Vanya Quinones-Jenab

Gonadal hormones differentially modulate cocaine-induced conditioned place preference in male and female rats.

There is accumulating evidence that suggests there are sex differences in behavioral and subjective responses to cocaine. However, it is not known whether differences in cocaine reward contribute to sex differences in these responses or whether gonadal hormones affect the rewarding properties of cocaine. In the present study, conditioned place preference (CPP), a measure of non-contingent reward, was used to determine the effects of endogenous gonadal hormones and of estrogen and progesterone replacement on cocaine reward. Neurochemical measurements were also taken to identify monoaminergic substrates which underlie the behavioral phenotype. Although both intact and gonadectomized male and female rats showed a significant CPP for cocaine, ovariectomy attenuated the magnitude of CPP. These alterations coincided with a decrease in serum levels of corticosterone. In ovariectomized rats, pretreatment with progesterone inhibited cocaine CPP while estrogen plus progesterone potentiated the magnitude of CPP. Additionally, gonadectomy and ovarian hormone replacement in female rats affected serotonin/dopamine levels and turnover ratios in the ventral tegmental area and nucleus accumbens shell. While no effects of castration were observed, ovariectomy decreased levels of dopamine and serotonin in the ventral tegmental area. In females, progesterone replacement increased levels of serotonin and dopamine in the ventral tegmental area, while estrogen plus progesterone replacement increased dopamine levels in the nucleus accumbens. Collectively, these results indicate that ovarian hormones may influence cocaine reward by altering monoaminergic systems, which, in turn, may contribute to the current sex disparities in overall cocaine use.

Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels

Female rats display a more robust behavioral response to acute cocaine administration than do male rats. However, a clear understanding of the biological mechanisms underlying these differences remains elusive. The present study investigated whether sexual dimorphisms in cocaine-induced motor behavior might be based on monoaminergic levels and/or cocaine pharmacokinetics. An acute injection of cocaine (5, 15, 20 or 30 mg/kg) or saline was administered to male and female rats, and behavioral activity was monitored for 3 h. Following acute cocaine or saline administration motor behavior varied according to dose and sex; overall, female rats displayed greater rearing counts and stereotypic scores, greater total locomotor counts at 15, 20, and 30 mg/kg of cocaine, and greater ambulatory counts at 20 and 30 mg/kg of cocaine than did male rats. Neurochemical determinations in post-mortem tissue showed that both male and female rats had increases in total dopamine (DA) in the caudate putamen (CPu) 15 min following cocaine administration. Additionally, male rats had a decrease in dihydroxyphenylacetic acid (DOPAC)/DA turnover. Female rats showed significant reductions in total levels of DA, DOPAC, HVA, serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and DOPAC/DA turnover in the nucleus accumbens (NAc). Male rats displayed a reduction only in DOPAC/DA turnover and increases in 5-HT in the NAc following cocaine administration. Furthermore, sex differences in cocaine metabolism were observed where females had greater brain/blood levels of norcocaine and ecgonine methyl ester while male rats had higher blood levels of benzoylecgonine. These results suggest that sex differences in the behavioral responses to cocaine administration could be explained in part by intrinsic differences in both monoaminergic levels and metabolic processes.

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

Both clinical and rodent studies show sexually dimorphic patterns in the behavioral response to cocaine in all phases of the addiction process (induction, maintenance, and relapse). Clinical and rodent studies also indicate that hormonal fluctuations during the menstrual/estrous cycle modulate cocaine-induced subjective effects in women and locomotor activity in female rats. Evidence suggests that gonadal hormones underlie these observed differences and could be the biological basis of sex-specific differences in cocaine addiction. To study the effects of gonadal hormones on cocaine-induced activity, two approaches have been used. First, studies have examined the role of endogenous hormones through gonadectomy (GDX) and side-by-side comparisons with intact rats. Second, the individual contributions of testosterone, progesterone, and estrogen have been determined by hormone replacement in GDX rats. In this review, we discuss gonadal hormones as the biological basis for the behavioral responses to cocaine, and the clinical implications of these findings.

Effects of Estrogen on Oxytocin Receptor Messenger Ribonucleic Acid Expression in the Uterus, Pituitary, and Forebrain of the Female Rat

Oxytocin receptors are regulated during parturition and lactation. Gonadal steroids are thought to be key players in this regulation. It is not well documented how oxytocin receptor gene expression is regulated in the CNS. In this study we analyzed potential estrogen effects on the oxytocin receptor mRNA levels in some areas integral to the limbic-hypothalamic system, namely the ventromedial nucleus of the hypothalamus (VMH), posterior medial nucleus of amygdala (MeAmyg), and arcuate nucleus (ARC), as well as the caudate putamen (CPu), CA1 region of the hippocampus, anterior pituitary, and uterine tissue of ovariectomized (OVX) female rats. By in situ hybridization we observed a 4.4-fold increase in oxytocin receptor mRNA levels in the VMH after 48 h of estrogen treatment when compared to OVX rats. Smaller increases were observed in the MeAmyg, hippocampus, and anterior pituitary (3.18, 1.76, and 2.55, respectively). No changes in oxytocin receptor mRNA levels were observed in the CPu or ARC after estrogen treatment. A similar finding resulted from slot-blot analysis of total mRNA extracts. In uterine tissue, 48 h of estrogen treatment increased oxytocin receptor mRNA level in the myometrium (3.13-fold). No changes in oxytocin receptor mRNA levels were observed after 12 and 24 h of estrogen treatment. These findings suggest that the estrogenic regulation of oxytocin receptor binding in both CNS and uterine tissues may in part be mediated by de novo synthesis of oxytocin receptor mRNA or by alterations in the stability of oxytocin receptor gene transcripts.

Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration

Recent evidence demonstrates that there are sex differences in behavioral responses to cocaine. Further, reproductive gonadal hormones (estrogen, progesterone and testosterone) have been further implicated in mediating some of the cocaine-induced alterations. To better understand sex differences and the role of gonadal hormones in cocaine-induced locomotor and stereotypic behavior, intact and gonadectomized male and female Fischer rats were randomly assigned to either chronic cocaine (15 mg/kg) or saline treatments for 14 days followed by a challenge administration (7 days after the last cocaine/saline administration). Locomotor (ambulatory and rearing) and stereotypic activities were measured on days 1, 7 and 14 as well as after withdrawal/challenge with cocaine. Overall, intact female rats consistently showed a rapid (acquired by day 7) and longer lasting (persistent through the challenge dose) sensitization for all locomotor behaviors than any of the other groups. In contrast, intact males developed sensitization of these locomotor activities only in response to chronic cocaine administration, and after withdrawal and drug challenge the sensitization to cocaine-induced locomotor activity was no longer present. In female rats, gonadectomy affected ambulatory activity but not total and rearing responses after acute, sub-acute, chronic and challenge response to cocaine. On the other hand, castrated male rats were affected in cocaine-induced ambulatory activity but not rearing activity. In intact male rats, cocaine-induced stereotypic activity was rapidly and persistently sensitized after 7 days of cocaine administration, where gonadectomized male rats developed sensitization to cocaine-induced stereotypic activity only after a challenge cocaine administration. Although cocaine induced stereotypic activity, no statistically significant differences were observed between intact and ovariectomized female rats or throughout the different lengths of cocaine administration. After a challenge of cocaine, corticosterone levels were induced in all experimental groups. Moreover, no differences in levels of benzoylecgonine, a cocaine metabolite, were observed. Similar to our previous observations after acute cocaine administration, after challenge of cocaine, an increase in progesterone and a decrease in testosterone levels were observed in intact females and males, respectively. In summary, endogenous hormones seem to be involved in the behavioral activation and development of sensitization to cocaine.

Estradiol and progesterone differentially regulate formalin-induced nociception in ovariectomized female rats

Clinical and preclinical studies have found sex-specific differences in the discrimination and perception of inflammatory stimuli. The emerging picture suggests that the biological basis of these differences resides in the regulatory activity of gonadal hormones in the central nervous system. This study describes the effects of ovarian hormones in inflammatory pain processes. Ovariectomized rats received estradiol and/or progesterone, and the number of paw flinches was measured after 1, 2.5 or 5% formalin administration. Both estradiol and progesterone altered the number of flinches only after 1% formalin administration. Estradiol significantly reduced the overall number of flinches during Phase II of the formalin nociceptive response while progesterone attenuated Phase I of the response. After co-administration of estradiol and progesterone, progesterone reversed estradiols analgesic effect in Phase II, however, estradiol did not reverse progesterones analgesic activity in Phase I. To determine if estradiol effects are receptor-mediated, tamoxifen (selective estrogen receptor mediator, 15 mg/kg) or alpha-estradiol (an inactive isomer of estradiol, 20 microg) were utilized. Tamoxifen decreased the number of formalin-induced flinches during Phase II while alpha-estradiol did not affect any formalin-induced responses. When co-administered with estradiol, tamoxifen failed to reverse estradiols effect, suggesting both tamoxifen and estradiol activate similar intracellular mechanisms. Although Western blot analysis detected the presence of estradiol alpha and beta and progesterone B receptors in the spinal cord, hormone replacement treatments had no effects on the levels of these receptors. We postulate that the mechanisms by which estradiol and progesterone induce analgesia occur through the activation of their receptor at the spinal cord level.

The role of female gonadal hormones in behavioral sex differences in persistent and chronic pain: Clinical versus preclinical studies

Clinical and preclinical studies have found sex-specific differences in the discrimination and perception of nociceptive stimuli. This article reviews the current literature concerning the biological basis of sex differences in the behavioral response to persistent inflammatory and chronic pain stimuli. The emerging picture from both clinical and preclinical studies suggests that the basis of these differences in nociceptive responses to such stimuli resides in the regulatory activity of gonadal hormones in the central nervous system. Published reports suggest that pain management targeted at female patients should consider hormonal factors during the female reproductive cycle.

The role of D1 and D2 receptors in the cocaine conditioned place preference of male and female rats.

The rewarding effects of cocaine have been shown to be sexually dimorphic; female rats develop cocaine conditioned place preference at lower doses and with fewer cocaine pairings than male rats. The present study was conducted to determine whether D1 and D2 receptors contribute to sex differences in cocaine conditioned place preference using a 4-day paradigm. Fifteen minutes prior to receiving saline or cocaine (5mg/kg for females and 20mg/kg for males), rats were pretreated with either SCH 23390, a D1 receptor antagonist, (0.10, 0.25, or 0.50mg/kg), eticlopride, a D2 receptor antagonist, (0.05, 0.10, or 0.25mg/kg), or vehicle (saline). Antagonism of D1 receptors by SCH 23390 fully blocked cocaine conditioned place preference in male rats, while only the two lower doses of SCH 23390 blocked cocaine conditioned place preference in female rats. Conversely, antagonism of D2 receptors using eticlopride had no effect on cocaine conditioned place preference in male or female rats. Due to the known role of D1 receptors in cocaine conditioned place preference, sex differences in D1 receptor sensitivity may explain the differences observed in cocaine reward between male and female rats.

Progesterone attenuates cocaine-induced responses

In this review, we summarize literature focused on how progesterone alters cocaine-induced psychomotor, reinforcement, and physiological responses. Clinical studies suggest that progesterone attenuates the subjective effects of cocaine. Similarly, preclinical studies have demonstrated that cocaine-induced reward and psychomotor responses are attenuated after progesterone administration. In rats progesterone also reduces the reinforcement effects of cocaine attenuates acquisition, escalation, reinstatement of cocaine self-administration, and cocaine-seeking behaviors. Progesterone also counteracts the facilitatory effects of estrogen on cocaine self-administration and psychomotor activation. These findings suggest that progesterone has a potential in clinical applications as a treatment for cocaine addiction. Constantly changing progesterone serum levels in female humans and rats affect the females reinforcement responses to cocaine and may in part contribute to the known sex differences in cocaine responses.

Estrogen regulation of gonadotropin-releasing hormone receptor messenger RNA in female rat pituitary tissue

Gonadotropin releasing hormone (GnRH) is crucial in regulating the reproductive system of female vertebrates. In the present study we have analyzed the estrogen regulation of the GnRH receptor mRNA at the cellular level in Sprague-Dawley female rats. Northern blot analysis detected 3 species (5.0, 4.5 and 1.4 kb) of GnRH receptor mRNA in pituitary tissues. The GnRH receptor mRNA levels of these 3 species were increased by estrogen. By in situ hybridization we observed a 3.5-fold increase in GnRH receptor mRNA levels after 48 h of estrogen treatment when compared to ovariectomized (OVX) rats, 12 h of estrogen treatment did not change the GnRH mRNA levels. Similar increases in GnRH receptor mRNA levels by estrogen were also found in Wistar-Imamichi female rat pituitary tissue. In situ hybridization analysis identified clusters of anterior pituitary cells that expressed the GnRH receptor mRNA. The estradiol effect depends on increased mRNA levels in these clusters. Moreover, a significant increase in the number of pituitary cells that expressed GnRH receptor was observed after 48 h of estrogen treatment. These findings suggest that the mechanisms for estrogen regulation of GnRH receptor include changing levels of GnRH receptor mRNA in the rat pituitary.