Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens

Nazarian, Arbi; Sun, Wei-Lun; Zhou, Luyi; Kemen, Lynne M.; Jenab, Shirzad; Quiñones-Jenab, Vanya

doi:10.1007/s00213-008-1411-5

Cited by 43 publications

(34 citation statements)

References 57 publications

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“…With the relatively small number of individuals included this investigation should be regarded as preliminary in nature. As previously published in rodents (HebdaBauer et al 2007 ;Nazarian et al 2009), our statistical analyses similarly suggest weak but significant effects of age on expression and gender on phosphorylation of CREB in men. These findings need to be further explored in a larger sample population.…”

Section: Discussionsupporting

confidence: 85%

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Smoking behaviour is associated with expression and phosphorylation of CREB in human buffy coat

Lenz

Klafki

Hillemacher

et al. 2010

Int. J. Neuropsychopharm.

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Nicotine induces various acute und chronic pharmacological effects which can be long lasting and might lead to nicotine dependence. Nicotinic acetylcholine receptors (nAChRs) are involved in nicotine-induced phosphorylation of CREB (cyclic AMP response element-binding protein) in PC12h cells. Several studies, mainly done in animal models, report that CREB plays a role in anxiety, memory and substance abuse as well as in affective disorders. Information regarding nicotine effects on gene expression in humans in vivo is rare. The aim of our study was to determine whether or not there are differences between smokers and non-smoking controls in terms of CREB expression and phosphorylation in human buffy coat. Comparing 32 smokers with 76 non-smoking controls we found significantly elevated relative (p=0.043) and absolute (p=0.040) CREB phosphorylation in the blood of smokers who had smoked two cigarettes in the past 6 h. In contrast, the score of the State and Trait Anxiety Inventory, total-CREB and mRNA-CREB were not significantly different. Multiple regression analysis revealed a significant relation between the number of cigarettes smoked daily (R2=0.143, p=0.023), the Fagerström Test for Nicotine Dependence score (R2=0.145, p=0.022) and the expression of CREB. Moreover, in accord with previously published data our analysis suggests gender and age as factors that significantly influence expression and phosphorylation of CREB. It appears that human buffy coat is suitable for studying pharmacological effects of substances such as nicotine on selected signal transduction pathways in humans in vivo. This kind of study may be helpful for translating findings from animal models and cell cultures.

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Section: Discussionsupporting

confidence: 85%

“…As there is growing evidence for gender-specific effects of CREB in association with addiction from the animal model (Nazarian et al 2009), we investigated sex-specific differences. The variable phospho-CREB % was transformed using the natural logarithm in order to achieve normal distribution.…”

Section: Gender and Age Specific Effects On Crebmentioning

confidence: 99%

Smoking behaviour is associated with expression and phosphorylation of CREB in human buffy coat

Lenz

Klafki

Hillemacher

et al. 2010

Int. J. Neuropsychopharm.

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“…2005; Munro et al 2006). Gender-specific differences in the function of brain monoamine systems early trauma have previously been reported in rodents exposed to early life stress (Chocyk et al 2011; Festa et al 2004; Matthews et al 2001; Nazarian et al 2009; Walker et al 2006). Interestingly, maternal separation has been shown to be associated with ethanol consumption and preference in male, but not female rats (Gustafsson et al 2005; Jaworski et al 2005; Moffett et al 2007; Roman et al 2004).…”

Section: Discussionmentioning

confidence: 79%

History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine

et al. 2014

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Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear. This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans. Following intake assessment, 28 healthy male and female adults, ages 18–29 years, underwent two consecutive 90-minute positron emission tomography (PET) studies with high specific activity [11C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg). Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress. Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.

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“…These drug-induced changes in structural and functional plasticity are targeted toward medium spiny neurons (Dietz et al, 2009), the principal output neurons of the NAc. Similar to cocaine (Nazarian et al, 2008; Dumitriu et al, 2012), estradiol alters excitability (Mermelstein et al, 1996), gene expression (Grove-Strawser et al, 2010), and dendritic structure in medium spiny neurons (Staffend et al, 2011; Peterson et al, 2014). Consequently, estradiol may act in concert with drugs of abuse to induce plasticity within mesolimbic reward areas, thereby conferring increased susceptibility to the addictive effects of these drugs in females.…”

Section: Introductionmentioning

confidence: 99%

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

Martínez

Gross

Himmler

et al. 2016

eNeuro

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In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females.

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Sex differences in basal and cocaine-induced alterations in PKA and CREB proteins in the nucleus accumbens

Abstract: 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.

Cited by 43 publications

References 57 publications

Smoking behaviour is associated with expression and phosphorylation of CREB in human buffy coat

Smoking behaviour is associated with expression and phosphorylation of CREB in human buffy coat

History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine

Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5

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