Cocaine Disrupts Estrous Cyclicity and Alters the Reproductive Neuroendocrine Axis in the Rat

Abstract

Although a common drug of abuse, cocaine’s effects on cyclic reproductive functions and the neuroendocrine systems regulating these functions have not been studied. Here, we report the effects of cocaine on (1) estrous cyclicity and ovulation rates and (2) the stimulated in vitro release of hypothalamic GnRH and aminergic neurotransmitters directly involved in regulating or modulating GnRH release. Within 7 days of treatment with 10 mg kg^–1 day^–1 of cocaine HC1 subcutaneously, rats demonstrated significant estrous cycle irregularity including repetitive days of estrus and prolonged periods of diestrus. After 6 weeks of treatment, cocaine-treated rats exhibited a 44.3% decrease in ovulation rates. For the in vitro studies, bilaterally ovariectomized rats were injected with cocaine (10 mg kg^–1 day^–1) or with saline for 2 weeks. Each rat received estradiol benzoate (50 mg kg^–1 day^–1 s.c.) for 2 days before sacrifice. Hypothalamic slices were prepared, placed in 0.1 ml microchambers and perfused with modified Krebs buffer (pH 7.4) using a programmable perfusion system. Basal release of norepinephrine (NE) and serotonin (5HT) was significantly increased in the cocaine-treated group versus controls. Ten-minute pulses of 10^–7M progesterone (P4) increase NE and 5HT, but not dopamine (DA), release in the saline-treated group. In contrast, pulses of P4 increased NE, but not 5HT or DA, in the cocaine-treated rats. Ten-minute pulses of 0.1 µM NE increased GnRH release in both saline- and cocaine-treated rats. However, the response to pulsed NE was significantly attenuated in the cocaine-treated group. The results of this study demonstrate that cocaine disrupts estrous cyclicity by altering the hypothalamic amine activity necessary for pulsatile hypothalamic GnRH release. However, a direct effect of cocaine on the pituitary gland or ovaries cannot be excluded on the basis of these results.

Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle

“…While suggestive, our results are limited in that they cannot fully account for the complex interactions of endogenous ovarian hormones as they fluctuate across the cycle in intact animals. It should also be noted that while estradiol may have played a role in mediating reinstatement in the current study, it is also important to note that chronic cocaine exposure has been shown to disrupt estrous cycle activity in primates and rodents (Grimm and See 1997; King et al 1990; Mello et al 1997), with previous work in our laboratory demonstrating a decline in the estradiol peak of proestrus during and following chronic cocaine self-administration (Feltenstein and See 2007). Moreover, plasma levels of hormones do not necessarily indicate neuronal alterations that may occur in response to changes in endogenous hormone levels.…”

Attenuation of cocaine-seeking by progesterone treatment in female rats

“…Estradiol administration has been shown to increase the reinforcing effects of psychostimulants in humans (Justice and de Wit, 2000) and enhance the acquisition (Lynch et al, 2001; Hu et al, 2004; Jackson et al, 2006) and escalation (Larson et al, 2007) of cocaine self-administration in rats, with plasma estradiol levels showing a positive correlation with cocaine-seeking (Lynch, 2008). However, while endogenous plasma estradiol levels are enhanced during proestrus in drug-free females, this estradiol peak is not consistently seen after chronic cocaine self-administration (Feltenstein and See, 2007), due to cocaine's disruption of normal estrous cycle activity (King et al, 1990, 1993; Grimm and See, 1997; Mello et al, 1997). Thus, while elevated plasma estradiol during proestrus may have enhanced the reinforcing effects of cocaine early in self-administration, cocaine's disruption of estradiol following chronic cocaine exposure may reduce the impact of this hormone in enhancing cocaine self-administration.…”

The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women

“…Based on the preclinical literature, we had anticipated that female cocaine abusers would have had abnormal menstrual cycles. Several studies have shown that chronic cocaine use disrupts various aspects of the estrous cycle in rodents (King et al 1990(King et al , 1993Chen and Vandenbergh 1994;Quiñones-Jenab et al 2000a; but see Booze et al 1999) and the menstrual cycle in nonhuman primates (Mello et al 1997;Potter et al 1998Potter et al , 1999 and humans (Mello 1998). In the present study, women reported spending approximately US $400 per week on cocaine and using it 3-4 days each week.…”