Estradiol lowers intracranial self-stimulation thresholds and enhances cocaine facilitation of intracranial self-stimulation in rats
Research Highlights
►Estradiol increases rewarding effect of self-stimulation. ►Effect of estradiol on self-stimulation takes place 48 h after injection. ►Combination of estradiol and cocaine produces a greater effect on self-stimulation. ►Effects of cocaine and estradiol on self-stimulation are cumulative.
Introduction
The growing body of evidence indicate that women initiate cocaine use at a younger age and have more complications related to cocaine use than men and more frequent relapses during withdrawal (Van Etten and Anthony, 1999, Chen and Kandel, 2002). Although most of the studies that ignored menstrual cycle phase could not demonstrate differences in subjective effects of cocaine between men and women (Evans, 2007), it is well documented now that circulating levels of ovarian hormones observed during menstrual cycles influence the behavioral effects of stimulant drugs in women (Terner and de Wit, 2006, Evans, 2007). Additionally, it has been proposed that estrogens play an important role in these sex differences (Festa and Quinones-Jenab, 2004). A majority of studies revealed that women experience much greater subjective effects from cocaine and similar psychomotor stimulant amphetamine during the late follicular phase compared to the luteal phase (Justice and de Wit, 1999, White et al., 2002, Evans et al., 2002, Sofuoglu et al., 1999). The most consistent menstrual cycle differences have been shown with smoked cocaine, but not with intranasal or intravenous cocaine (Evans and Foltin, 2010). The intensity of subjective effects of psychostimulants (characterized as feeling “high”, “energetic and intellectually efficient”, and “euphoric”) has a direct correlation with the level of estradiol in blood samples (Justice and de Wit, 1999, White et al., 2002), and it increases after acute estradiol pretreatment (for d-amphetamine see Justice and de Wit, 2000). However, some authors suggest that in humans and primates attenuating effect of progesterone on rewarding properties of cocaine during lutheal phase plays a crucial role rather than enhancing effect of estradiol (Evans and Foltin, 2010).
Consistent with clinical studies, animal models of drug abuse showed the same sexually dimorphic patterns of behavioral response to cocaine in all phases of the addiction process (Becker and Hu, 2008). In studies of intravenous drug self-administration (IVSA), intact female rats initiate cocaine self-administration more rapidly than males (Jackson et al., 2006, Lynch and Carroll, 1999), obtain higher cumulative doses of cocaine during the maintenance phase (Lynch and Carroll, 1999), and demonstrate a greater readiness to reinstate extinguished behavior (Lynch and Carroll, 2000).
Convincing evidence of the crucial role of estradiol in establishment of increased sensitivity to cocaine is obtained from experiments in ovariectomized (OVX) rodents (see for review Festa and Quinones-Jenab, 2004, Hu et al., 2004). Removal of the ovaries markedly reduces self-administration of cocaine, and this effect can be reversed by estradiol replacement (Jackson et al., 2006, Lynch et al., 2001). Estradiol pretreatment also increases the amount of self-administered cocaine during the maintenance phase of IVSA (Yang et al., 2007) and increases relapses during the reinstatement phase (Larson et al., 2005). Estradiol is also known to facilitate development of behavioral sensitization in rats (Becker, 1999, Hu et al., 2004), which has been implicated in the transition to addiction (Robinson and Berridge, 1993). However, estradiol failed to alter cocaine discrimination or cocaine self-administration behavior in female monkeys (Mello et al., 2008).
Brain structures responsible for forming the brain reward system are known to play a critical role in drug dependence. It has been shown that estradiol rapidly increases dopamine efflux in the nucleus accumbens (Becker, 1999). Rapid nongenomic effect of estradiol on dopamine efflux has been demonstrated also in vitro using PC-12cells (Alyea et al., 2008). However, there are some data indicating the involvement of genomic mechanism in the estradiol regulation of dopamine system functioning (Shieh and Yang, 2008). The behavioral consequences of this effect of estradiol remain unknown.
Intracranial self-stimulation (ICSS) provides a unique opportunity to assess the influence of pharmacological compounds on the reward system directly. A number of studies have investigated the action of estradiol on ICSS in OVX females using the rate-dependent fixed ratio 1 (FR-1) schedule of reinforcement. Overall, results showed an increase in number of responses for rewarding impulses 48–72 h after the start of estradiol treatment with no relation to the site of electrode implantation (Prescott, 1966, Scott and Hoebel, 1966, Moss, 1968, Meyerson et al., 1969, Meyerson and Lindstrom, 1973, Drewett and Herberg, 1975, Cohen and Lieblich, 1981). Nevertheless, interpretation of some reports is complicated due to discrepancies in the data where estradiol increased, decreased or exerted no effect on response rate (Meyerson et al., 1969, Drewett and Herberg, 1975, Hodos and Valenstein, 1960, Hitt and Gerall, 1969, Lenzer, 1971).
The main disadvantage of rate-dependent techniques is that the instrumental response of the animals can be altered by the properties of compounds under investigation to improve or worsen motor performance. It would be expected that the rate of bar pressing might increase due to the well documented increase in motor activity correlated with increased endogenous estradiol. Therefore, it cannot be concluded from previous studies that estradiol affects the rewarding efficacy of electrical stimulation.
Bless et al. (1997) exploited the rate-independent ICSS procedure adopted from Gallistel (Campbell et al., 1985) to assess effects of sex hormones on ICSS, while Stratmann and Craft (1997) used a rate-independent ICSS method designed by Kornetsky and colleagues (Kornetsky and Esposito, 1981) to investigate sex differences in the action of various psychoactive substances. Bless reported no rewarding effect of estradiol when tested alone, and a slight increase in rewarding value of electrical stimulation when estradiol was tested in combination with progesterone (Bless et al., 1997). Stratmann and Craft found no effect of estrous cycle on threshold for ICSS, nor any differences in effects of various doses of amphetamine, cocaine or morphine between male and female rats. Over ten years since the last negative reports of Bless et al., 1997, Stratmann and Craft, 1997 about the rewarding properties of estradiol, little work has been conducted to clarify the modulatory effects of estradiol on the activity of the reward system.
We hypothesized that estradiol effects on ICSS behavior are so subtle that they were not detected in previous studies. So, we modified the rate-independent ICSS procedure of Kornetsky to attempt to make it more sensitive to the effects of manipulations by decreasing the step of titration and utilizing more strict criteria for selection of stable threshold baselines (see Discussion). We examined the effects of cocaine on ICSS with or without estradiol as well.
Section snippets
Subjects
Sixteen adult female Wistar rats (250–300 g) were purchased from the State Breeding Farm ‘Rappolovo’ (St.-Petersburg, Russian Federation). Animals were housed individually in Type 3 standard rodent cages under standard laboratory conditions, 21 ± 1 °C and 40–70% humidity, with food and water available ad libitum. All experiments were approved by Pavlov Medical University Ethics Committee and were performed in accordance with the European Council Directive 86/609/EEC. All experiments were performed
Effect of estradiol on ICSS thresholds
Administration of sesame oil was not followed by cytological changes in vaginal smears or changes in thresholds. After administration of estradiol (5 μg/animal, SC, 2 days), the cytological changes were observed in vaginal smears, with a shift from diestrus to proestrus on day 3 after the first injection of estradiol and to estrous from day 4 to day 10.
Estradiol produced a long-lasting gradual lowering of ICSS thresholds after the first injection of estradiol (Fig. 1, P < 0.05, Friedman analysis).
Discussion
The main finding of the present study is that estradiol significantly lowers the threshold of ICSS and in combination with cocaine has a cumulative effect resulting in a decrease of self-stimulation thresholds. On this basis, we conclude that estradiol sensitizes the reward system and enhances rewarding effects of cocaine.
Estradiol is shown to modulate behavioral effects of different classes of abused drugs (cocaine, heroin, morphine, nicotine) in IVSA studies using OVX female rats (Alexander
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