Shieh KR, Yang SC. 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 154: 1589-1597

Institute of Neuroscience, Tzu Chi University, Hualien, Taiwan.
Neuroscience (Impact Factor: 3.36). 08/2008; 154(4):1589-97. DOI: 10.1016/j.neuroscience.2008.01.086
Source: PubMed


The present studies aimed to determine whether estradiol (E(2)) modulates the stimulation of cocaine- and amphetamine-regulated transcript (CART) peptide in the mesolimbic and nigrostriatal dopaminergic systems. I.c.v. administration of the CART peptide (55-102, 1 microg/3 microl) increased dopamine turnover (3,4-dihydroxyphenylacetic acid, DOPAC) in the nucleus accumbens (NA) and striatum (ST) in ovariectomized (OVX) female Sprague-Dawley rats with E(2)-priming. This stimulation of NA and ST DOPAC contents by CART peptide was found in OVX+E(2) female rats, but not in OVX only female rats, suggesting E(2) is an important factor in modulating the stimulatory effect of CART in the regulation of NA and ST DOPAC contents. This stimulation by CART peptide was also restored by treatment with the water-soluble form of E(2), but not by treatment with the membrane-impermeable form of E(2) in OVX female rats, suggesting that E(2) acts through intracellular rather than extracellular mechanisms to modulate the effects of CART peptide. Furthermore, the effects of water-soluble form of E(2) were blocked by E(2) antagonist, tamoxifen, but not by testosterone antagonist, flutamide. Our findings are the first to demonstrate that that E(2) plays a regulatory role in stimulation of CART peptide in mesolimbic and nigrostriatal dopaminergic systems in female rats, and E(2) acts through its own receptor(s) and intracellular mechanisms.

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    • "Further, the present finding that estrogen administration increases cocaine choice in OVX females is in agreement with studies reporting that estrogen enhances the reinforcing properties of cocaine (Lynch et al, 2001; Larson et al, 2007; Zhao and Becker, 2010). The ability of estrogen to increase the preference for cocaine in females may be to due to estrogenregulating dopamine transmission, as estrogen increases dopamine turnover, regulates dopamine receptor (D1R) calcium/calmodulin-dependent protein kinase II activity, and alters dopamine neural firing in the mesolimbic dopamine system in female rats (Shieh and Yang, 2008; Zhang et al, 2008; Zhen et al, 2007). Accordingly, it would be of interest to investigate the potential of dopaminergic mechanism in mediating cocaine choice, as distinct from those increasing response rates in rats. "
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    ABSTRACT: Cocaine-dependent women, relative to their male counterparts, report shorter cocaine-free periods and report transiting faster from first use to entering treatment for addiction. Similarly, preclinical studies indicate that female rats, particularly those in the estrus phase of their reproductive cycle, show increased operant responding for cocaine under a wide variety of schedules. Making maladaptive choices is a component of drug dependence, and concurrent reinforcement schedules that examine cocaine choice offers an animal model of the conditions of human drug use; therefore, the examination of sex differences in decision-making may be critical to understanding why women display a more severe profile of cocaine addiction than men. Accordingly, we assessed sex and estrous cycle differences in choice between food (45 mg grain pellets) and intravenous cocaine (0.4 or 1.0 mg/kg per infusion) reinforcement in male, female (freely cycling), and ovariectomized (OVX) females treated with either estrogen benzoate (EB; 5 μg per day) or vehicle. At both cocaine doses, intact female rats choose cocaine over food significantly more than male rats. However, the estrous cycle did not impact the level of cocaine choice in intact females. Nevertheless, OVX females treated with vehicle exhibited a substantially lower cocaine choice compared with those receiving daily EB or to intact females. These results demonstrate that intact females have a greater preference for cocaine over food compared with males. Furthermore, this higher preference is estrogen-dependent, but does not vary across the female reproductive cycle, suggesting that ovarian hormones regulate cocaine choice. The present findings indicate that there is a biological predisposition for females to forgo food reinforcement to obtain cocaine reinforcement, which may substantially contribute to women experiencing a more severe profile of cocaine addiction than men.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2012; 37(12):2605-14. DOI:10.1038/npp.2012.99 · 7.05 Impact Factor
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    • "mechanism that is dependent on the CART neuron-restrictive silencer element (Li et al., 2008). Estradiol E(2), acting through its own receptor(s) and intracellular mechanisms, plays a regulatory role in stimulating the CART peptide in mesolimbic and nigrostriatal dopaminergic systems in female rats (Shieh and Yang, 2008). The putative receptor target for CART has not yet been identified, but in vitro studies strongly suggest that CART facilitates activation of extracellular signal-regulated kinase within the cell (Lakatos et al., 2005; Vicentic et al., 2005; Maletinska et al., 2007). "
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    ABSTRACT: The cocaine- and amphetamine-regulated transcript (CART) gene encodes an anorexigenic peptide. It has a key role in the hypothalamic regulation of energy balance through reducing food intake and enhancing lipid substrate utilization. To detect the CART expression pattern in pigs, reverse transcription (RT)-polymerase chain reaction (PCR) and real-time PCR were performed in various tissues. Our RT-PCR results revealed that the pig CART gene was ubiquitously expressed in all examined tissues including hypothalamus, m. longissimus, backfat, heart, liver, spleen, lung, kidney, stomach, bladder, belly fat, brain, large intestine, lymph, and skin. Real-time quantitative PCR experiments revealed that the cDNA level of CART in both the hypothalamus and backfat of adult Landrace pig (lean-type) was significantly higher than that of Chinese indigenous Lantang pig (fat-type), and it was in the hypothalamus where the highest expression of CART was observed for both adult Lantang and Landrace pigs, compared with backfat and m. longissimus muscle. To understand the regulation of the pig CART gene, the 5'-flanking region was isolated from a pig bacterial artificial chromosome library and used in a luciferase reporter assay. A positive cis-acting element for efficient CART expression was identified at nucleotides -73 to -53, using 5'-serial deletion of the promoter. Electrophoretic mobility shift assays with competing oligonucleotides revealed that the critical region contained a cis-acting element for the zinc-binding protein factor, a zinc-finger transcription factor of the Kruppel family. This element has not been reported in human or mouse CART genes. Our results indicated that zinc-binding protein factor might be an essential regulatory factor for transcription of pig CART, providing important insight into mechanisms involved in energy homeostasis regulation in the porcine and human brain.
    DNA and cell biology 02/2011; 30(2):91-7. DOI:10.1089/dna.2010.1101 · 2.06 Impact Factor
    • "In another study, the induction of DA by cocaine-and amphetamine-regulated transcript (CART), a protein the regulates mesolimbic function in response to stimulants (Kuhar et al. 2005), was enhanced by EST administration in OVX rats relative to OVX rats treated with VEH (Shieh and Yang 2008). Furthermore, this effect was attributed to an intracellular mechanism as only administration of EST that was permeable to cellular membranes facilitated CART-induced DA turnover (Shieh and Yang 2008). EST treatment also facilitated nicotine-evoked DA release in the striatum in female, but not male rats (Dluzen and Anderson 1997), suggesting that the effects of EST on stimulant-induced DA are sex specific. "
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    ABSTRACT: Human and animal research indicates the presence of sex differences in drug abuse. These data suggest that females, compared to males, are more vulnerable to key phases of the addiction process that mark transitions in drug use such as initiation, drug bingeing, and relapse. Recent data indicate that the female gonadal hormone estrogen may facilitate drug abuse in women. For example, phases of the menstrual cycle when estrogen levels are high are associated with enhanced positive subjective measures following cocaine and amphetamine administration in women. Furthermore, in animal research, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior. Neurobiological data suggest that estrogen may facilitate drug taking by interacting with reward- and stress-related systems. This chapter discusses sex differences in and hormonal effects on drug-seeking behaviors in animal models of drug abuse. The neurobiological basis of these differences and effects are also discussed.
    Current Topics in Behavioral Neurosciences 01/2011; 8(8):73-96. DOI:10.1007/7854_2010_93
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