J Pharmacol Exp Ther January 2004 308:156-167
ENDOCRINE AND REPRODUCTIVE
Ovarian Steroid Hormone Modulation of the Acute Effects of Cocaine on Luteinizing Hormone and Prolactin Levels in Ovariectomized Rhesus Monkeys
Nancy K. Mello, Jack H. Mendelson, S. Stevens Negus, and Maureen Kelly
Alcohol and Drug Abuse Research Center,McLean Hospital-Harvard Medical School, Belmont, Massachusetts
Address correspondence to:
Dr. Nancy K. Mello, Alcohol and Drug Abuse Research Center, Harvard Medical School-McLean Hospital, 115 Mill St., Belmont, MA 02478. E-mail: email@example.com
Received July 17, 2003; accepted September 26, 2003.
| | Abstract|
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Cocaine stimulates significant increases in luteinizing hormone (LH) and decreases prolactin levels in gonadally intact rhesus monkeys, but cocaine did not alter plasma levels ofthese anterior pituitary hormones in ovariectomized females. These findings suggested that ovarian steroid hormones may contribute to the endocrine effects of acute cocaine administration. To test this hypothesis, the acute effects of cocaine and placebo-cocaine on plasma LH and prolactin levels were examined in five ovariectomized rhesus females during three chronic hormone replacement conditions:1) estradiol (E2[pic]) treatment (0.0015-0.006 mg/kg/day i.m.), 2) progesterone treatment (0.32 mg/kg/day i.m.), and 3) combinations of progesterone (0.32 mg/kg/day i.m.) and E2[pic] (0.002 and 0.004 mg/kg/day i.m.). Cocaine (0.8 mg/kg i.v.) did not alter prolactin or LH in ovariectomized monkeys without ovarian steroid replacement. During chronic estradiol treatment, cocaine produced anestradiol dosedependent decrease in prolactin. Cocaine also decreased prolactin during treatment with progesterone alone and progesterone + E2[pic] (0.004 mg/kg/day i.m.). Cocaine stimulated a significant increase in LH during treatment with progesterone alone, but not during treatment with progesterone + E2[pic], or three of four estradiol treatment doses. Cocaine pharmacokinetics did not differ as afunction of hormone replacement conditions. Together, these data suggest that both E2[pic] and progesterone modulate cocaine's effects on prolactin, whereas E2[pic] alone and in combination with progesterone, do not facilitate LH release in response to cocaine in ovariectomized rhesus females.
There is increasing evidence that ovarian steroid hormones may modulate some biological andbehavioral effects of cocaine, but the nature of these interactions is poorly understood (for review, see Mello and Mendelson, 2002[pic]). In behavioral studies, estradiol may enhance the reinforcing and locomotor effects of cocaine in rats (Roberts et al., 1989[pic]; Lynch et al., 2000[pic]; Sell et al., 2000[pic]). In endocrine studies, cocaine stimulates a rapid increase in estradiol in female rhesusmonkeys during the follicular phase of the menstrual cycle when ovarian steroid hormone levels are low, but not during the luteal phase when ovarian steroid hormone levels are high (Mello et al., 2000[pic]). Moreover, there is general agreement that cocaine stimulates release of some anterior pituitary hormones (Mello and Mendelson, 2002[pic]). For example, acute cocaine administration stimulatessignificant increases in luteinizing hormone (LH) and adrenocorticotropin hormone (ACTH) in humans (Mendelson et al., 1992[pic], 2001[pic]; Sholar et al., 1998[pic]) and in rhesus monkeys (Mello et al., 1990a[pic], 1993[pic]; Sarnyai et al., 1996[pic]; Broadbear et al., 1999a[pic],b[pic]).
The influence of the ovarian steroid hormone milieu on the hormonal effects of cocaine has not been...