Possible changes in response of the hypothalamo-pituitary prolactin. (PRL) axis to long acting. (fluphenazine enanthate;. FPZ) and short acting. (chlorpromazine ...
BIOLOGY
OF REPRODUCTION
15,
168-1
72 (1976)
and Sex Differences
Age
in Prolactin
to Phenothiazines H. C.
BOI-INET’
Department
in Rats
C. ARAGONA
,
of Physiology,
Response
and University
H. C.
FRIES
EN
of Manitoba,
770 Bannatyne Avenue Winnipeg, Manitoba
ABST
RACT
Possible changes in response of the hypothalamo-pituitary prolactin (PRL) axis to long acting (fluphenazine enanthate; FPZ) and short acting (chlorpromazine; CPZ) phenothiazine derivatives were investigated in male and female rats at different stages of maturation. Maximal serum PRL concentrations after CPZ were not different in male rats aged 20, 40 or 60 days (130 ng/ml). Serum PRL levels were elevated for 3 h in the prepubertal and pubertal males and for 4 h in adult rats. The decline of PRL was most rapid in the youngest rats, and slowest in the 60 day old males. In females, maximal serum PRL concentrations after CPZ were 2 to 3 times higher in 40 and 60 day old rats than in 20 day old animals (100 ng/ml). The decline in serum PRL in female rats again was most rapid in younger rats. The elevation of PRL lasted as long as 4 h in all age groups. Ten days after FPZ serum PRL was not increased in prepubertal rats, but still was twice as high in peripubertal and adult animals as compared to control values in both sexes prior to treatment. These studies indicate significant age and sex differences in PRL response after phenothiazines and these variations must be taken into account when using this drug to maintain elevated serum prolactin levels.
INTRODUCTION Fluphenazine tranquillizer, dent
is reported
mammotropic
in
female
1970). a similar one
of
a long to have lasting
effect
rats
In the dose our
MATERIALS
enanthate,
(Ben-David,
light and
acting
over
20
1968;
to
days
Sulman,
of this information preparation in the
experiments
depen-
a dose
we used course of
maintain
elevated
serum prolactin (PRL) concentrations for a 10 day period. Immature and adult male rats were used but only in the latter group were elevated levels found. These observations
prompted
take a more ferences in
investigation to long
thorough responsiveness
(chlorpromazine) tives in male of
and
acting female
us
to
under-
of the difand short
phenothiazine rats at different
derivastages
maturation. Changes
in
amo-pituitary course been Geschwind, Dohler
responsiveness
axis to reported 1972;
and
Accepted Received ‘Research dation (DFG).
Wuttke,
of
the
hypothal-
et
al.,
In the second part of the study fluphenazine enanthate (25 mg/kg body weight; Moditen R, 25 mgI ml) was given subcutaneously on Day 20, 30 and 60 of age, controls received the same volume of sesame oil. Before and 10 days after treatment blood samples were taken by cardiac puncture under light ether anesthesia. Rat PRL was measured with the radioimmunoassay kit supplied by NIAMDD and expressed as ng/ml using the NIAMDD rat PRL reference preparation RP-1.
1973;
1974).
April 15, 1976. January 1, 1976. Fellow of the German
Research
METHODS
used.
various stimuli have of previously (Moger and
Negro-Vilar
AND
Sprague-Dawley rats aged 20, 40 and 60 days were purchased from Biolab Inc., St. Paul, Minn. The weights of male and female animals were not significantly different and were at 20 days, 65 ± 4.4 g (mean ± SD), at 40 days, 154 ± 10 g, and at 60 days, 235 ± 10.3 g. After weighing, all animals were lightly anesthetized with ether (1-2 mm) and immediately 0.5 to 1 ml blood samples were taken by cardiac puncture from all groups. Then chlorpromazine hydrochloride (25 mg/kg body weight; Largactil R, 50 mg/2 ml per ampoule) was injected intraperitoneally using a 1 ml tuberculin syringe. According to body weight, controls were injected with the same volume of saline, e.g., 70 to 245 ul. Thereafter without anesthesia additional blood samples of 0.5 to 1 ml were taken by cardiac puncture at 15 to 60 mm intervals for the following 4 h. For each time interval a different group of rats was bled so that no rat was bled more than 2 times during the course of the experiment in which not more than 2.0 ml blood was taken. Controls were bled twice and at both occasions ether anesthesia was
major
Foun-
168
DIFFERENCES
IN PROLACTIN
169
RESPONSE
N.
IC.,. a I2
32
‘I
a
i_.___7
II
-1
Il
121
t
N
Ii
a
Is.
in MINUTIS
FIG. 1. Serum PRL concentrations after administration of chlorpromazine (CPZ, 25 mg/kg body weight) to male rats aged 20, 40 and 60 days. (The mean ± SE is shown Numbers above the bars indicate the number of rats studied. Serum PRL levels in controls obtained at time intervals shown were not significantly different from those obtained from the first bleeding and therefore are not shown).
Is
S
a
ii.
is
MINUTSS
FIG. 2. Serum PRL concentrations after administration of chlorpromazine (CPZ, 25 mg/kg body weight) to female rats aged 20, 40 and 60 days. (The mean ± SE is shown. Numbers above the bars indicate the number of rats studied. Serum PRL levels in controls obtained at time intervals shown were not signi ficantly different from those obtained from the first bleeding and therefore are not shown).
RESULTS
Figure under
1 shows basal
serum
PRL
conditions
zinc
administration
PRL
concentrations
days
to 40
in
concentrations
and
after
chlorproma-
male
rats.
Basal
with
age
increased
days
(P
