0021-972X/90/7106-1434$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 71, No. 6 Printed in U.S.A.
Cocaine Effects on Luteinizing Hormone-Releasing Hormone-Stimulated Anterior Pituitary Hormones in Female Rhesus Monkey* NANCY K. MELLO, JACK H. MENDELSON, JOHN DRIEZE, AND MAUREEN KELLY Endocrine Research Unit, Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, Massachusetts 02178
ABSTRACT. The effects of acute cocaine administration on synthetic LHRH-stimulated anterior pituitary hormones (LH, FSH, and PRL) were studied in 6 female rhesus monkeys during the follicular phase of the menstrual cycle (days 4-7). Integrated plasma samples were collected every 10 min for 40 min before iv administration of cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control solution. Synthetic LHRH (100 fig, iv) was administered 10 min after cocaine or placebo-cocaine administration, and 10 plasma samples were collected for an additional 100 min. LHRH stimulated a significant increase in LH within 10 min after placebo-cocaine administration (P < 0.05) and after each dose of cocaine (P < 0.0001). Cocaine (0.4 mg/kg) significantly enhanced LHRH stimulation of LH compared to placebo or 0.8 mg/kg cocaine administration (P < 0.01). FSH increased significantly within 20-30 min after LHRH alone (P < 0.008) and after 0.4 mg/kg cocaine (P < 0.0001). LHRH-stimulated FSH levels also were significantly higher after 0.4 mg/kg cocaine than
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HE RECENT increase in cocaine abuse (1) has been paralleled by clinical evidence that chronic cocaine abuse is associated with reproductive system dysfunctions in men and women (2-4; see Ref. 5 for review). Amenorrhea and dysmenorrhea have been reported in women who abuse cocaine (2, 3). There is also evidence that cocaine use during pregnancy may be associated with fetal malformation and impaired neurobehavioral development (6) as well as increased risk for spontaneous abortion and abruptio placentae (5). The mechanisms underlying cocaine's toxic effects on reproductive function are unknown, but cocaine could disrupt Received March 19,1990. Address requests for reprints to: Nancy K. Mello, Ph.D., Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02178. * This work was supported in part by Grants DA-00101, DA-00064, and DA-04059 from the National Institute on Drug Abuse, Alcohol, Drug Abuse, and Mental Health Administration and Grant RR-05484 awarded to the McLean Hospital by the Biomedical Research Program, Division of Research Resources, NIH. Preliminary data were reported at the Annual Meeting of the Committee on Problems of Drug Dependence in 1989 and to the 21st Congress of the International Society of Psychoneuroendocrinology in 1990.
after placebo or 0.8 mg/kg cocaine (P < 0.01). These data indicate that cocaine does not suppress LHRH stimulation of pituitary gonadotropins, and low doses of cocaine significantly enhance LH and FSH release. Consequently, cocaine does not compromise anterior-pituitary function at the level of the gonadotroph and may stimulate hypothalamic release of endogenous LHRH. PRL levels were unchanged by LHRH and placebo-cocaine administration. After LHRH and cocaine administration, PRL levels decreased significantly (P < 0.05-0.01) and remained suppressed throughout the 110-min postcocaine sampling period. These data indicate that cocaine's significant suppression of PRL is not blocked by LHRH. These findings are consistent with dopaminergic inhibitory control of PRL and suggest that cocaine's inhibition of dopamine reuptake down-regulates pituitary lactotroph activity in rhesus monkey. (J Clin Endocrinol Metab 7 1 : 1434-1441, 1990)
menstrual cycle regularity by impairment of normal gonadotropin and/or PRL regulation. Hyperprolactinemia is the endocrine abnormality most often reported in clinical studies of cocaine abusers. Elevated PRL levels have been observed during cocaine abuse and cocaine withdrawal (2, 7, 8). Hyperprolactinemia with galactorrhea was reported in a female cocaine abuser 18 days after cocaine withdrawal (2). We recently found that male cocaine abusers with hyperprolactinemia had significantly higher peak PRL pulses and overall PRL levels (valley analysis) than normal controls or cocaine abusers with normal PRL levels, but PRL pulse frequency was equivalent in each group (8). These data are consistent with the hypothesis that chronic cocaine abuse may disrupt dopaminergic inhibition of PRL release. However, relatively low PRL levels during cocaine abuse have also been reported (9). We are unaware of any controlled clinical studies of the effects of acute cocaine intoxication on anterior pituitary function, and there have been surprisingly few studies in animal models. We recently found that cocaine significantly stimulated basal levels of LH within 20 min
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COCAINE EFFECTS ON LH, FSH, AND PRL in female rhesus monkeys during the follicular phase of the menstrual cycle (10). LH remained elevated for about 60 min, then gradually returned to baseline levels (10). There was no corresponding change in FSH after cocaine administration (10). These data are consistent with previous observations in ovariectomized rats that were given very high (10-20 mg/kg) doses of cocaine which produced seizure-like activity and occasionally death (11). However, LH decreased significantly in male rats after administration of 10 and 40 mg/kg cocaine (12) and in ovariectomized females after 40 mg/kg cocaine (11). One goal of the present study was to examine cocaine's effects on anterior pituitary function under conditions of synthetic LHRH stimulation. Synthetic LHRH mimics endogenous hypothalamic LHRH, which stimulates the release of anterior pituitary gonadotropins, LH and FSH (13). Synthetic LHRH is commonly used to assess pituitary function in clinical endocrinology (13). Attenuation of LHRH-stimulated LH and FSH would suggest that cocaine interferes with normal anterior pituitary function. Augmentation of LHRH stimulation would suggest that cocaine enhances pituitary release of gonadotropins and/or stimulates hypothalamic release of endogenous LHRH. The cocaine-induced increase in LH we previously observed in female rhesus monkeys was paralleled by a significant decrease in PRL (10). Since cocaine blocks dopamine reuptake (14), the PRL decrease was interpreted as reflecting an increase in dopamine inhibition. A rebound increase in PRL began about 80 min after cocaine administration (10), a period that corresponds to the half-life of cocaine in monkeys (15). It was not clear if this rebound PRL increase could be attributed to the pharmacokinetics of cocaine or was related to the antecedent increase in LH (10). LH and PRL pulsatile secretory activity is synchronous in human females, and LHRH stimulation increased the synchronous pulsatile release of LH and PRL (16, 17). Stimulation with the opioid antagonist naloxone also increased the number of synchronous pulses of LH and PRL in luteal phase women (18). In contrast, in intact and ovariectomized rhesus females, synchronous release of LH and PRL did not occur unless monkeys were anesthetized with pentobarbital (19,20). A midcycle increase in PRL occurs in concert with a preovulatory increase in LH in normal women (21) and rats (22), but this LH-PRL relationship has not been demonstrated in rhesus monkey (23). A second goal of the current study was to examine cocaine's effects on PRL under conditions of LHRH stimulation to determine if exogenous stimulation of gonadotropins influenced cocaine's suppressive effects on PRL. LHRH increases PRL in normal women at high doses (50 /ig iv bolus or 0.2 /ug/min infusion) (16, 17),
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but not at low doses (10 ng iv bolus) (24). Braund and co-workers (17) suggest that in humans, LHRH releases PRL stores in the lactotroph, but does not activate new synthesis or depletion transformation. The effect of LHRH on PRL in rhesus females is unknown. The present report is one of a series of studies designed to examine the acute and chronic effects of cocaine on pituitary and gonadal hormones in the primate model. This report describes a cocaine-related enhancement of LHRH-stimulated LH, a finding that confirms and extends our earlier observation that cocaine per se stimulates a significant increase in LH (10). Cocaine administration suppressed PRL levels despite LHRH administration, and LHRH alone had no significant effect on PRL. We interpret these data to indicate that acute exposure to cocaine does not compromise anterior pituitary function over the dose range studied.
Materials and Methods Subjects Six adult female rhesus monkeys (Macaca mulatto,; 4.9-9.6 kg) lived in individual cages in a room with sexually mature male monkeys and were maintained on ad libitum food and water. Monkey chow was supplemented with fresh fruit, vegetables, and multiple vitamins each day. A 12-h light, 12-h dark cycle (0700-1900 h) was in effect. All females had normal ovulatory menstrual cycles and had been adapted to the laboratory for at least 12 months before these studies began. No subject had a history of chronic drug exposure. All studies were conducted in the early follicular phase of the menstrual cycle (days 4-7). Vaginal swabs were performed daily to determine the onset and duration of menstrual bleeding. Each subject was used as her own control across conditions, and consecutive studies were separated by two menstrual cycles or about 8 weeks. Animal maintenance and research were conducted in accordance with the guidelines provided by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The facility is licensed by the U.S. Department of Agriculture. This protocol was approved by the McLean Hospital Institutional Animal Care and Use Committee. The health of the monkeys was periodically monitored by a consultant veterinarian from the New England Regional Primate Research Center. Cocaine dose and sequence of conditions
The acute effects of cocaine (0.4 and 0.8 mg/kg, iv) or placebo-cocaine and synthetic LHRH (gonadorelin hydrochloride; Factrel; 100 /ig, iv) on anterior pituitary hormones were evaluated under identical conditions. These cocaine doses are within the range shown to produce subjective and physiological effects in humans (total dose, 32-96 mg divided by 70 kg equals 0.457-1.37 mg/kg) (25). A cocaine dose of 1 mg/kg, iv, is safely tolerated in rhesus monkey (15), and the convulsant dose range is 3-8 mg/kg, iv (15, 26).
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Basal levels of LH, FSH, and PRL were measured for 40 min before cocaine or cocaine-placebo was administered. LHRH was administered 10 min after cocaine injection, and LH, FSH, and PRL were measured for an additional 100 min after LHRH administration. Integrated plasma samples were collected at 10-min intervals throughout the 150-min sampling period. The duration of sampling was determined in part by the half-life of cocaine, which is estimated to average 80 min after an iv bolus injection of 1 mg/kg in rhesus monkey (15). The 110-min postcocaine sampling period enabled us to follow hormonal changes during and after the period of maximal cocaine concentrations in plasma. The frequency of sampling was dictated by the pharmacokinetics of cocaine. Peak plasma levels of cocaine occur within 7.3 min in humans (27) and are well correlated with maximal increases in heart rate 8-12 min after cocaine treatment (28). Venous catheterization and integrated plasma sample collection procedures Monkeys were anesthetized with ketamine hydrochloride (510 mg/kg, im), which has been shown to have no effect on pituitary gonadotropins (29, 30). Ketamine doses of 10 mg increase PRL within 30 min, but PRL returns to baseline levels within 120 min (31). A 10-gauge needle containing a 22-gauge Deseret radiopaque intracath (Deseret Medical, Parke-Davis Co., Sandy, UT) was inserted into the saphenous vein using aseptic techniques. After removal of the needle and internal stylet, the catheter was joined to heparin-impregnated sterile silicon tubing and secured with sutures. The monkey was placed in a standard primate chair about 30 min before sample collection began. Blood was exfused with a Rainin Rabbit Miniature Peristaltic Pump (Rainin Instrument, Woburn, MA) into heparinized vacutainer tubes in chipped ice. An integrated plasma collection procedure was used because pituitary gonadotropins are secreted episodically (32). An integrated plasma sample reflects the true mean level of each hormone measured during the sample period, whereas a bolus sample might coincide with either the peak or the nadir of a LH pulse. Blood samples were exfused continuously over 150 min, and each sample contained 3-4 mL. Immediately after exfusion, samples were centrifuged, aliquots of plasma were withdrawn, and samples were frozen at -70 C. Cocaine administration Cocaine hydrochloride was obtained from NIDA, and solutions were prepared by dissolving cocaine in sterile saline for injection U.S.P. The solution was filter sterilized using a 0.11Hg Millipore filter (Bedford, MA). Cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control was infused into the saphenous vein of the leg opposite the exfusion catheter in a single bolus injection. LHRH administration Synthetic LHRH (gonadorelin hydrochloride; Factrel; 100 Hg, iv) was injected into the saphenous vein of the leg opposite the exfusion catheter in a single bolus injection 10 min after cocaine administration. This is the standard LHRH dose used
JCE & M • 1990 Vol 71 • No 6
for clinical evaluation of pituitary function, and it stimulated LH and FSH in female rhesus monkeys in our previous studies (33). The 10-min interval between cocaine infusion and LHRH administration was intended to ensure that the maximal effects of cocaine occurred during the initial phase of LHRH stimulation of LH. LH usually increases rapidly after iv LHRH administration and reached statistically significant peak levels within 30 min (33). Plasma hormone analyses Plasma LH, FSH, and PRL concentrations were determined in duplicate by a double antibody RIA procedure. The tube volume for each assay was as follows: LH, 0.1 mL; FSH, 0.1 mL; and PRL, 0.05 mL. The assay sensitivities for LH, FSH, and PRL were 1.33 IU/L; 0.05 IU/L; and 6.5 Mg/L, respectively. Intra- and interassay coefficients of variation were as follows: LH, 4.1% and 10.3%; FSH, 8.5% and 15.1%; PRL, 4% and 11.8%, respectively. Details of these RIA procedures, as used in this laboratory, have been reported previously (10). Statistical analysis The effects of cocaine and its placebo and LHRH on anterior pituitary hormones were evaluated with analysis of variance (ANOVA) for repeated measures. If ANOVA showed a significant main effect, Dunnett's multiple comparison procedure was used to determine which groups were statistically different from each other. ANOVA for repeated measures was also run for each dose group, and the significance of group mean values at each sample period was compared with the baseline mean using Dunnett's test for comparison of multiple experimental groups with a single control group. Probability levels of P < 0.050.0001 are reported as statistically significant.
Results LHRH effects on LH and FSH after placebo-cocaine and cocaine administration LHRH stimulated a significant increase in LH after both placebo-cocaine and low and high dose cocaine administration (P < 0.0001; Fig. 1, rows 1-3). LH increased significantly within 10 min after LHRH administration and reached peak levels within 20 min (P < 0.01). However, the LHRH-stimulated increase in LH was significantly higher after 0.4 mg/kg cocaine than after either placebo-cocaine or 0.8 mg/kg cocaine administration (P < 0.01; Fig. 1). The increase in LH after 0.4 mg/kg cocaine was 72%, in contrast to 33% and 45% after placebo-cocaine and 0.8 mg/kg cocaine, respectively. Baseline LH levels (samples 1-4) were equivalent in each cocaine dose condition and averaged between 5.4 ± 0.24 and 5.74 ± 0.20 IU/L. The pattern of LHRH-stimulated changes in FSH after placebo-cocaine and cocaine administration (Fig. 2) paralleled changes in LH (Fig. 1). LHRH stimulated a significant increase in FSH after placebo-cocaine ad-
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COCAINE EFFECTS ON LH, FSH, AND PRL
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N = 6 Cocaine Placebo, LHRH (100 meg)
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Consecutive 10 Min Samples 1
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Consecutive 10 Min Samples FIG. 1. Effects of cocaine or placebo on LHRH-stimulated LH (international units per L). Cocaine (0.4 or 0.8 mg/kg, iv) or placebo-cocaine was administered after sample 4. LHRH (100 tig, iv) was administered after sample 5. Integrated plasma samples were collected at 10-min intervals over 150 min. Each data point represents the mean (±SE) of six monkeys. Statistically significant changes from baseline LH levels (samples 1-4) are indicated by stars (*, P < 0.05; **, P < 0.01).
ministration (P < 0.008). FSH increased significantly within 30 min after LHRH administration, and peak FSH levels (P < 0.01) occurred within 40 min (sample 9; Fig. 2, row 1). FSH also increased significantly after LHRH and 0.4 mg/kg cocaine (P < 0.0001), but increases in FSH after 0.8 mg/kg cocaine were not statistically
FlG. 2. Effects on cocaine or placebo on LHRH-stimulated FSH (international units per L). Cocaine (0.4 or 0.8 mg/kg, iv) or placebo-cocaine was administered after sample 4. LHRH (100 fig, iv) was administered after sample 5. Integrated plasma samples were collected at 10-min intervals over 150 min. Each data point represents the mean (±SE) of six monkeys. Statistically significant changes from baseline FSH levels (samples 1-4) are indicated by stars (*, P < 0.05; **, P < 0.01).
significant (Fig. 2, rows 2 and 3). The LHRH-stimulated increase in FSH was significantly higher after 0.4 mg/kg cocaine than after placebo-cocaine or 0.8 mg/kg (P < 0.01). FSH increased by 42% within 30 min after 0.4 mg/ kg cocaine, in contrast to 22% and 23% after placebococaine and 0.8 mg/kg cocaine, respectively. Baseline FSH levels (samples 1-4) were significantly higher before 0.4 mg/kg cocaine administration (P < 0.05) than before placebo or 0.8 mg/kg cocaine administration. Baseline FSH levels averaged 0.45 ± 0.01 to 0.51 ± 0.02 IU/L.
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JCE & M • 1990 Vol 71 • No 6
N = 6
LHRH effects on PRL after placebo-cocaine and cocaine administration Baseline PRL levels (samples 1-4) averaged 32 ± 1.4, 35.5 ± 1.1, and 29 ± 1 Mg/L before administration of placebo and 0.4 and 0.8 mg/kg cocaine, respectively. PRL levels were significantly lower before 0.8 mg/kg cocaine administration than before the other two conditions (P < 0.01). These basal PRL levels are comparable to those previously measured in midluteal phase rhesus females (29.4 ± 5 to 39.6 ± 0.7 ^g/L) and follicular phase rhesus females (29.2 ± 0.89 to 35.7 ± 0.85 Mg/L) studied under comparable conditions (10, 34) and are within the normal range for venipuncture-adapted rhesus females (35 ng/ L) (35). PRL levels did not change significantly after placebococaine and LHRH administration (Fig. 3, row 1). PRL levels decreased significantly after cocaine (0.4 and 0.8 mg/kg) and LHRH administration (P < 0.05-0.01). PRL decreased by 22% to a nadir of 27.7 ± 4.4 ng/L within 80 min (sample 12) after 0.4 mg/kg cocaine administration (Fig. 3, row 2). PRL decreased by 22% to a nadir of 22.6 ± 4.5 Mg/L within 110 min (sample 15) after 0.8 mg/kg cocaine administration (Fig. 3, row 3). Discussion Acute effects of cocaine and LHRH on pituitary gonadotropins LHRH stimulated a significant increase in LH and FSH after placebo and cocaine administration. The magnitude of LHRH stimulation of LH (1.94-4.17 IU/L) was similar to that in our previous studies in follicular phase rhesus females (2.78 IU/L) (33). The low dose of cocaine (0.4 mg/kg) significantly enhanced LHRH-stimulated LH and FSH compared to placebo-cocaine conditions. These data are consistent with our previous report that cocaine alone (0.4 and 0.8 mg/kg) significantly increased LH in follicular phase rhesus females (10). Cocaine's augmentation of LHRH-stimulated LH was not dose related, and this also corresponds to our previous observations of the effects of cocaine alone on LH (10). LHRH plus cocaine significantly increased FSH levels in the present study, but cocaine alone did not change FSH levels (10). Synthetic LHRH mimics the effect of endogenous hypothalamic LHRH in stimulating the release of pituitary gonadotropins (13), and data shown in Figs. 1 and 2 suggest that cocaine does not impair the anterior pituitary response to LHRH stimulation. Cocaine's enhancement of LHRH-stimulated LH and FSH may reflect its stimulation of pituitary gonadotrophs, hypothalamic LHRH release, or both. Studies of cocaine's effects on LH after stimulation of hypothalamic release of en-
Cocaine Placebo, LHRH (100 meg)
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5
6
7
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9 10 11 12 13 14 15
Consecutive 10 Min Samples FIG. 3. Effects of cocaine or placebo and LHRH on PRL (micrograms per L). Cocaine (0.4 or 0.8 mg/kg, iv) or placebo-cocaine was administered after sample 4. LHRH (100 fig, iv) was administered after sample 5. Integrated plasma samples were collected at 10-min intervals over 150 min. Each data point represents the mean (±SE) of six monkeys.
dogenous LHRH with an opioid antagonist, such as naloxone or naltrexone, may help to clarify the site of cocaine's stimulatory actions (36, 37). Studies of cocaine's effects on naloxone-stimulated gonadotropins are currently underway in our laboratory. The increase in plasma LH levels also could be due to cocaine's effects on LH metabolism and/or secretion by the kidney. Cocaine administration may induce a brief but significant change in cardiovascular function (see Refs. 38 and 39 for review), which, in turn, could alter renal blood flow. However, the very rapid effect of cocaine on plasma LH observed in this study probably was
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COCAINE EFFECTS ON LH, FSH, AND PRL not due to a drug-induced change in LH metabolism. The circulating half-life of LH is approximately 1 h (40). Consequently, the significant increase in plasma LH within 10 min after cocaine administration could not be accounted for by a decrease in LH metabolism or excretion. A similar enhancement of LHRH-stimulated LH in follicular phase rhesus females was observed after acute administration of a high dose of alcohol (3.5 g/kg) when peak blood alcohol levels exceeded 300 mg/dL (33). Since alcohol significantly stimulates estradiol in women under basal conditions (41) and after opioid antagonist stimulation (42, 43), we postulated that alcohol might enhance pituitary sensitivity to LHRH by concurrent increases in estradiol (see Ref. 44 for review), but the applicability of such arguments to cocaine's effects on LH is unknown since we are unaware of any systematic studies of cocaine's effects on estradiol. The possible role of gonadal steroid modulation in cocaine's stimulation of LH remains to be determined. Cocaine's stimulation of LH and FSH and suppression of PRL are consistent with evidence that dopamine did not suppress basal LH levels or LHRH-stimulated LH at dose levels that significantly suppressed PRL in rhesus monkeys (45, 46). Pulsatile release of LH and PRL does not appear to be synchronous in rhesus monkey, as it is in women (16,17), unless monkeys are anesthetized with pentobarbital (19, 20). Physiological evidence also suggests that areas that regulate PRL and gonadotropin release are anatomically separate in monkeys (47). Acute effects of cocaine and LHRH on PRL LHRH did not stimulate pituitary PRL release after placebo-cocaine and did not prevent cocaine's suppression of PRL. The magnitude of PRL suppression after LHRH and low and high dose cocaine administration (22%; 7.74 and 6.25 /*g/L) was less than values we observed after low and high dose cocaine alone (9.7 and 11.09 /ug/L), but these differences were not statistically significant (10). PRL remained significantly suppressed throughout the 110-min postcocaine sampling period. These data are at variance with our previous observation that a rebound increase in PRL occurred within 80 min after the administration of cocaine alone (10), a period that corresponds to the half-life of iv cocaine in monkey plasma (15). A rebound increase in PRL also occurs after termination of dopamine infusions in rhesus monkeys (48) and humans (49). The persistence of cocaine-induced PRL suppression after cocaine plus LHRH observed in the present study probably reflects the influence of LHRH. LHRH stimulates PRL in normal women (16, 17, 50), but had no effect on PRL after placebo-cocaine treatment in these
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rhesus females. In ovariectomized rhesus monkeys, LHRH antagonists suppress PRL levels, and these effects can be reversed by the administration of a dopamine antagonist (51). However, these findings do not necessarily permit the inference that PRL suppression by a LHRH antagonist means that a LHRH agonist should stimulate PRL. We were unable to locate any previous studies of the effects of an LHRH agonist on PRL in female rhesus monkeys. Although anesthetization with ketamine (10 mg/kg) has been shown to increase PRL levels in monkeys (31), it is unlikely that ketamine contributed to the postcocaine suppression of PRL shown in Fig. 3. Ketamine-induced increases in PRL usually occur within 30 min, then return to baseline within 120 min (31). The first postcocaine sample (sample 5) was collected 102 ± 7 and 114 ± 8 min postketamine after the administration of 0.4 and 0.8 mg/kg cocaine, respectively. Moreover, PRL did not decrease after ketamine and placebo-cocaine treatment, which suggests that cocaine, rather than ketamine, accounted for the PRL suppression observed. Cocaine's blockade of dopamine reuptake and/or stimulation of hypothalamic dopamine release probably accounts for its acute effects on PRL. These data are consistent with evidence that PRL is under inhibitory dopaminergic control (see Refs. 22,40, and 50 for review). Dopamine infusions suppressed PRL levels in rhesus monkey (48, 52, 53) and humans (49). Moreover, dopamine suppression of PRL was not dose related over a range of 10-40 /ig/kg (52), a finding analogous to the effects of cocaine on PRL (10). Data shown in Fig. 3 confirm and extend previous observations of a significant suppression of PRL after acute cocaine administration to rhesus females (10) as well as male and ovariectomized female rats (11, 54). Acute and chronic cocaine exposure appear to have opposite effects on PRL. Chronic cocaine abuse is often associated with hyperprolactinemia during both active use and cocaine withdrawal in humans (2, 7, 8, 55), whereas single doses of cocaine suppress PRL in rhesus monkeys (10). A dissociation between acute and chronic effects of cocaine on PRL is consistent with current thinking about dopamine-cocaine interactions (see Ref. 55 for review). Although acute cocaine administration increases brain dopamine, probably by blocking synaptic reuptake (14), chronic cocaine administration may deplete dopamine. Protracted dopamine depletion is consistent with clinical observations of hyperprolactinemia during and after chronic cocaine abuse (55). In conclusion, the findings of the present study suggest that acute cocaine administration does not compromise anterior pituitary function, as assessed by gonadotropin response to LHRH stimulation. The cocaine-related enhancement of LHRH-stimulated LH and FSH release
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further suggests that cocaine may stimulate hypothalamic release of endogenous LHRH, which augments the effects of synthetic LHRH. It is possible that cocaine may reduce endogenous opioid peptide inhibition of hypothalamic LHRH. Studies of cocaine's effects on opioid antagonist-stimulated gonadotropins may clarify its effects on endogenous LHRH activity. Alternatively, cocaine may stimulate LH and FSH release at the level of the gonadotroph, but this cannot be determined from these data. The implications of the lack of a PRL response to LHRH are unclear. The discrepancy between LHRH effects on PRL in women (16, 17, 50) and female rhesus monkeys is most parsimoniously attributed to an unexplained species difference.
Acknowledgments We thank Nicolas Diaz-Migoyo and Michelle Kaviani for excellent technical assistance in data collection. We are grateful to Dr. James Ellingboe for advice on the RIA and the gas chromatographic procedures and to Dr. Prabhat Sehgal for veterinary consultation.
References 1. Kozel NJ, Adams EH. Epidemiology of drug abuse: an overview. Science. 1986;34:970-4. 2. Cocores JA, Dackis CA, Gold MS. Sexual dysfunction secondary to cocaine abuse in two patients. J Clin Psychiatry. 1986;47:384-7. 3. Siegel RK. Cocaine and sexual dysfunction: the curse of mama coca. J Psychoactive Drugs. 1982;14:71. 4. Smith DE, Wesson DR, Apter-Marsh M. Cocaine- and alcoholinduced sexual dysfunction in patients with addictive disease. J Psychoactive Drugs. 1984;16:359-61. 5. Creigler LL, Mark H. Medical complications of cocaine abuse. N Engl J Med. 1986;315:1495-500. 6. Chasnoff IJ, Burns WJ, Schnoll SH, Burns KA. Cocaine use in pregnancy. N Engl J Med. 1985;1313:666-9. 7. Mendelson JH, Teoh SK, Lange U, Mello NK, Weiss R, Skupny AST. Hyperprolactinemia during cocaine withdrawal. In: Harris LS, ed. Problems of drug dependence 1987. NIDA research monogr 81. DHHS publication (ADM) 88-1564. Washington DC: U.S. Government Printing Office; 1988;67-73. 8. Mendelson JH, Mello NK, Teoh SK, Ellingboe J, Cochin J. Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones. J Clin Endocrinol Metab. 1989;69:1256-60. 9. Gawin FH, Kleber HD. Neuroendocrine findings in chronic cocaine abusers: a preliminary report. Br J Psychiatry. 1985;247:569-73. 10. Mello N, Mendelson J, Drieze J, Kelly M. Acute effects of cocaine on prolactin and gonadotropins in female rhesus monkey during the follicular phase of the menstrual cycle. J Pharmacol Exp Ther. 1990;254:815-23. 11. Steger RW, Silverman AY, Johns A, Asch RH. Interactions of cocaine and delta-9-tetrahydrocannabinol with the hypothalamichypophysial axis of the female rat. Fertil Steril. 1981;35:567. 12. Berul CI, Harclerode JE. Effects of cocaine hydrochloride on the male reproductive system. Life Sci. 1989;45:91-5. 13. Yen SSC. Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs. Fertil Steril. 1983;39:257-66. 14. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237:1219-23. 15. Misra AL, Giri VV, Patel MN, Alluri VR, Mule SJ. Disposition and metabolism of (3H) cocaine in acutely and chronically treated monkeys. Drug Alcohol Depend. 1977;2:261-71. 16. Yen SSC, Hoff JD, Lasley BI, Casper RF, Sheehan K. Induction
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
30.
31. 32. 33. 34.
35.
36. 37.
38.
39. 40.
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of prolactin release by LRF and LRF-agonist. Life Sci. 1980;26:1963-7. Braund W, Roeger DC, Judd SJ. Synchronous secretion of luteinizing hormone and prolactin in the human luteal phase: neuroendocrine mechanisms. J Clin Endocrinol Metab. 1984;58:293. Gindoff PR, Jewelewicz R, Hembree W, Wardlaw S, Ferin M. Sustained effects of opioid antagonism during the normal human luteal phase. J Clin Endocrinol Metab. 1988;66:1000-4. Belchetz P, Dufy B, Knobil E. Identification of inhibitory and stimulatory control of prolactin secretion in the rhesus monkey. Neuroendocrinology. 1978;27:32-8. Wehrenberg WB, Ferin M. Regulation of pulsatile prolactin secretion in primates. Biol Reprod. 1982;27:99-103. Lenton EA, Landgren B. The normal menstrual cycle. In: Shearman RP, ed. Clinical reproductive endocrinology. Edinburgh: Churchill Livingstone; 1985;81-108. Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev. 1985;6:564-89. Quadri SK, Spies HG. Cyclic and diurnal patterns of serum prolactin in the rhesus monkey. Biol Reprod. 1976;14:495-501. Mais V, Yen SSC. Prolactin-releasing action of gonadotropinreleasing hormone in hypogonadal women. J Clin Endocrinol Metab. 1986;62:1089-92. Fischman MW, Schuster CR, Javaid J, Hatano Y, Davis J. Acute tolerance development to the cardiovascular and subjective effects of cocaine. J Pharmacol Exp Ther. 1985;235:677-82. Matsuzaki M, Misra AL. Comparison of the convulsant effects of cocaine and pseudococaine in the rhesus monkey. Brain Res Bull. 1977;2:421-4. Chow MJ, Ambre JJ, Ruo TI, Atkinson AJ, Bowsher DJ, Fischman MW. Kinetics of cocaine distribution, elimination, and chronotropic effects. Clin Pharmacol Ther. 1985;38:318-24. Fischman MW, Schuster CR. Cocaine self-administration in humans. Fed Proc. 1982;41:241-6. Ferin M, Carmel PW, Warren MP, Himsworth RL, Frantz AG. Phencyclidine sedation as a technique for handling rhesus monkeys: effects on LH, GnRH and prolactin secretion. Proc Soc Exp Biol Med. 1976;151:428-33. Fuller GB, Hobson WC, Reyes FI, Winter JSD, Faimans C. Influence of restraint and ketamine anesthesia on adrenal steroids, progesterone and gonadotropins in rhesus monkeys. Proc Soc Exp Biol Med. 1984;175:487-90. Quadri SK, Pierson C, Spies HG. Effects of centrally acting drugs on serum prolactin levels in rhesus monkeys. Neuroendocrinology. 1978;27:136-47. Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53-88. Mello NK, Mendelson JH, Bree MP, Skupny AST. Alcohol effects on LHRH stimulated LH and FSH in female rhesus monkeys. J Pharmacol Exp Ther. 1986;236:590-5. Mello NK, Mendelson JH, Bree MP, Skupny A. Alcohol effects on naloxone-stimulated luteinizing hormone, follicle stimulating hormone and prolactin plasma levels in female rhesus monkeys. J Pharmacol Exp Ther, 1988;245:895-904. Blank MS, Gordon TP, Wilson ME. Effects of capture and venipuncture on serum levels of prolactin, growth hormone and cortisol in outdoor compound-housed female rhesus monkeys (Macaca mulatta). Acta Endocrinol (Copenh). 1983;102:190-5. Mendelson JH, Mello NK, Cristofaro P, Skupny A, Ellingboe J. Use of naltrexone as a provocative test for hypothalamic-pituitary hormone function. Pharmacol Biochem Behav. 1986;24:309-13. Yen SSC, Quigley ME, Reid RL, Ropert JF, Cetel NS. Neuroendocrinology of opioid peptides and their role in the control of gonadotropin and prolactin secretion. Am J Obstet Gynecol. 1985;152:485-93. Mendelson JH, Mello NK. Commonly abused drugs. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison's principles of internal medicine, 11th ed. New York: McGraw-Hill; 1986;2115-8. Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol Rev. 1989;41:3-52. Yen SSC. Neuroendocrine control of hypophyseal function. In: Yen
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41. 42. 43.
44.
45.
46.
47.
SSC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia: Saunders; 1986;33-74. Mendelson JH, Lukas SE, Mello NK, Amass L, Ellingboe J, Skupny A. Acute alcohol effects on plasma estradiol levels in women. Psychopharmacology. 1988;94:464-7. Mendelson JH, Mello NK, Cristofaro P, et al. Alcohol effects on naloxone-stimulated luteinizing hormone, prolactin and estradiol in women. J Stud Alcohol. 1987;48:287-94. Teoh SK, Mendelson JH, Mello NK, Skupny A. Alcohol effects on naltrexone-induced stimulation of pituitary, adrenal and gonadal hormones during the early follicular phase of the menstrual cycle. J Clin Endocrinol Metab. 1988;66:1181-6. Mello NK, Mendelson JH, Teoh SK. Neuroendocrine consequences of alcohol abuse in women. In: Hutchings DE, ed. Prenatal abuse of licit and illicit drugs. New York: New York Academy of Sciences; 1989;562:211-40. Spies HG, Quadri SK, Chappel SC, Norman RL. Dopaminergic and opioid compounds: effects on prolactin and LH release after electrical stimulation of the hypothalamus in ovariectomized rhesus monkeys. Neuroendocrinology. 1980;30:249-56. Pavasuthipaisit K, Hess DL, Norman RL, Adams TE, Baughman WL, Spies HG. Dopamine: effects on prolactin and luteinizing hormone secretion in ovariectomized rhesus macaques after transection of the pituitary stalk. Neuroendocrinology. 1981;32:42-9. Plant TM, Krey LC, Moossy J, McCormack JT, Hess DL, Knobil E. The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatto).
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Endocrinology. 1978;102:52-62. 48. Frawley LS, Neill JD. Brief decreases in dopamine result in surges of prolactin secretion in monkeys. Am J Physiol. 1984;247:E77880. 49. Yen SSC. Studies of the role of dopamine in the control of prolactin and gondotropic secretion in humans. In: Fuxe K, Hokfelt T, Luft R, eds. Central regulation of the endocrine system. New York: Plenum Press; 1979;387-416. 50. Yen SSC. Prolactin in human reproduction. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia: Saunders; 1986;178-263. 51. Geisthoevel F, Arana JB, Balmaceda JP, Rojas FJ, Asch RH. Prolactin and gonadotrophin dynamics in response to antagonists of LHRH and dopamine in ovariectomized rhesus monkeys: a dissection of their common secretion. Hum Reprod. 1988;3:591-5. 52. Norman RL, Quadri SK, Spies HG. Differential sensitivity of prolactin release to dopamine and thyrotrophin-releasing hormone in intact and pituitary stalk-sectioned rhesus monkeys. J Endocrinol. 84:479-87. 53. Neill JD, Frawley LS, Plotsky PM, Tindall GI. Dopamine in hypophysial stalk blood of the rhesus monkey and its role in regulating prolactin secretion. Endocrinology. 1981;108:489-94. 54. Ravitz AJ, Moore KE. Effects of amphetamine, methylphenidate and cocaine on serum prolactin concentrations in the male rat. Life Sci. 1977;21:167-272. 55. Dackis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev. 1985;9:469-77.
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Vol. 71, No. 6 Printed in U.S.A.
Cocaine Effects on Luteinizing Hormone-Releasing Hormone-Stimulated Anterior Pituitary Hormones in Female Rhesus Monkey* NANCY K. MELLO, JACK H. MENDELSON, JOHN DRIEZE, AND MAUREEN KELLY Endocrine Research Unit, Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, Belmont, Massachusetts 02178
ABSTRACT. The effects of acute cocaine administration on synthetic LHRH-stimulated anterior pituitary hormones (LH, FSH, and PRL) were studied in 6 female rhesus monkeys during the follicular phase of the menstrual cycle (days 4-7). Integrated plasma samples were collected every 10 min for 40 min before iv administration of cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control solution. Synthetic LHRH (100 fig, iv) was administered 10 min after cocaine or placebo-cocaine administration, and 10 plasma samples were collected for an additional 100 min. LHRH stimulated a significant increase in LH within 10 min after placebo-cocaine administration (P < 0.05) and after each dose of cocaine (P < 0.0001). Cocaine (0.4 mg/kg) significantly enhanced LHRH stimulation of LH compared to placebo or 0.8 mg/kg cocaine administration (P < 0.01). FSH increased significantly within 20-30 min after LHRH alone (P < 0.008) and after 0.4 mg/kg cocaine (P < 0.0001). LHRH-stimulated FSH levels also were significantly higher after 0.4 mg/kg cocaine than
T
HE RECENT increase in cocaine abuse (1) has been paralleled by clinical evidence that chronic cocaine abuse is associated with reproductive system dysfunctions in men and women (2-4; see Ref. 5 for review). Amenorrhea and dysmenorrhea have been reported in women who abuse cocaine (2, 3). There is also evidence that cocaine use during pregnancy may be associated with fetal malformation and impaired neurobehavioral development (6) as well as increased risk for spontaneous abortion and abruptio placentae (5). The mechanisms underlying cocaine's toxic effects on reproductive function are unknown, but cocaine could disrupt Received March 19,1990. Address requests for reprints to: Nancy K. Mello, Ph.D., Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, 115 Mill Street, Belmont, Massachusetts 02178. * This work was supported in part by Grants DA-00101, DA-00064, and DA-04059 from the National Institute on Drug Abuse, Alcohol, Drug Abuse, and Mental Health Administration and Grant RR-05484 awarded to the McLean Hospital by the Biomedical Research Program, Division of Research Resources, NIH. Preliminary data were reported at the Annual Meeting of the Committee on Problems of Drug Dependence in 1989 and to the 21st Congress of the International Society of Psychoneuroendocrinology in 1990.
after placebo or 0.8 mg/kg cocaine (P < 0.01). These data indicate that cocaine does not suppress LHRH stimulation of pituitary gonadotropins, and low doses of cocaine significantly enhance LH and FSH release. Consequently, cocaine does not compromise anterior-pituitary function at the level of the gonadotroph and may stimulate hypothalamic release of endogenous LHRH. PRL levels were unchanged by LHRH and placebo-cocaine administration. After LHRH and cocaine administration, PRL levels decreased significantly (P < 0.05-0.01) and remained suppressed throughout the 110-min postcocaine sampling period. These data indicate that cocaine's significant suppression of PRL is not blocked by LHRH. These findings are consistent with dopaminergic inhibitory control of PRL and suggest that cocaine's inhibition of dopamine reuptake down-regulates pituitary lactotroph activity in rhesus monkey. (J Clin Endocrinol Metab 7 1 : 1434-1441, 1990)
menstrual cycle regularity by impairment of normal gonadotropin and/or PRL regulation. Hyperprolactinemia is the endocrine abnormality most often reported in clinical studies of cocaine abusers. Elevated PRL levels have been observed during cocaine abuse and cocaine withdrawal (2, 7, 8). Hyperprolactinemia with galactorrhea was reported in a female cocaine abuser 18 days after cocaine withdrawal (2). We recently found that male cocaine abusers with hyperprolactinemia had significantly higher peak PRL pulses and overall PRL levels (valley analysis) than normal controls or cocaine abusers with normal PRL levels, but PRL pulse frequency was equivalent in each group (8). These data are consistent with the hypothesis that chronic cocaine abuse may disrupt dopaminergic inhibition of PRL release. However, relatively low PRL levels during cocaine abuse have also been reported (9). We are unaware of any controlled clinical studies of the effects of acute cocaine intoxication on anterior pituitary function, and there have been surprisingly few studies in animal models. We recently found that cocaine significantly stimulated basal levels of LH within 20 min
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COCAINE EFFECTS ON LH, FSH, AND PRL in female rhesus monkeys during the follicular phase of the menstrual cycle (10). LH remained elevated for about 60 min, then gradually returned to baseline levels (10). There was no corresponding change in FSH after cocaine administration (10). These data are consistent with previous observations in ovariectomized rats that were given very high (10-20 mg/kg) doses of cocaine which produced seizure-like activity and occasionally death (11). However, LH decreased significantly in male rats after administration of 10 and 40 mg/kg cocaine (12) and in ovariectomized females after 40 mg/kg cocaine (11). One goal of the present study was to examine cocaine's effects on anterior pituitary function under conditions of synthetic LHRH stimulation. Synthetic LHRH mimics endogenous hypothalamic LHRH, which stimulates the release of anterior pituitary gonadotropins, LH and FSH (13). Synthetic LHRH is commonly used to assess pituitary function in clinical endocrinology (13). Attenuation of LHRH-stimulated LH and FSH would suggest that cocaine interferes with normal anterior pituitary function. Augmentation of LHRH stimulation would suggest that cocaine enhances pituitary release of gonadotropins and/or stimulates hypothalamic release of endogenous LHRH. The cocaine-induced increase in LH we previously observed in female rhesus monkeys was paralleled by a significant decrease in PRL (10). Since cocaine blocks dopamine reuptake (14), the PRL decrease was interpreted as reflecting an increase in dopamine inhibition. A rebound increase in PRL began about 80 min after cocaine administration (10), a period that corresponds to the half-life of cocaine in monkeys (15). It was not clear if this rebound PRL increase could be attributed to the pharmacokinetics of cocaine or was related to the antecedent increase in LH (10). LH and PRL pulsatile secretory activity is synchronous in human females, and LHRH stimulation increased the synchronous pulsatile release of LH and PRL (16, 17). Stimulation with the opioid antagonist naloxone also increased the number of synchronous pulses of LH and PRL in luteal phase women (18). In contrast, in intact and ovariectomized rhesus females, synchronous release of LH and PRL did not occur unless monkeys were anesthetized with pentobarbital (19,20). A midcycle increase in PRL occurs in concert with a preovulatory increase in LH in normal women (21) and rats (22), but this LH-PRL relationship has not been demonstrated in rhesus monkey (23). A second goal of the current study was to examine cocaine's effects on PRL under conditions of LHRH stimulation to determine if exogenous stimulation of gonadotropins influenced cocaine's suppressive effects on PRL. LHRH increases PRL in normal women at high doses (50 /ig iv bolus or 0.2 /ug/min infusion) (16, 17),
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but not at low doses (10 ng iv bolus) (24). Braund and co-workers (17) suggest that in humans, LHRH releases PRL stores in the lactotroph, but does not activate new synthesis or depletion transformation. The effect of LHRH on PRL in rhesus females is unknown. The present report is one of a series of studies designed to examine the acute and chronic effects of cocaine on pituitary and gonadal hormones in the primate model. This report describes a cocaine-related enhancement of LHRH-stimulated LH, a finding that confirms and extends our earlier observation that cocaine per se stimulates a significant increase in LH (10). Cocaine administration suppressed PRL levels despite LHRH administration, and LHRH alone had no significant effect on PRL. We interpret these data to indicate that acute exposure to cocaine does not compromise anterior pituitary function over the dose range studied.
Materials and Methods Subjects Six adult female rhesus monkeys (Macaca mulatto,; 4.9-9.6 kg) lived in individual cages in a room with sexually mature male monkeys and were maintained on ad libitum food and water. Monkey chow was supplemented with fresh fruit, vegetables, and multiple vitamins each day. A 12-h light, 12-h dark cycle (0700-1900 h) was in effect. All females had normal ovulatory menstrual cycles and had been adapted to the laboratory for at least 12 months before these studies began. No subject had a history of chronic drug exposure. All studies were conducted in the early follicular phase of the menstrual cycle (days 4-7). Vaginal swabs were performed daily to determine the onset and duration of menstrual bleeding. Each subject was used as her own control across conditions, and consecutive studies were separated by two menstrual cycles or about 8 weeks. Animal maintenance and research were conducted in accordance with the guidelines provided by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The facility is licensed by the U.S. Department of Agriculture. This protocol was approved by the McLean Hospital Institutional Animal Care and Use Committee. The health of the monkeys was periodically monitored by a consultant veterinarian from the New England Regional Primate Research Center. Cocaine dose and sequence of conditions
The acute effects of cocaine (0.4 and 0.8 mg/kg, iv) or placebo-cocaine and synthetic LHRH (gonadorelin hydrochloride; Factrel; 100 /ig, iv) on anterior pituitary hormones were evaluated under identical conditions. These cocaine doses are within the range shown to produce subjective and physiological effects in humans (total dose, 32-96 mg divided by 70 kg equals 0.457-1.37 mg/kg) (25). A cocaine dose of 1 mg/kg, iv, is safely tolerated in rhesus monkey (15), and the convulsant dose range is 3-8 mg/kg, iv (15, 26).
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Basal levels of LH, FSH, and PRL were measured for 40 min before cocaine or cocaine-placebo was administered. LHRH was administered 10 min after cocaine injection, and LH, FSH, and PRL were measured for an additional 100 min after LHRH administration. Integrated plasma samples were collected at 10-min intervals throughout the 150-min sampling period. The duration of sampling was determined in part by the half-life of cocaine, which is estimated to average 80 min after an iv bolus injection of 1 mg/kg in rhesus monkey (15). The 110-min postcocaine sampling period enabled us to follow hormonal changes during and after the period of maximal cocaine concentrations in plasma. The frequency of sampling was dictated by the pharmacokinetics of cocaine. Peak plasma levels of cocaine occur within 7.3 min in humans (27) and are well correlated with maximal increases in heart rate 8-12 min after cocaine treatment (28). Venous catheterization and integrated plasma sample collection procedures Monkeys were anesthetized with ketamine hydrochloride (510 mg/kg, im), which has been shown to have no effect on pituitary gonadotropins (29, 30). Ketamine doses of 10 mg increase PRL within 30 min, but PRL returns to baseline levels within 120 min (31). A 10-gauge needle containing a 22-gauge Deseret radiopaque intracath (Deseret Medical, Parke-Davis Co., Sandy, UT) was inserted into the saphenous vein using aseptic techniques. After removal of the needle and internal stylet, the catheter was joined to heparin-impregnated sterile silicon tubing and secured with sutures. The monkey was placed in a standard primate chair about 30 min before sample collection began. Blood was exfused with a Rainin Rabbit Miniature Peristaltic Pump (Rainin Instrument, Woburn, MA) into heparinized vacutainer tubes in chipped ice. An integrated plasma collection procedure was used because pituitary gonadotropins are secreted episodically (32). An integrated plasma sample reflects the true mean level of each hormone measured during the sample period, whereas a bolus sample might coincide with either the peak or the nadir of a LH pulse. Blood samples were exfused continuously over 150 min, and each sample contained 3-4 mL. Immediately after exfusion, samples were centrifuged, aliquots of plasma were withdrawn, and samples were frozen at -70 C. Cocaine administration Cocaine hydrochloride was obtained from NIDA, and solutions were prepared by dissolving cocaine in sterile saline for injection U.S.P. The solution was filter sterilized using a 0.11Hg Millipore filter (Bedford, MA). Cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control was infused into the saphenous vein of the leg opposite the exfusion catheter in a single bolus injection. LHRH administration Synthetic LHRH (gonadorelin hydrochloride; Factrel; 100 Hg, iv) was injected into the saphenous vein of the leg opposite the exfusion catheter in a single bolus injection 10 min after cocaine administration. This is the standard LHRH dose used
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for clinical evaluation of pituitary function, and it stimulated LH and FSH in female rhesus monkeys in our previous studies (33). The 10-min interval between cocaine infusion and LHRH administration was intended to ensure that the maximal effects of cocaine occurred during the initial phase of LHRH stimulation of LH. LH usually increases rapidly after iv LHRH administration and reached statistically significant peak levels within 30 min (33). Plasma hormone analyses Plasma LH, FSH, and PRL concentrations were determined in duplicate by a double antibody RIA procedure. The tube volume for each assay was as follows: LH, 0.1 mL; FSH, 0.1 mL; and PRL, 0.05 mL. The assay sensitivities for LH, FSH, and PRL were 1.33 IU/L; 0.05 IU/L; and 6.5 Mg/L, respectively. Intra- and interassay coefficients of variation were as follows: LH, 4.1% and 10.3%; FSH, 8.5% and 15.1%; PRL, 4% and 11.8%, respectively. Details of these RIA procedures, as used in this laboratory, have been reported previously (10). Statistical analysis The effects of cocaine and its placebo and LHRH on anterior pituitary hormones were evaluated with analysis of variance (ANOVA) for repeated measures. If ANOVA showed a significant main effect, Dunnett's multiple comparison procedure was used to determine which groups were statistically different from each other. ANOVA for repeated measures was also run for each dose group, and the significance of group mean values at each sample period was compared with the baseline mean using Dunnett's test for comparison of multiple experimental groups with a single control group. Probability levels of P < 0.050.0001 are reported as statistically significant.
Results LHRH effects on LH and FSH after placebo-cocaine and cocaine administration LHRH stimulated a significant increase in LH after both placebo-cocaine and low and high dose cocaine administration (P < 0.0001; Fig. 1, rows 1-3). LH increased significantly within 10 min after LHRH administration and reached peak levels within 20 min (P < 0.01). However, the LHRH-stimulated increase in LH was significantly higher after 0.4 mg/kg cocaine than after either placebo-cocaine or 0.8 mg/kg cocaine administration (P < 0.01; Fig. 1). The increase in LH after 0.4 mg/kg cocaine was 72%, in contrast to 33% and 45% after placebo-cocaine and 0.8 mg/kg cocaine, respectively. Baseline LH levels (samples 1-4) were equivalent in each cocaine dose condition and averaged between 5.4 ± 0.24 and 5.74 ± 0.20 IU/L. The pattern of LHRH-stimulated changes in FSH after placebo-cocaine and cocaine administration (Fig. 2) paralleled changes in LH (Fig. 1). LHRH stimulated a significant increase in FSH after placebo-cocaine ad-
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COCAINE EFFECTS ON LH, FSH, AND PRL
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N = 6 Cocaine Placebo, LHRH (100 meg)
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Consecutive 10 Min Samples FIG. 1. Effects of cocaine or placebo on LHRH-stimulated LH (international units per L). Cocaine (0.4 or 0.8 mg/kg, iv) or placebo-cocaine was administered after sample 4. LHRH (100 tig, iv) was administered after sample 5. Integrated plasma samples were collected at 10-min intervals over 150 min. Each data point represents the mean (±SE) of six monkeys. Statistically significant changes from baseline LH levels (samples 1-4) are indicated by stars (*, P < 0.05; **, P < 0.01).
ministration (P < 0.008). FSH increased significantly within 30 min after LHRH administration, and peak FSH levels (P < 0.01) occurred within 40 min (sample 9; Fig. 2, row 1). FSH also increased significantly after LHRH and 0.4 mg/kg cocaine (P < 0.0001), but increases in FSH after 0.8 mg/kg cocaine were not statistically
FlG. 2. Effects on cocaine or placebo on LHRH-stimulated FSH (international units per L). Cocaine (0.4 or 0.8 mg/kg, iv) or placebo-cocaine was administered after sample 4. LHRH (100 fig, iv) was administered after sample 5. Integrated plasma samples were collected at 10-min intervals over 150 min. Each data point represents the mean (±SE) of six monkeys. Statistically significant changes from baseline FSH levels (samples 1-4) are indicated by stars (*, P < 0.05; **, P < 0.01).
significant (Fig. 2, rows 2 and 3). The LHRH-stimulated increase in FSH was significantly higher after 0.4 mg/kg cocaine than after placebo-cocaine or 0.8 mg/kg (P < 0.01). FSH increased by 42% within 30 min after 0.4 mg/ kg cocaine, in contrast to 22% and 23% after placebococaine and 0.8 mg/kg cocaine, respectively. Baseline FSH levels (samples 1-4) were significantly higher before 0.4 mg/kg cocaine administration (P < 0.05) than before placebo or 0.8 mg/kg cocaine administration. Baseline FSH levels averaged 0.45 ± 0.01 to 0.51 ± 0.02 IU/L.
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JCE & M • 1990 Vol 71 • No 6
N = 6
LHRH effects on PRL after placebo-cocaine and cocaine administration Baseline PRL levels (samples 1-4) averaged 32 ± 1.4, 35.5 ± 1.1, and 29 ± 1 Mg/L before administration of placebo and 0.4 and 0.8 mg/kg cocaine, respectively. PRL levels were significantly lower before 0.8 mg/kg cocaine administration than before the other two conditions (P < 0.01). These basal PRL levels are comparable to those previously measured in midluteal phase rhesus females (29.4 ± 5 to 39.6 ± 0.7 ^g/L) and follicular phase rhesus females (29.2 ± 0.89 to 35.7 ± 0.85 Mg/L) studied under comparable conditions (10, 34) and are within the normal range for venipuncture-adapted rhesus females (35 ng/ L) (35). PRL levels did not change significantly after placebococaine and LHRH administration (Fig. 3, row 1). PRL levels decreased significantly after cocaine (0.4 and 0.8 mg/kg) and LHRH administration (P < 0.05-0.01). PRL decreased by 22% to a nadir of 27.7 ± 4.4 ng/L within 80 min (sample 12) after 0.4 mg/kg cocaine administration (Fig. 3, row 2). PRL decreased by 22% to a nadir of 22.6 ± 4.5 Mg/L within 110 min (sample 15) after 0.8 mg/kg cocaine administration (Fig. 3, row 3). Discussion Acute effects of cocaine and LHRH on pituitary gonadotropins LHRH stimulated a significant increase in LH and FSH after placebo and cocaine administration. The magnitude of LHRH stimulation of LH (1.94-4.17 IU/L) was similar to that in our previous studies in follicular phase rhesus females (2.78 IU/L) (33). The low dose of cocaine (0.4 mg/kg) significantly enhanced LHRH-stimulated LH and FSH compared to placebo-cocaine conditions. These data are consistent with our previous report that cocaine alone (0.4 and 0.8 mg/kg) significantly increased LH in follicular phase rhesus females (10). Cocaine's augmentation of LHRH-stimulated LH was not dose related, and this also corresponds to our previous observations of the effects of cocaine alone on LH (10). LHRH plus cocaine significantly increased FSH levels in the present study, but cocaine alone did not change FSH levels (10). Synthetic LHRH mimics the effect of endogenous hypothalamic LHRH in stimulating the release of pituitary gonadotropins (13), and data shown in Figs. 1 and 2 suggest that cocaine does not impair the anterior pituitary response to LHRH stimulation. Cocaine's enhancement of LHRH-stimulated LH and FSH may reflect its stimulation of pituitary gonadotrophs, hypothalamic LHRH release, or both. Studies of cocaine's effects on LH after stimulation of hypothalamic release of en-
Cocaine Placebo, LHRH (100 meg)
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Consecutive 10 Min Samples FIG. 3. Effects of cocaine or placebo and LHRH on PRL (micrograms per L). Cocaine (0.4 or 0.8 mg/kg, iv) or placebo-cocaine was administered after sample 4. LHRH (100 fig, iv) was administered after sample 5. Integrated plasma samples were collected at 10-min intervals over 150 min. Each data point represents the mean (±SE) of six monkeys.
dogenous LHRH with an opioid antagonist, such as naloxone or naltrexone, may help to clarify the site of cocaine's stimulatory actions (36, 37). Studies of cocaine's effects on naloxone-stimulated gonadotropins are currently underway in our laboratory. The increase in plasma LH levels also could be due to cocaine's effects on LH metabolism and/or secretion by the kidney. Cocaine administration may induce a brief but significant change in cardiovascular function (see Refs. 38 and 39 for review), which, in turn, could alter renal blood flow. However, the very rapid effect of cocaine on plasma LH observed in this study probably was
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COCAINE EFFECTS ON LH, FSH, AND PRL not due to a drug-induced change in LH metabolism. The circulating half-life of LH is approximately 1 h (40). Consequently, the significant increase in plasma LH within 10 min after cocaine administration could not be accounted for by a decrease in LH metabolism or excretion. A similar enhancement of LHRH-stimulated LH in follicular phase rhesus females was observed after acute administration of a high dose of alcohol (3.5 g/kg) when peak blood alcohol levels exceeded 300 mg/dL (33). Since alcohol significantly stimulates estradiol in women under basal conditions (41) and after opioid antagonist stimulation (42, 43), we postulated that alcohol might enhance pituitary sensitivity to LHRH by concurrent increases in estradiol (see Ref. 44 for review), but the applicability of such arguments to cocaine's effects on LH is unknown since we are unaware of any systematic studies of cocaine's effects on estradiol. The possible role of gonadal steroid modulation in cocaine's stimulation of LH remains to be determined. Cocaine's stimulation of LH and FSH and suppression of PRL are consistent with evidence that dopamine did not suppress basal LH levels or LHRH-stimulated LH at dose levels that significantly suppressed PRL in rhesus monkeys (45, 46). Pulsatile release of LH and PRL does not appear to be synchronous in rhesus monkey, as it is in women (16,17), unless monkeys are anesthetized with pentobarbital (19, 20). Physiological evidence also suggests that areas that regulate PRL and gonadotropin release are anatomically separate in monkeys (47). Acute effects of cocaine and LHRH on PRL LHRH did not stimulate pituitary PRL release after placebo-cocaine and did not prevent cocaine's suppression of PRL. The magnitude of PRL suppression after LHRH and low and high dose cocaine administration (22%; 7.74 and 6.25 /*g/L) was less than values we observed after low and high dose cocaine alone (9.7 and 11.09 /ug/L), but these differences were not statistically significant (10). PRL remained significantly suppressed throughout the 110-min postcocaine sampling period. These data are at variance with our previous observation that a rebound increase in PRL occurred within 80 min after the administration of cocaine alone (10), a period that corresponds to the half-life of iv cocaine in monkey plasma (15). A rebound increase in PRL also occurs after termination of dopamine infusions in rhesus monkeys (48) and humans (49). The persistence of cocaine-induced PRL suppression after cocaine plus LHRH observed in the present study probably reflects the influence of LHRH. LHRH stimulates PRL in normal women (16, 17, 50), but had no effect on PRL after placebo-cocaine treatment in these
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rhesus females. In ovariectomized rhesus monkeys, LHRH antagonists suppress PRL levels, and these effects can be reversed by the administration of a dopamine antagonist (51). However, these findings do not necessarily permit the inference that PRL suppression by a LHRH antagonist means that a LHRH agonist should stimulate PRL. We were unable to locate any previous studies of the effects of an LHRH agonist on PRL in female rhesus monkeys. Although anesthetization with ketamine (10 mg/kg) has been shown to increase PRL levels in monkeys (31), it is unlikely that ketamine contributed to the postcocaine suppression of PRL shown in Fig. 3. Ketamine-induced increases in PRL usually occur within 30 min, then return to baseline within 120 min (31). The first postcocaine sample (sample 5) was collected 102 ± 7 and 114 ± 8 min postketamine after the administration of 0.4 and 0.8 mg/kg cocaine, respectively. Moreover, PRL did not decrease after ketamine and placebo-cocaine treatment, which suggests that cocaine, rather than ketamine, accounted for the PRL suppression observed. Cocaine's blockade of dopamine reuptake and/or stimulation of hypothalamic dopamine release probably accounts for its acute effects on PRL. These data are consistent with evidence that PRL is under inhibitory dopaminergic control (see Refs. 22,40, and 50 for review). Dopamine infusions suppressed PRL levels in rhesus monkey (48, 52, 53) and humans (49). Moreover, dopamine suppression of PRL was not dose related over a range of 10-40 /ig/kg (52), a finding analogous to the effects of cocaine on PRL (10). Data shown in Fig. 3 confirm and extend previous observations of a significant suppression of PRL after acute cocaine administration to rhesus females (10) as well as male and ovariectomized female rats (11, 54). Acute and chronic cocaine exposure appear to have opposite effects on PRL. Chronic cocaine abuse is often associated with hyperprolactinemia during both active use and cocaine withdrawal in humans (2, 7, 8, 55), whereas single doses of cocaine suppress PRL in rhesus monkeys (10). A dissociation between acute and chronic effects of cocaine on PRL is consistent with current thinking about dopamine-cocaine interactions (see Ref. 55 for review). Although acute cocaine administration increases brain dopamine, probably by blocking synaptic reuptake (14), chronic cocaine administration may deplete dopamine. Protracted dopamine depletion is consistent with clinical observations of hyperprolactinemia during and after chronic cocaine abuse (55). In conclusion, the findings of the present study suggest that acute cocaine administration does not compromise anterior pituitary function, as assessed by gonadotropin response to LHRH stimulation. The cocaine-related enhancement of LHRH-stimulated LH and FSH release
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MELLO ETAL.
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further suggests that cocaine may stimulate hypothalamic release of endogenous LHRH, which augments the effects of synthetic LHRH. It is possible that cocaine may reduce endogenous opioid peptide inhibition of hypothalamic LHRH. Studies of cocaine's effects on opioid antagonist-stimulated gonadotropins may clarify its effects on endogenous LHRH activity. Alternatively, cocaine may stimulate LH and FSH release at the level of the gonadotroph, but this cannot be determined from these data. The implications of the lack of a PRL response to LHRH are unclear. The discrepancy between LHRH effects on PRL in women (16, 17, 50) and female rhesus monkeys is most parsimoniously attributed to an unexplained species difference.
Acknowledgments We thank Nicolas Diaz-Migoyo and Michelle Kaviani for excellent technical assistance in data collection. We are grateful to Dr. James Ellingboe for advice on the RIA and the gas chromatographic procedures and to Dr. Prabhat Sehgal for veterinary consultation.
References 1. Kozel NJ, Adams EH. Epidemiology of drug abuse: an overview. Science. 1986;34:970-4. 2. Cocores JA, Dackis CA, Gold MS. Sexual dysfunction secondary to cocaine abuse in two patients. J Clin Psychiatry. 1986;47:384-7. 3. Siegel RK. Cocaine and sexual dysfunction: the curse of mama coca. J Psychoactive Drugs. 1982;14:71. 4. Smith DE, Wesson DR, Apter-Marsh M. Cocaine- and alcoholinduced sexual dysfunction in patients with addictive disease. J Psychoactive Drugs. 1984;16:359-61. 5. Creigler LL, Mark H. Medical complications of cocaine abuse. N Engl J Med. 1986;315:1495-500. 6. Chasnoff IJ, Burns WJ, Schnoll SH, Burns KA. Cocaine use in pregnancy. N Engl J Med. 1985;1313:666-9. 7. Mendelson JH, Teoh SK, Lange U, Mello NK, Weiss R, Skupny AST. Hyperprolactinemia during cocaine withdrawal. In: Harris LS, ed. Problems of drug dependence 1987. NIDA research monogr 81. DHHS publication (ADM) 88-1564. Washington DC: U.S. Government Printing Office; 1988;67-73. 8. Mendelson JH, Mello NK, Teoh SK, Ellingboe J, Cochin J. Cocaine effects on pulsatile secretion of anterior pituitary, gonadal, and adrenal hormones. J Clin Endocrinol Metab. 1989;69:1256-60. 9. Gawin FH, Kleber HD. Neuroendocrine findings in chronic cocaine abusers: a preliminary report. Br J Psychiatry. 1985;247:569-73. 10. Mello N, Mendelson J, Drieze J, Kelly M. Acute effects of cocaine on prolactin and gonadotropins in female rhesus monkey during the follicular phase of the menstrual cycle. J Pharmacol Exp Ther. 1990;254:815-23. 11. Steger RW, Silverman AY, Johns A, Asch RH. Interactions of cocaine and delta-9-tetrahydrocannabinol with the hypothalamichypophysial axis of the female rat. Fertil Steril. 1981;35:567. 12. Berul CI, Harclerode JE. Effects of cocaine hydrochloride on the male reproductive system. Life Sci. 1989;45:91-5. 13. Yen SSC. Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs. Fertil Steril. 1983;39:257-66. 14. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987;237:1219-23. 15. Misra AL, Giri VV, Patel MN, Alluri VR, Mule SJ. Disposition and metabolism of (3H) cocaine in acutely and chronically treated monkeys. Drug Alcohol Depend. 1977;2:261-71. 16. Yen SSC, Hoff JD, Lasley BI, Casper RF, Sheehan K. Induction
17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
30.
31. 32. 33. 34.
35.
36. 37.
38.
39. 40.
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of prolactin release by LRF and LRF-agonist. Life Sci. 1980;26:1963-7. Braund W, Roeger DC, Judd SJ. Synchronous secretion of luteinizing hormone and prolactin in the human luteal phase: neuroendocrine mechanisms. J Clin Endocrinol Metab. 1984;58:293. Gindoff PR, Jewelewicz R, Hembree W, Wardlaw S, Ferin M. Sustained effects of opioid antagonism during the normal human luteal phase. J Clin Endocrinol Metab. 1988;66:1000-4. Belchetz P, Dufy B, Knobil E. Identification of inhibitory and stimulatory control of prolactin secretion in the rhesus monkey. Neuroendocrinology. 1978;27:32-8. Wehrenberg WB, Ferin M. Regulation of pulsatile prolactin secretion in primates. Biol Reprod. 1982;27:99-103. Lenton EA, Landgren B. The normal menstrual cycle. In: Shearman RP, ed. Clinical reproductive endocrinology. Edinburgh: Churchill Livingstone; 1985;81-108. Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev. 1985;6:564-89. Quadri SK, Spies HG. Cyclic and diurnal patterns of serum prolactin in the rhesus monkey. Biol Reprod. 1976;14:495-501. Mais V, Yen SSC. Prolactin-releasing action of gonadotropinreleasing hormone in hypogonadal women. J Clin Endocrinol Metab. 1986;62:1089-92. Fischman MW, Schuster CR, Javaid J, Hatano Y, Davis J. Acute tolerance development to the cardiovascular and subjective effects of cocaine. J Pharmacol Exp Ther. 1985;235:677-82. Matsuzaki M, Misra AL. Comparison of the convulsant effects of cocaine and pseudococaine in the rhesus monkey. Brain Res Bull. 1977;2:421-4. Chow MJ, Ambre JJ, Ruo TI, Atkinson AJ, Bowsher DJ, Fischman MW. Kinetics of cocaine distribution, elimination, and chronotropic effects. Clin Pharmacol Ther. 1985;38:318-24. Fischman MW, Schuster CR. Cocaine self-administration in humans. Fed Proc. 1982;41:241-6. Ferin M, Carmel PW, Warren MP, Himsworth RL, Frantz AG. Phencyclidine sedation as a technique for handling rhesus monkeys: effects on LH, GnRH and prolactin secretion. Proc Soc Exp Biol Med. 1976;151:428-33. Fuller GB, Hobson WC, Reyes FI, Winter JSD, Faimans C. Influence of restraint and ketamine anesthesia on adrenal steroids, progesterone and gonadotropins in rhesus monkeys. Proc Soc Exp Biol Med. 1984;175:487-90. Quadri SK, Pierson C, Spies HG. Effects of centrally acting drugs on serum prolactin levels in rhesus monkeys. Neuroendocrinology. 1978;27:136-47. Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53-88. Mello NK, Mendelson JH, Bree MP, Skupny AST. Alcohol effects on LHRH stimulated LH and FSH in female rhesus monkeys. J Pharmacol Exp Ther. 1986;236:590-5. Mello NK, Mendelson JH, Bree MP, Skupny A. Alcohol effects on naloxone-stimulated luteinizing hormone, follicle stimulating hormone and prolactin plasma levels in female rhesus monkeys. J Pharmacol Exp Ther, 1988;245:895-904. Blank MS, Gordon TP, Wilson ME. Effects of capture and venipuncture on serum levels of prolactin, growth hormone and cortisol in outdoor compound-housed female rhesus monkeys (Macaca mulatta). Acta Endocrinol (Copenh). 1983;102:190-5. Mendelson JH, Mello NK, Cristofaro P, Skupny A, Ellingboe J. Use of naltrexone as a provocative test for hypothalamic-pituitary hormone function. Pharmacol Biochem Behav. 1986;24:309-13. Yen SSC, Quigley ME, Reid RL, Ropert JF, Cetel NS. Neuroendocrinology of opioid peptides and their role in the control of gonadotropin and prolactin secretion. Am J Obstet Gynecol. 1985;152:485-93. Mendelson JH, Mello NK. Commonly abused drugs. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison's principles of internal medicine, 11th ed. New York: McGraw-Hill; 1986;2115-8. Johanson CE, Fischman MW. The pharmacology of cocaine related to its abuse. Pharmacol Rev. 1989;41:3-52. Yen SSC. Neuroendocrine control of hypophyseal function. In: Yen
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 15 November 2015. at 22:24 For personal use only. No other uses without permission. . All rights reserved.
COCAINE EFFECTS ON LH, FSH, AND PRL
41. 42. 43.
44.
45.
46.
47.
SSC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia: Saunders; 1986;33-74. Mendelson JH, Lukas SE, Mello NK, Amass L, Ellingboe J, Skupny A. Acute alcohol effects on plasma estradiol levels in women. Psychopharmacology. 1988;94:464-7. Mendelson JH, Mello NK, Cristofaro P, et al. Alcohol effects on naloxone-stimulated luteinizing hormone, prolactin and estradiol in women. J Stud Alcohol. 1987;48:287-94. Teoh SK, Mendelson JH, Mello NK, Skupny A. Alcohol effects on naltrexone-induced stimulation of pituitary, adrenal and gonadal hormones during the early follicular phase of the menstrual cycle. J Clin Endocrinol Metab. 1988;66:1181-6. Mello NK, Mendelson JH, Teoh SK. Neuroendocrine consequences of alcohol abuse in women. In: Hutchings DE, ed. Prenatal abuse of licit and illicit drugs. New York: New York Academy of Sciences; 1989;562:211-40. Spies HG, Quadri SK, Chappel SC, Norman RL. Dopaminergic and opioid compounds: effects on prolactin and LH release after electrical stimulation of the hypothalamus in ovariectomized rhesus monkeys. Neuroendocrinology. 1980;30:249-56. Pavasuthipaisit K, Hess DL, Norman RL, Adams TE, Baughman WL, Spies HG. Dopamine: effects on prolactin and luteinizing hormone secretion in ovariectomized rhesus macaques after transection of the pituitary stalk. Neuroendocrinology. 1981;32:42-9. Plant TM, Krey LC, Moossy J, McCormack JT, Hess DL, Knobil E. The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatto).
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Endocrinology. 1978;102:52-62. 48. Frawley LS, Neill JD. Brief decreases in dopamine result in surges of prolactin secretion in monkeys. Am J Physiol. 1984;247:E77880. 49. Yen SSC. Studies of the role of dopamine in the control of prolactin and gondotropic secretion in humans. In: Fuxe K, Hokfelt T, Luft R, eds. Central regulation of the endocrine system. New York: Plenum Press; 1979;387-416. 50. Yen SSC. Prolactin in human reproduction. In: Yen SSC, Jaffe RB, eds. Reproductive endocrinology. Philadelphia: Saunders; 1986;178-263. 51. Geisthoevel F, Arana JB, Balmaceda JP, Rojas FJ, Asch RH. Prolactin and gonadotrophin dynamics in response to antagonists of LHRH and dopamine in ovariectomized rhesus monkeys: a dissection of their common secretion. Hum Reprod. 1988;3:591-5. 52. Norman RL, Quadri SK, Spies HG. Differential sensitivity of prolactin release to dopamine and thyrotrophin-releasing hormone in intact and pituitary stalk-sectioned rhesus monkeys. J Endocrinol. 84:479-87. 53. Neill JD, Frawley LS, Plotsky PM, Tindall GI. Dopamine in hypophysial stalk blood of the rhesus monkey and its role in regulating prolactin secretion. Endocrinology. 1981;108:489-94. 54. Ravitz AJ, Moore KE. Effects of amphetamine, methylphenidate and cocaine on serum prolactin concentrations in the male rat. Life Sci. 1977;21:167-272. 55. Dackis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev. 1985;9:469-77.
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