fuged at 40000 × g for 15 min. The resulting
membrane pellet was reconstituted in 5 volumes of
Tris buffer and used for the binding studies. Pro-
tein concentrations was determined by a modifica-
tion (Miller, 1959) of the method of Lowry et al.
(1951).
oPRL was iodinated by the lactoperoxidase
method and was purified by chromatography on
Sephadex G-100 as previously described in detail
(Rogol and Chrambach, 1975; Barkey et al., 1977).
The specific activity was - 80 Ci/g.
[125I]oPRL (1 ng/0.1 ml) was incubated with
0.1 ml membrane fractions (0.5-0.8 mg protein) in
the absence or presence of excess unlabeled oPRL
(1 t~g/0.1 ml) to determine non-specific binding,
as previously described (Barkey et al., 1979). In-
cubations were carried out in 0.3 ml final volume
at 20°C for 44 h. These incubation conditions
have previously been determined as optimal
(Barkey et al., 1979). The incubations were
terminated by dilution with 2 ml of 0.01 M Tris
buffer, pH 7.6, and centrifugation at 5 000 × g for
40 min at 4°C. The supernatant was decanted and
the pellet counted. Specific binding was the dif-
ference between total binding and binding in the
presence of unlabeled hormone. The specific bind-
ing was corrected for the individual protein con-
centration of each membrane preparation, and the
binding/mg protein was expressed as a percentage
of the total cpm incubated. The number of binding
sites and the affinity constant (Ka) were calcu-
lated by Scatchard analysis (Scatchard, 1949), using
increasing concentrations of unlabeled oPRL with
a fixed amount of tracer,
Endogenously bound ligand was removed from
the receptor by exposing the membranes to 4 M
MgCI2, essentially as described by Kelly et al.
(1979b).
2.5. Statistics
Statistical analysis of the data was based on
Student's two-tailed t-test, comparing experimen-
tal group means + estimated S.E. for significance,
261
3. Results
3.1. Hemoglobin and serum iron levels
The hemoglobin and serum iron levels of male
rats fed an ID diet for 4 weeks were 5.67 + 0.52
g/100 ml and 1.01 _+ 0.08 /zg/ml (n = 6), respec-
tively, compared to control values of 14.67 _+ 0.48
g/100 ml and 3.03 _+ 0.13 ~tg/ml (n = 10), respec-
tively.
In recovery studies the hemoglobin and serum
iron levels of the ID rats were 9.31 _+ 0.7 g/100 ml
and 0.87 _+ 0.16 /~g/ml (n = 6), respectively; after
feeding the ID rats for 9 days with the ID diet
supplemented with iron, the hemoglobin and serum
iron levels reached control values: 15.2 _+ 0.3 g/100
ml and 2.8 _+ 0.2 /zg/ml, respectively.
3.2. Induction of hepatic PRL receptors by ID and
neuroleptics
The effects of ID and chronic neuroleptic treat-
ment on PRL receptors are shown in fig. 1.
Fluphenazine caused a 2.7-fold increase, chlor-
promazine 8.0-fold, haloperidol 6.3-fold and I D a
7.1-fold increase in PRL specific binding in the
liver membrane preparations, confirming our pre-
vious results (Barkey et al., 1985). The combina-
tion of chronic haloperidol treatment and 4 weeks
of ID resulted in a far greater increase in PRL
binding (14.6-fold) than that observed with either
treatment alone.
Feeding the ID rats for 9 days with the ID diet
supplemented with iron completely restored the
raised PRL binding to the normally low control
levels (fig. 2).
3.3. Characterization of the hepatic PRL receptors
induced by ID and neuroleptics
3.3.1. Scatchard analysis
Transformation according to Scatchard (1949)
of [I25I]oPRL binding data from competition stud-
ies with oPRL revealed a single class of binding
sites in the ID-induced rat liver, with Ka of 2.38 ×
10 l° M -1 and a binding capacity of 4.87 f m o l / m g
protein (fig. 3). A similar value was also observed
with [lzSI]oPRL binding in livers of chronically
262

.. "--

i/
° 1 T e

i 2 I o Control I.D. Control Iron-repleted

-- (control diet)
(lO)

_17 Fig. 2. Effect of iron repletion in ID rats nn hepatic PRL

binding. Hepatic PRL binding was studied after nutritional ID
Control FLU CPZ HALq ID ID f o r 4 weeks and after the ID rats had been given an iron-plus

HALO (control) diet for 9 days (iron-repleted), The ID and iron-re-

Fig. 1. Induction of hepatic PRL receptors by neuroleptics and pleted groups were compared with parallel control groups that
by ID. Male rats (21 days old) were injected i.p. daily with were fed the ID diet supplemented with ammonium ferrous
eilher fluphenazine(FLU: 5 mg/kg) or chlorpromazine(CPZ; sulfate from the start. [12511oPRL specific binding was de-
10 m g / k g l for 21 days, or haloperidol (HALO: 5 m g / k g ) for 9 retrained as described in the legend to fig. 1. Each value is
days. ID was induced by feeding the rats an ID diet for 4 mean+S.E, for 6 rats per experimental group. * P < 0.01 vs.
weeks. Control rats were either injected with saline or fed the control.
1D diet supplemented with iron. One group of rats was injected
i.p. daily with haloperidol (5 mg/kg) for 9 days subsequent to
induction of ID. The rats were killed 3 days after the last
injection and the livers excised and frozen for subsequent
determination of PRL binding sites as described in Materials TABLE 1
and methods. [1251]oPRL specific binding was expressed as a Hormonal specificity of [1251]oPRL binding to iron deficiency-
percentage of the total cpm incubated and corrected per mg or haloperidol-induced hepatic receptors. Liver membranes,
protein, as determined for each membrane preparation (range: prepared as described under Materials and methods, were
0.5-0.8 mg/tube). Each value is the mean + S.E. for the number incubated with tracer amounts of [125I]oPRL and excess con-
of rats shown in parentheses above each column. * P < 0.05, centration of lactogenic and non-lactogenic hormones. Maxi-
• * P < 0.02, *** P < 0.001, all vs. controls: **** P < 0.02 vs. mal binding and non-specific binding of [i251]oPRL were de-
ll) or vs. HALO. termined in each assay, and the competitive displacement data
for other hormones are expressed as a percentage of the maxi-
mal specific binding determined with excess oPRL. Results are
haloperidol-treated male rats (data not shown), means±S.E, of 4 experiments in triplicate.
The degree of specific P R L binding in control
Treatment Hormone added Displacement of
male rat liver was too low to allow a meaningful (1 # g / t u b e ) specific binding
Scatchard analysis. (%)
3.3.2. Specificity studies Iron deficiency rPRL 96.24_+0.52
- hGH 99.92 _4_0.04
Table 1 summarizes the findings that the lacto- hPL 92.93 ± 1.69
genic hormones rPRL, h G H and h P L all c o m p e t e d hCG No effect
with o P R L for binding to its receptor in ID or hFSH No effect
haloperidol-treated rat liver, while h C G and h F S H Haloperidol rPRL 99.91 ± 0.09
hGH 90.90 _+0.09
had no effect, hPL 97.87 + 2.13
hCG No effect
3. 3.3. Effect of anti-PRL receptor antiserum hFSH No effect
Additional specificity studies were undertaken
 263

100

E 0.0,~
x
. ;
- o.ot-
_.==~5o ~ ~ - I ~ I -~Xx'5~l
~1"J
-- f m o l / m g protein)

0' I J i I
10-2 10-1 100 101 10 2
oPRL ( n o / t u b e )
Fig. 3. Competition between [12Sl]oPRL and native oPRL for the hepatic PRL receptors induced by ID. [125[]oPRL was incubated
with liver membranes in the presence of increasing amounts of unlabeled oPRL. Binding of [1251]oPRL at each concentration of
unlabeled hormone was compared to the control to which no unlabeled hormone was added. Results are expressed as percent
inhibition of maximal binding of [125|]oPRL. Inset: Scatchard plot of competition data. The ordinate represents the ratio of
bound/free oPRL and the abscissa, the number of fmol oPRL b o u n d / m g membrane protein. K was calculated from the negative
slope of the line and was 2.38 × 10 ~(~ M - i. The binding capacity of the receptors was calculated from the intercept on the abscissa to
be 4.87 f m o l / m g protein. Results are means of triplicates from a representative experiment which was repeated 3 times.

100,

8C
E
.E_
X " "6
m 60
E

~ 40
.c_
"O
c
;~ ~ ~ control serum ..
.j _- e anti- PRL receptor antiserum
n-
Q.
2G
O
i

i i
1:104 1:102 1110 I

Serum Dilution
Fig. 4. Effect of anti-PRL receptor antiserum on hepatic PRL binding induced by ID. [1251]oPRL (1 ng/0.1 ml) was incubated with
liver membranes (0.3 mg protein/tube) in the presence of increasing concentrations of either control serum or an antiserum from
sheep, raised against a partially purified rabbit mammary PRL receptor. Binding is expressed as percentage of maximal specific
binding in the absence of serum. Points are means + S.E. of triplicate determinations. * P < 0.001 vs. incubations with control serum
only.
264
with the specific anti-PRL receptor antibody de-
scribed by Djiane et al. (1981). Antiserum of sheep
injected with partially purified receptor from
lactating rabbit mammary glands was assayed for
its capacity to inhibit the binding of [125I]oPRL to
the induced hepatic receptors in the ID rats. The
antiserum of immunized sheep caused a concentra-
tion-dependent reduction in the binding of oPRL
to its receptor, which was significantly greater than
the effect of non-immunized sheep serum (fig. 4).
3.3.4. Desaturation of binding sites with MgCl e
Since an increase in serum PRL could lead to
occupied PRL receptors, thereby masking part of
the induced receptors, hepatic membranes from
control and ID rats were treated with 4 M MgCI 2,
as described in Materials and methods, in order to
dissociate bound PRL from its receptor. As can be
seen from fig. 5, this procedure caused a further
significant increase in specific PRL binding com-
pared with non-desaturated membranes from ID
livers, indicating that some of the occupied bind-
ing sites were exposed by the MgC12 treatment,
PRL-binding sites in membranes from control
~ Free , accompanied by high serum PRL levels, which is
o ~] Total
~.,:i7~7
@~Z-:
g ~:~'<"
a [
~:~:~
g ;,~:~'!
,, ,,~v:::~
~!::~:s
[{~[i7:
-~ 'Z%
Control Iron Deficiency
Fig. 5. Effect of desaturation of PRL binding sites with 4 M
MgC12. Liver membranes of control or ID rats were treated
with 4 M MgC1 z (see Materials and methods) prior to de-
termination of free and total (MgC12-treated) PRL receptor
levels. Binding is expressed as a percentage of total cpm and
corrected per mg protein. MgCI 2 treatment reduced membrane
protein by 22%. Values are means_+ S.E. for 5 rats per experi-
mental group. * P < 0.05 vs, free hepatic PRL receptor level in
ID rats, ** P < 0.001 vs. hepatic PRL receptor level in control
rats.
livers were unchanged. These results completely
correlate with our recent findings that ID resulted
in a rise in serum PRL (Barkey et al., 1985).
4. Discussion
This study has clearly shown the ability of
nutritional ID and chronic neuroleptic treatment
to induce PRL receptors in the male rat liver. The
binding sites induced were characterized and their
PRL receptor-like properties demonstrated. There
is considerable evidence supporting the inhibitory
role of dopaminergic mechanisms in the regulation
of PRL release (Meites, 1977; Neill, 1980). Thus,
in ID and neuroleptic-treated rats, increased serum
PRL levels would be expected to result from the
reduction in dopaminergic activity observed fol-
lowing these treatments (Ashkenazi et al., 1982;
Youdim, 1985). Indeed, Rupniak et al. (1983) have
recently reported a 12-fold increase in serum PRL
of rats treated chronically with neuroleptics, and
we have recently observed elevated serum PRL
levels in ID male rats compared with control
animals (Barkey et al., 1985). Thus, it is apparent
that the elevation in hepatic PRL receptors ob-
served following ID and neuroleptic treatment is
in agreement with earlier suggestions that PRL
could be the inducing agent for its own receptor
up-regulation (Costlow et al., 1975; Posner et al.,
1975; Posner, 1976; Manni et al., 1978; Barkey et
al., 1981; Amit et al., 1984; 1985).
In addition, we have shown that chronic neuro-
leptic treatment exerted a stimulatory effect on
PRL receptors which was additive to that observed
in the ID state. One possible interpretation of
these results is that neuroleptic treatment and ID
can lead to two independent processes causing
PRL release, possibly via dopaminergic inhibition,
with a resultant additive up-regulation of hepatic
P R L binding. A s i m i l a r phenomenon with additive
effects of maximal doses of haloperidol and 6-hy-
droxydopamine-induced postjunctional dopamin-
ergic supersensitivity has been demonstrated by
Staunton et al. (1982). Furthermore, we consider
the dose and time course of haloperidol t r e a t m e n t
to have been maximal, and a longer duration of

ID (7 weeks) did not lead to any greater up-regu-
lation of hepetic PRL receptors than seen after 4
weeks of ID (unpublished data). Nevertheless, ad-
ditional direct or indirect effects of neuroleptics or
ID on PRL receptors cannot be ruled out, and the
complexity of the effects of these treatments makes
a direct and quantitative correlation very difficult,
The modulating effect of dopaminergic activity on
PRL receptors is further supported by the demon-
stration that after 9 days of recovery from ID, the
induced hepatic PRL receptors were sharply re-
duced to the control level. This is in direct correla-
tion with the recovery of dopaminergic activity
(DA-D 2 receptor number) (Ashkenazi et al., 1982)
when the hemoglobin and iron levels of ID rats
were normalized,
Further evidence that ID indeed elevates PRL
levels was provided indirectly by the MgC12 pro-
cedure, which has been reported to desaturate
endogenously or exogenously saturated G H or
PRL receptors (Kelly et al., 1979b). This technique
allows the elevated endogenous masking PRL
(Barkey et al., 1985) to be dissociated from its
receptor, leading to an even greater stimulatory
effect of the ID treatment on hepatic PRL recep-
tors.
The effects of PRL on its own receptors have
frequently seemed contradictory. Recently, the oc-
currence of an immunological response following
long-term treatment with heterologous hormones
stressed the need to separate the induced receptors
from the attached antibodies in the lung and liver
of male rats treated with oPRL (Amit et al., 1984;
1985). Thus, in order to show that ID or chronic
neuroleptic treatment indeed induces PRL recep-
tors, a detailed characterization of the induced
binding sites was carried out. The results now
presented indicate that ID or neuroleptic treat-
ment induces hepatic PRL binding sites that show
many of the features used for defining hormone-
target cell interaction. These included many of the
properties reported for 'natural' or non-induced
P R L receptors, namely, immunological and
hormonal specificities as well as the kinetic prop-
erties. The hormone specificity of the induced
receptors in its study was similar to that observed
in rabbit mammary gland (Shiu et al., 1973) and
liver (Parke and Forsyth, 1975) as well as that
265
induced in the male rat liver by estradiol (Amit et
al., 1984), since the lactogenic hormones effec-
tively competed for [125I]oPRL binding. The in-
hibition of PRL binding to the induced receptors
by anti-PRL receptor antiserum is particularly rel-
evant, since this antiserum, which was raised in
sheep against a partially purified rabbit-PRL re-
ceptor, has been shown to block a biological re-
sponse of mammary tissue to PRL (Djiane et al.,
1981). The binding K a, calculated by means of
Scatchard analysis, is within the same range as
values previously reported for various organs from
intact animals (Waters et al., 1984), as well as for
estradiol-induced hepatic PRL binding (Amit et
al., 1984). This would suggest that ID induces an
increase in the number of PRL sites without
changing the affinity for the hormone, although
this could not be determined in the control male
rat livers, in view of the very low binding levels in
this tissue.
Several studies have indicated that the extent of
PRL binding by its target tissues can be mod-
ulated by other hormones and that, in the liver,
PRL apparently regulates its own receptors (Kelly
et al., 1979a). Since the initial action of PRL
involves binding to its receptors, modulation of
tissue receptor levels may be an important way of
regulating peripheral sensitivity to the hormone.
The reported effects of PRL on RNA synthesis
(Chen et al., 1972), ornithine decarboxylase activ-
ity (Richard, 1975), somatomedin production
(Francis and Hill, 1970) and estrogen receptor
levels (Chamness et al., 1975) in the liver suggest
that the interaction of PRL with the liver mem-
branes has an important biological function. Thus,
besides using PRL serum level as an index to
evaluate a drug's antipsychotic potency, it is im-
portant to take into account the changes in PRL
receptor level at the target organ. Considering the
similarity of ID and chronic neuroleptic treat-
ments in reducing central dopaminergic activity,
with the resultant elevation in serum prolactin
levels and hepatic PRL receptors (Barkey et al.,
1985), at least some of the previously reported
neuroendocrine effects of neuroleptic treatment
(Beumont et al., 1974; Collu et al., 1975; Rubin et
al., 1976) also seen in ID may now be explainable.
266
Acknowledgements
This work was supported in part by grants from the Chief
Scientist's Office of the Israel Ministry of Health and from the
Wellcome Trust (London) to M.B.H.Y. and RJ.B. We are
grateful to the N I A D D K , NIH, for providing the various PRL
preparations used in the present study. The excellent technical
assistance of Naomi Bar-Yosef is appreciated. We thank Ruth
Singer for typing this manuscript.
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