Effects of estradiol on the stimulation of dopamine turnover in mesolimbic and nigrostriatal systems by cocaine- and amphetamine-regulated transcript peptide in female rats.
ABSTRACT 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.
SourceAvailable from: Marta C. Antonelli[Show abstract] [Hide abstract]
ABSTRACT: We have previously demonstrated that prenatal stress (PS) exerts an impairment of midbrain dopaminergic (DA) system metabolism especially after puberty, suggesting a particular sensitivity of DA development to variations in gonadal hormonal peaks. Furthermore we demonstrated that PS alters the long term androgens profile of the rat male offspring from prepubertal to adult stages. In this work we evaluated the sexual hormones activational effects on the DA system by analysing PS effects on the dopaminergic D2-like (D2R) and on the gonadal hormones receptor levels on cortical and hippocampal areas of prepubertal and adult male offspring. We further evaluated the dendritic arborization in the same areas by quantifying MAP2 immunoexpresion. Our results show that PS affected oestrogen receptor alpha (ERα) expression: mRNA er1s and ERα protein levels were decreased on prefrontal cortex and hippocampus of adult offspring. Moreover, PS reduced D2R protein levels in hippocampus of prepubertal rats. Morphological studies revealed that prepubertal PS rats presented decreased MAP2 immunoexpression in both areas suggesting that PS reduces the number of dendritic arborizations. Our findings suggest that PS exerts long-term effects on the DA system by altering the normal connectivity in the areas, and by modulating the expression of D2R and ERα in an age-related pattern. Since the developing forebrain DA system was shown to be influenced by androgen exposure, and PS was shown to disrupt perinatal testosterone surges, our results suggest that prenatal insults might be affecting the organizational role of androgens and differentially modulating their activational role on the DA development.Neurochemical Research 09/2013; DOI:10.1007/s11064-013-1143-8 · 2.55 Impact Factor
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ABSTRACT: Epidemiological data demonstrate that while women report lower rates of drug use than men, the number of current drug users and abusers who are women continues to increase. In addition women progress through the phases of addiction differently than men; women transition from casual drug use to addiction faster, are more reactive to stimuli that trigger relapse, and have higher rates of relapse then men. Sex differences in physiological and psychological responses to drugs of abuse are well documented and it is well established that estrogen effects on dopamine (DA) systems are largely responsible for these sex differences. However, the downstream mechanisms that result from interactions between estrogen and the effects of drugs of abuse on the DA system are just beginning to be explored. Here we review the basic neurocircuitry which underlies reward and addiction; highlighting the neuroadaptive changes that occur in the mesolimbic dopamine reward and anti-reward/stress pathways. We propose that sex differences in addiction are due to sex differences in the neural systems which mediate positive and negative reinforcement and that these differences are modulated by ovarian hormones. This forms a neurobehavioral basis for the search for the molecular and cellular underpinnings that uniquely guide motivational behaviors and make women more vulnerable to developing and sustaining addiction than men.Experimental Neurology 09/2014; DOI:10.1016/j.expneurol.2014.01.022 · 4.62 Impact Factor
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ABSTRACT: We have previously demonstrated that male rats exposed to stress during the last week of gestation present age-specific impairments of brain development. Since the organisation of the foetal developing brain is subject to androgen exposure and prenatal stress was reported to disrupt perinatal testosterone surges, the aim of this research was to explore whether abnormal androgen concentrations during late gestation affects the morphology of the prefrontal cortex (PFC), hippocampus (HPC) and ventral tegmental area (VTA), three major areas that were shown to be affected by prenatal stress in our previous studies. We administered 10 mg/Kg/day of the androgen receptor antagonist flutamide (4'nitro-3'-trifluoromethylsobutyranilide) or vehicle injections to pregnant rats from days 15-21 of gestation. The antiandrogenic effects of flutamide were confirmed by the analysis of androgen-dependent developmental markers: flutamide exposed rats showed reduced anogenital distance, delay in the completion of testis descent, hypospadias, cryptorchidism and atrophied seminal vesicles. Brain morphological studies revealed that prenatal flutamide decreased the number of MAP2 (a microtubule-associated protein type 2, present almost exclusively in dendrites) immunoreactive neuronal processes in all evaluated brain areas, both in prepubertal and adult offspring, suggesting that prenatal androgen disruption induces long term reductions of the dendritic arborisation of several brain structures, affecting the normal connectivity between areas. Moreover, the number of tyrosine hydroxylase (TH) immunopositive neurons in the VTA of prepubertal offspring was reduced in flutamide rats but reach normal values at adulthood. Our results demonstrate that the effects of prenatal flutamide on the offspring brain morphology resemble several prenatal stress effects suggesting that the mechanism of action of prenatal stress might be related to the impairment of the organisational role of androgens on brain development.Neuroscience 08/2014; 278. DOI:10.1016/j.neuroscience.2014.07.074 · 3.33 Impact Factor