Elsevier

Hormones and Behavior

Volume 58, Issue 5, November 2010, Pages 827-834
Hormones and Behavior

Estradiol lowers intracranial self-stimulation thresholds and enhances cocaine facilitation of intracranial self-stimulation in rats

https://doi.org/10.1016/j.yhbeh.2010.08.006Get rights and content

Abstract

Women initiate cocaine use at a younger age and have more complications (e.g., higher rates of major or minor depression) related to cocaine use than men. It has been proposed that estrogens play an important role in these sex differences. The addictive potential of psychoactive drugs can be measured in rats via a rewarding intracranial self-stimulation (ICSS) procedure. The rate-independent method of ICSS allows researchers to assess the “pure” rewarding effect of cocaine without influence of nonspecific motor reactions. The present study aimed to estimate effects of estradiol and a combination of estradiol and cocaine on ICSS in ovariectomized female rats. 17-β-estradiol (5 μg/animal/day, 2 days) produced a long-lasting gradual lowering of the thresholds for ICSS. The ability of estradiol to decrease thresholds for ICSS has never been shown previously. Combination of 17-β-estradiol and cocaine (5.0 mg/kg, 5 days) produced a greater effect on ICSS thresholds than the effect of either compound alone. No tolerance or sensitization to cocaine developed during the study. Present findings suggest estradiol increases sensitivity of the brain reward system in rats, which may have an important implication in understanding sex differences in cocaine effects.

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

References (69)

  • K.A. Disshon et al.

    Inhibition of striatal dopamine transporter activity by 17beta-estradiol

    Eur. J. Pharmacol.

    (1998)
  • R.F. Drewett et al.

    Hypothalamic self-stimulation in the female rat: effects of oestrus and food deprivation

    Physiol. Behav.

    (1975)
  • S.M. Evans et al.

    Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates?

    Horm. Behav.

    (2010)
  • E.D. Festa et al.

    Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine

    Horm. Behav.

    (2004)
  • R.A. Frank et al.

    The effect of chronic cocaine on self-stimulation train-duration thresholds

    Pharmacol. Biochem. Behav.

    (1988)
  • R.E. Hruska et al.

    Characterization of the striatal dopamine receptor supersensitivity produced by estrogen treatment of male rats

    Neuropharmacology

    (1980)
  • C. Kornetsky et al.

    Reward and detection thresholds for brain stimulation: dissociative effects of cocaine

    Brain Res.

    (1981)
  • E.B. Larson et al.

    Effect of short- vs. long-term estrogen on reinstatement of cocaine-seeking behavior in female rats

    Pharmacol. Biochem. Behav.

    (2005)
  • M. Le Saux et al.

    ERbeta mediates the estradiol increase of D2 receptors in rat striatum and nucleus accumbens

    Neuropharmacology

    (2006)
  • D. Levesque et al.

    Rapid conversion of high into low striatal D2-dopamine receptor agonist binding states after an acute physiological dose of 17 beta-estradiol

    Neurosci. Lett.

    (1988)
  • W.J. Lynch et al.

    Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats

    Pharmacol. Biochem. Behav.

    (2001)
  • J.K. McQueen et al.

    Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain

    Brain Res. Mol. Brain Res.

    (1997)
  • B.J. Meyerson et al.

    Effects of estrogen on self-stimulation behavior in ovariectomized rats

    Physiology and Behavior

    (1969)
  • P. Micevych et al.

    Membrane estradiol signaling in the brain

    Front. Neuroendocrinol.

    (2009)
  • M. Morissette et al.

    Effect of estradiol and progesterone on rat striatal dopamine uptake sites

    Brain Res. Bull.

    (1990)
  • T. Niyomchai et al.

    Estrogen and progesterone affect cocaine pharmacokinetics in female rats

    Brain Res. Bull.

    (2006)
  • T.E. Robinson et al.

    The neural basis of drug craving: an incentive-sensitization theory of addiction

    Brain Res. Brain Res. Rev.

    (1993)
  • E.L. Sabban et al.

    Divergent effects of estradiol on gene expression of catecholamine biosynthetic enzymes

    Physiol. Behav.

    (2010)
  • S.L. Sell et al.

    Influence of estrous cycle and estradiol on behavioral sensitization to cocaine in female rats

    Drug Alcohol Depend.

    (2002)
  • K.R. Shieh et al.

    Effects of estradiol on the stimulation of dopamine turnover in mesolimbic and nigrostriatal systems by cocaine- and amphetamine-regulated transcript peptide in female rats

    Neuroscience

    (2008)
  • J.A. Stratmann et al.

    Intracranial self-stimulation in female and male rats: no sex differences using a rate-independent procedure

    Drug and Alcohol Dependence

    (1997)
  • J.M. Terner et al.

    Menstrual cycle phase and responses to drugs of abuse in humans

    Drug Alcohol Depend.

    (2006)
  • T.L. Thompson

    Attenuation of dopamine uptake in vivo following priming with estradiol benzoate

    Brain Res.

    (1999)
  • M.L. Van Etten et al.

    Comparative epidemiology of initial drug opportunities and transitions to first use: marijuana, cocaine, hallucinogens and heroin

    Drug Alcohol Depend.

    (1999)
  • Cited by (0)

    View full text