Progesterone does not affect cocaine-induced conditioned place preference or locomotor activity in male rats.

INTRODUCTION: The present study aimed to determine if, as occurs in female rats, progesterone attenuates cocaine-induced reward and psychomotor responses in male rats. METHODS: The role of progesterone in the acquisition and/or expression of cocaine-induced conditioned place preference (CPP) and locomotor responses of intact male rats was studied. For chronic progesterone treatment, rats received Silastic capsules with either progesterone (100%) or vehicle 1 week prior to conditioning. For acute progesterone treatment, rats received subcutaneous injections of progesterone (500 microg) or vehicle (sesame oil) 4 hours before intraperitoneal injections of saline or cocaine administration (20 mg/kg) on conditioning days (acquisition phase-formation of reward associations) or before testing (expression phase-recall of reward associations). RESULTS: Both progesterone-treatment paradigms produced equivalent progesterone serum levels. Progesterone administered chronically or acutely during the acquisition and expression phases of cocaine conditioning did not block cocaine-induced CPP. Nor did progesterone affect ambulatory or rearing behaviors after cocaine administration. CONCLUSION: These results suggest that, unlike the findings with female rats (in which similar treatment paradigms inhibited the formation and recall of cocaine-induced CPP), progesterone plays a limited role in the cocaine-induced reward or psychomotor responses of male rats.

Progesterone attenuates cocaine-induced conditioned place preference in female rats.

Progesterone replacement attenuates the intensity of cocaine-induced conditioned place preference (CPP) behaviors in female rats. The present study aimed to expand that finding by (i) determining the role of progesterone in the acquisition and/or expression of cocaine-induced CPP and (ii) determining if progesterone's effects might be meditated through learning and memory. To this end, female rats were administered progesterone during cocaine conditioning or object recognition tasks; rats received subcutaneous injections of progesterone (500 microg) or vehicle (sesame oil) 4 h before saline or cocaine (5 mg/kg) on conditioning days (acquisition phase) or before testing (expression phase or object recognition tasks). Progesterone treatment during both the acquisition and the expression phases of cocaine conditioning blocked cocaine-induced CPP. Progesterone affected neither the number of entrances and explorations in the CPP chambers nor the ambulatory and rearing behaviors. In the object recognition task (a non-spatial learning and memory task), progesterone treatment had no effect. However, in the object placement task (a spatial learning and memory task), progesterone treatment significantly impaired retention in hormone-treated rats as compared with control groups. These results suggest that progesterone treatment interferes with cocaine-induced reward associations, possibly through effects on spatial working memory consolidation The observed effects of acute progesterone treatment on cocaine-induced CPP may in part contribute reported menstrual effects and sex disparities in overall cocaine use and rates of relapse.

Coadministration of estrogen and progesterone differentially affects locomotor responses to cocaine in rats.

Fluctuations in ovarian hormones throughout the estrous cycle may underlie sex differences in behavior. In this study, estrogen plus progesterone were coadministered at different ratios to determine whether the interaction of those hormones during the estrous cycle contributes to cocaine-induced alterations in behavior. Before cocaine (15 mg/kg) or saline administration, ovariectomized female rats received either vehicle or estrogen (10 microg or 50 microg) and progesterone (100 microg or 500 microg). Cocaine-induced locomotor activity was affected by estrogen plus progesterone ratio. While administration of 50 microg estrogen plus 500 microg progesterone increased total locomotor behavior, administration of 10 microg estrogen plus 500 microg progesterone inhibited total locomotor activity. This study suggests that alterations of estrogen and progesterone serum levels may underlie the observed changes in cocaine-induced behavior during the estrous cycle.

Effects of RU 486 and tamoxifen on cocaine-induced behavioral and endocrinologic activations in male and female Fischer rats.

Evidence suggests that sex differences in response to cocaine administration may be regulated by activation of progesterone and estrogen receptors. To test this hypothesis, rats were pretreated with either RU 486 (progesterone antagonist; 0, 3, or 25 mg/kg), tamoxifen (estrogen antagonist; 0, 1, or 3 mg/kg), or vehicle followed by saline or cocaine administration (15 mg/kg). Although RU 486 did not affect cocaine-induced locomotor activity in female rats, it dose-dependently decreased such activity in males (3 mg/kg significantly attenuated locomotor responses in cocaine-treated rats as compared with vehicle treatment or 25 mg/kg of RU 486). RU 486 also affected baseline serum levels of corticosterone. Males treated with 3 mg/kg of RU 486 plus cocaine had higher progesterone and corticosterone serum levels than vehicle-treated groups. In females, both doses (3 and 25 mg/kg) of RU 486 significantly attenuated corticosterone serum levels compared with vehicle treatment. For both sexes overall, tamoxifen neither significantly influenced cocaine-induced ambulatory and rearing responses nor altered cocaine-induced progesterone and corticosterone serum levels. Taken together, our results suggest that progesterone receptors have a sexually dimorphic role in cocaine-induced effects, but estrogen receptors have only a limited role. Moreover, both receptor antagonists modulate neurochemical responses differentially.

Effects of short- and long-term estrogen and progesterone replacement on behavioral responses and c-fos mRNA levels in female rats after acute cocaine administration.

It is well established that there are estrous cycle differences in cocaine-induced behavioral activity, implicating fluctuations in levels of estrogen and progesterone throughout the cycle in these alterations in behavior. However, the mechanisms by which steroids alter cocaine-induced behavioral responses have yet to be determined. The aim of this study was to determine whether short- or long-term estrogen and progesterone administration differentially alters behavioral responses to cocaine. Estrogen (50 microg) was administered 30 min or 48 h before cocaine (15 mg/kg, i.p.) administration; progesterone (500 microg) was administered 30 min or 24 h before cocaine. Short-term estrogen replacement decreased cocaine-induced ambulations. Short-term progesterone decreased rearing, whereas long-term progesterone decreased ambulations. Although cocaine increased levels of c-fos mRNA, none of the estrogen or progesterone replacement paradigms affected this measure. Because long-term estrogen replacement has been shown to have no effect on locomotor activity after acute cocaine administration, our observations suggest that short-term estrogen may underlie behavioral alterations. These findings suggest that after acute cocaine administration, while estrogen may activate only membrane receptors to alter behavioral responses to cocaine, progesterone activates both nuclear and membrane receptors.

Estrogen and progesterone affect cocaine pharmacokinetics in female rats.

Several studies have reported sex differences in behavioral responses to cocaine whereby females display a greater degree of locomotor activity. Fluctuations in estrogen and progesterone during the estrous cycle have been postulated to underlie these behavioral differences. In this study, we tested the hypothesis that hormonal replacement (estrogen or progesterone) in ovariectomized rats affects cocaine pharmacokinetics. We found that estrogen replacement did not affect cocaine-induced locomotor activity, but progesterone attenuated locomotor counts in comparison with control groups receiving only sesame oil. Estrogen, however, decreased brain levels of cocaine and norcocaine 30 min after cocaine administration in comparison to the group-receiving vehicle at that time point. In addition, in progesterone-treated rats, levels of benzoylecgonine and ecgonine methylester were higher at 30 min post-administration than at 15 min. No changes were found in blood levels of the metabolites. These findings suggest that while progesterone has an impact on locomotor behavior, pharmacokinetic effects may have a limited role in mediating behavioral responses to cocaine.

Cocaine-induced sex differences in D1 receptor activation and binding levels after acute cocaine administration.

Although it is established that female rats have a more robust behavioral response to acute cocaine administration than male rats, the neurobiological mechanisms underlying these differences remain unclear. The purpose of the present study was to determine whether dopamine (DA) receptor activation influences sex differences in cocaine-induced behaviors. A second study was performed to determine sex differences in D1/D2 receptor levels prior to and post-cocaine administration. Male and female Fischer rats were pre-treated with the D1 antagonist SCH-23390 (0.05, 0.1, and 0.25 mg/kg, i.p.), the D2 antagonist eticlopride (0.03, 0.1 mg/kg, i.p.), or vehicle (saline) 15 min before acute cocaine (20 mg/kg, i.p.) or saline administration. Cocaine-induced ambulatory and rearing activity was greater in female than male rats. Pre-treatment with SCH-23390 affected cocaine-induced ambulatory, rearing, and stereotypic activity in a sex-dependent manner; cocaine-induced ambulatory and stereotypic behavior in female rats was reduced by the lowest dose of SCH-23390. Eticlopride did not alter behavioral responses to cocaine in male or female rats. These results suggest that in both male and female rats, activation of the D1, but not the D2, receptor modulates cocaine's motor effects. There were no sex differences in baseline levels of D1, D2, and DA transporter binding in the caudate putamen (CPu) and the nucleus accumbens (NAc). Cocaine administration reduced D1 binding levels in the CPu only in male rats. Our findings suggest that the regulation of striatal D1 binding levels after acute cocaine administration is a sexually dimorphic process. We also hypothesize that the greater sensitivity to D1 receptor blockade in female rats, as compared to male rats, may contribute to their overall increased hyperactivity in response to acute cocaine. Taken together, the D1 receptor may be an important substrate in the regulation of sex differences to cocaine-induced locomotor activity.

Progesterone inhibits behavioral responses and estrogen increases corticosterone levels after acute cocaine administration.

Accumulating evidence suggests that estrogen and progesterone contribute to the sexually dimorphic behavioral response to cocaine. In this study, we tested the hypothesis that varying the level of estrogen or progesterone affects cocaine-induced locomotive behavior in female rats. Ovariectomized (OVX) rats received estrogen (0, 5, 10, 20, or 50 microg) 48 h or progesterone (0, 50, 100, 250, or 500 microg) 24 h before acute saline or cocaine (15 mg/kg) administration. Although estrogen did not affect cocaine-induced ambulatory and rearing behaviors, it affected stereotypic behaviors regardless of cocaine administration (animals receiving 50 microg had higher stereotypic counts than did the OVX group). In contrast, progesterone affected rearing activity dose-dependently: 50 and 500 microg of progesterone inhibited, whereas 100 microg and 250 microg stimulated, rearing in response to cocaine. That estrogen and progesterone did not affect overall baseline behavioral activity suggests their effects are mediated in part through interactions with cocaine. Progesterone administration did not affect corticosterone levels in saline- or cocaine-treated rats. Estrogen administration, however, affected levels of corticosterone both at baseline and after cocaine treatment. After accounting for baseline differences, we found that rats receiving 5 or 10 microg of estrogen and cocaine had higher percentage increases in serum corticosterone levels than did the control group that did not receive estrogen. On the basis of these observations, we suggest that progesterone fluctuations during the estrous cycle impact cocaine-induced behavioral responses, whereas estrogen may affect activity in the hypothalamic-pituitary-adrenal axis. Thus, dose-dependent effects of gonadal hormones may underlie some of the reported sex differences and reproductive cycle effects of cocaine.

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.

Effects of cocaine on c-fos and preprodynorphin mRNA levels in intact and ovariectomized Fischer rats.

Psychostimulants such as cocaine have been shown to regulate c-fos and opioid gene expression in male rats. However, little information is available on cocaine effects in female rats or how the ovarian hormones, estrogen and progesterone, modulate these effects. In this study we used quantitative solution hybridization assays to measure c-fos and preprodynorphin (PDYN) mRNA levels after cocaine administration in the caudate/putamen of intact male and female rats or ovariectomized (OVX) female rats that were pretreated with vehicle, estrogen and/or progesterone. The c-fos mRNA levels were increased in intact male and female rats after 30min or 3h of one single cocaine injection and after 14 days of single daily cocaine injections. The c-fos mRNA levels were also increased after 30min of a single cocaine injection in OVX female rats that were treated with vehicle, estrogen and/or progesterone. The PDYN mRNA levels did not change after 30min, 3h or 14 days in intact male or female rats. However, PDYN mRNA levels were increased in the caudate/putamen of OVX female rats pretreated with vehicle or a combination of estrogen and progesterone but not in OVX female rats that were pretreated with either estrogen or progesterone alone. Our data suggest hormonal regulation of cocaine effects on PDYN mRNA levels which may modulate cocaine-induced behaviors in female rats.

Testosterone differentially alters cocaine-induced ambulatory and rearing behavioral responses in adult and adolescent rats.

Little is known about the physiological and behavioral effects of testosterone when co-administered with cocaine during adolescence. The present study aimed to determine whether exogenous testosterone administration differentially alters psychomotor responses to cocaine in adolescent and adult male rats. To this end, intact adolescent (30-days-old) and adult (60-day-old) male Fisher rats were pretreated with vehicle (sesame oil) or testosterone (5 or 10mg/kg) 45 min prior to saline or cocaine (20mg/kg) administration. Behavioral responses were monitored 1h after drug treatment, and serum testosterone levels were determined. Serum testosterone levels were affected by age: saline- and cocaine-treated adults in the vehicle groups had higher serum testosterone levels than adolescent rats, but after co-administration of testosterone the adolescent rats had higher serum testosterone levels than the adults. Pretreatment with testosterone affected baseline activity in adolescent rats: 5mg/kg of testosterone increased both rearing and ambulatory behaviors in saline-treated adolescent rats. After normalizing data to % saline, an interaction between hormone administration and cocaine-induced behavioral responses was observed; 5mg/kg of testosterone decreased both ambulatory and rearing behaviors among adolescents whereas 10mg/kg of testosterone decreased only rearing behaviors. Testosterone pretreatment did not alter cocaine-induced behavioral responses in adult rats. These findings suggest that adolescents are more sensitive than adults to an interaction between testosterone and cocaine, and, indirectly, suggest that androgen abuse may lessen cocaine-induced behavioral responses in younger cocaine users.