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ABSTRACT: The present study aimed to determine if, as occurs in female rats, progesterone attenuates cocaine-induced reward and psychomotor responses in male rats.
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).
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.
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.
Ethnicity & disease 01/2010; 20(1 Suppl 1):S1-73-7. · 0.90 Impact Factor
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ABSTRACT: Alterations in protein kinase (PKA) protein levels have been implicated in the regulation of responses to and development of cocaine addiction. However, the contribution of differences in PKA intracellular cascade to the known sex differences in responses to cocaine is not well understood. This study examined whether there are intrinsic or cocaine-induced alterations in PKA-mediated responses, such as phosphorylation of cyclic AMP response element binding protein, in male and female rats.
To this end, protein levels of PKA and phosphorylated CREB (pCREB) in the caudate putamen (CPu) and nucleus accumbens (NAc) of male and female rats were measured basally or after acute (one 30-mg/kg intraperitoneal injection) or chronic (twice-daily 15-mg/kg injections for 14 days) cocaine administration. Behavioral responses to both cocaine administration paradigms were also studied.
Similar to previous findings, ambulatory, rearing, and stereotypic activities were higher in female rats after acute cocaine administration. Sex differences in cocaine-induced responses were also observed after chronic cocaine administration: While males developed a robust sensitization in ambulatory activities to cocaine, females developed tolerance in cocaine-induced rearing and stereotypic activities. In the basal group, females had significantly higher PKA protein levels in the NAc. Regardless of the cocaine administration paradigm, PKA protein levels in the NAc were higher overall in females than in males. Furthermore, after cocaine administration, while pCREB protein levels in male rats were induced for a longer amount of time than in female rats, the magnitude of change on pCREB levels were higher in female than male rats. However, in the CPu, no sex differences in PKA or pCREB protein levels were observed either in the basal group or after acute or chronic cocaine administration.
Taken together, these findings suggest that sex differences in basal and cocaine-induced alterations in the PKA signaling regulation in the NAc may contribute to sex differences in the psychomotor responses to cocaine.
Psychopharmacologia 01/2009; 203(3):641-50. · 4.08 Impact Factor
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ABSTRACT: Behavioral and dopamine responses to cocaine are sexually dimorphic: Female rats exhibit higher levels of locomotor and reward-associated behaviors after cocaine administration and dopamine release than do males. Activation of the dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32) intracellular cascade mediates responses to cocaine.
To examine the possibility that acute cocaine administration alters the DARPP-32 cascade in a sexually dimorphic pattern.
Male and female rats received either saline or cocaine (30 mg/kg). Protein levels of DARPP-32, phosphorylation of DARPP-32 at the Thr34 site (P-Thr34-DARPP-32), protein phosphatase 1 (PP-1), and protein phosphatase 2B (PP-2B) in nucleus accumbens were measured via Western blot analysis.
Females had higher protein levels of DARPP-32, P-Thr34-DARPP-32, calcineurin A (CaN-A; catalytic subunit of PP-2B), and calcineurin B (CaN-B; regulatory subunit of PP-2B) than males 5 min after saline treatment. In females, CaN-A protein levels were also higher at 15 min and PP-1 protein levels were higher 30 min after saline administration than males. In male rats, cocaine significantly increased CaN-A protein levels at 30 min and CaN-B protein levels at 15 min. In females, cocaine administration significantly decreased protein levels of DARPP-32, P-Thr34-DARPP-32, and CaN-A at 45 min but increased PP-1 protein levels at 30 min. Overall, males had higher activation of the DARPP-32 pathway after cocaine administration than did females.
These novel results show that basal and cocaine-induced sex differences in the DARPP-32/PP-1 cascade may be responsible for the sexual dimorphism in acute cocaine-induced behavioral responses.
Psychopharmacologia 12/2008; 203(1):175-83. · 4.08 Impact Factor
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Scott J Russo,
Wei Lun Sun,
Ana Christina E Minerly,
Karen Weierstall, Arbi Nazarian,
Eugene D Festa,
Tipyamol Niyomchai,
Alaleh Akhavan,
Victoria Luine,
Shirzad Jenab,
Vanya Quiñones-Jenab
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ABSTRACT: 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.
Brain Research 02/2008; 1189:229-35. · 2.73 Impact Factor
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ABSTRACT: Growing evidence suggests that sex differences in cocaine reward responses are regulated by endogenous gonadal hormones. However, few studies have addressed the role of testosterone on cocaine reward and psychomotor activation. This study aimed to determine whether testosterone influences the development of psychomotor and reward responses to cocaine. Castrated 8-week-old male Fisher rats received placebo or testosterone via Silastic capsules (1-3 capsules of 100% testosterone) or subcutaneous injections (400, 800, or 1200 microg/kg) concurrent with cocaine administration. Although chronic testosterone administration did not alter cocaine-induced conditioned place preference (CPP), concurrent administration of testosterone and cocaine affected the development of cocaine CPP dose-dependently; 400 microg/kg blocked the expression of cocaine-induced CPP. Testosterone did not affect cocaine-induced locomotor activity. Furthermore, testosterone-saline-treated controls did not develop CPP, suggesting that at these doses, testosterone does not produce rewarding or motor responses. These data suggest that testosterone may play a limited role in cocaine-induced reward associations and locomotor responses and thus has a limited effect in the previously reported sexually dimorphic responses to cocaine.
Ethnicity & disease 01/2008; 18(2 Suppl 2):S2-200-4. · 0.90 Impact Factor
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ABSTRACT: 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 estradiol's analgesic effect in Phase II, however, estradiol did not reverse progesterone's 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 estradiol's 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.
Hormones and Behavior 05/2006; 49(4):441-9. · 3.87 Impact Factor
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ABSTRACT: 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.
Brain Research Bulletin 02/2006; 68(4):277-84. · 2.82 Impact Factor
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ABSTRACT: Cocaine is an addictive psychostimulant that induces fos and opioid gene expression by activating the dopamine receptors and the PKA pathways in dopamine D1 and a glutamate NMDA-dependent mechanisms in the striatum. In this study, we show that a single cocaine administration induces ERK phosphorylation in the caudate/putamen of Fischer rats. This increase in Phospho-ERK is diminished by pre-administration of SCH23390, or MK801 but not with pre-administration of eticlopride. Furthermore, this single cocaine administration does not alter the levels of phospho-CREB protein or CREB-DNA bindings in the caudate/putamen protein extracts but does increase phospho-Elk-1 protein levels in the same extracts.
Molecular Brain Research 01/2006; 142(2):134-8. · 2.00 Impact Factor
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ABSTRACT: 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.
Brain Research Bulletin 06/2004; 63(4):295-9. · 2.82 Impact Factor
