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Try out PMC Labs and tell us what you think. Learn More. Alcohol use disorder is a widespread mental illness characterized by periods of abstinence followed by recidivism, and stress is the primary trigger of relapse. Despite the higher prevalence of alcohol use disorder in males, the relationship between stress and behavioral features of relapse, such as craving, is stronger in females.

Given the greater susceptibility of females to stress-related psychiatric disorders, understanding sexual dimorphism in the relationship between stress and alcohol use is essential to identifying better treatments for both male and female alcoholics. This review addresses sex differences in the impact of stressors on alcohol drinking and seeking in rodents and humans. As these behavioral differences in alcohol use and relapse originate from sexual dimorphism in neuronal function, the impact of stressors and alcohol, and their interaction, on molecular adaptations and neural activity in males and females will also be discussed.

Department of Health and Human Services, Given the chronically relapsing nature of AUDs, determining the neurobiological underpinnings of differential susceptibility to AUDs can promote the development of more effective treatments for both sexes. Of particular interest as a source for sexual dimorphism in disease prevalence, progression and resurgence is the impact of stress on neurobiology and behavior.

Stress-related disorders, including anxiety disorders, mood disorders and post-traumatic stress disorder PTSD , are twice as frequently diagnosed in females as compared to males World Health Organization, Data indicate that females may display a more direct relationship between current or past stress exposure and relapse-related variables.

Moreover, chronic drug abuse shows differential neuroadaptations in men and women. Importantly, these measures have been associated with high risk of relapse and poor treatment outcomes Back et al. These differential sensitivities to alcohol and stress in males and females suggest circuit dichotomies between the sexes — yet most preclinical research to date has focused on elucidating factors promoting alcohol use, relapse, and stress responses solely in males.

The limited of studies that have, to date, investigated sex differences in stress-alcohol interactions, or effects in females, are reviewed herein and summarized in Table 1. One primary intersection between stress and abused drugs like alcohol, which may generate divergent neuroadaptations in males and females, is the activation of systemic stress response systems. Summary of literature investigating sex differences or female effects of stress on alcohol-related behaviors.

Sex differences in substance misuse, as well as the long-term impact of stressors on drinking or other drug use and relapse, may stem from sexual divergence in systemic stress responses. At present, the effects of alcohol dependence on these parameters in females remain unknown and as such are a critical future direction of preclinical research, as polymorphisms in the glucocorticoid receptor gene were associated with earlier onset of alcohol use or misuse in females, more than in males, in a large cohort of Finnish teenagers Desrivieres et al.

Early abstinence from alcohol in humans is marked by dysregulated basal physiological and neuroendocrine tone, and stress- and cue-induced physiological, HPA axis and emotional changes are strongly associated with increased drug and alcohol craving, drug use and relapse risk Back et al. Administration of the glucocorticoid receptor antagonist mifepristone reduced alcohol craving, relative to placebo, in a mixed-sex clinical treatment population with AUD, similar to effects observed in male alcohol-dependent rats Vendruscolo et al.

Together, these data implicate stress responses, particularly CORT function via glucocorticoid receptors, as intrinsic drivers of alcohol use in both sexes and suggest overlapping neurocircuitry and similar neuroadaptations may drive the interaction between stress and drug use in males and females. Despite long-standing knowledge of increased systemic HPA axis response to stressors and alcohol in females, most research into neuroadaptations caused by alcohol, stress, or their co-occurrence, and the impact of such adaptations on alcohol-related behaviors, has focused exclusively on male subjects.

To date, only a small fraction of preclinical investigations into stress, alcohol and their interaction have explored sex differences, at either the molecular or behavioral level, as detailed in the following sections. This suggests that overlapping neurocircuits support behavioral responses to both alcohol and stress, with intrinsic sex differences in the circuitry producing different behavioral responses in males and females. Candidate regions activated by both stress and alcohol that display divergent structural or electrophysiological responses between the sexes include regions of the limbic system and extended amygdala, where stress and alcohol interact to regulate neuronal activity, as well the locus coeruleus LC , responsible for controlling arousal.

Together these studies implicate the LC as one neuronal locus displaying intrinsic sexual dimorphism, yielding sex differences in activation by acute stressors, as well as sex differences in adaptation to the chronic stress of alcohol dependence. In particular, the central nucleus of the amygdala CeA , the output nucleus of the amygdala complex, has long been implicated in alcohol dependence and alcohol-stress interactions.

In males, CeA neuron activity is altered by various neuropeptides whose expression is changed by substantial alcohol exposure in a direction associated with elevated anxiety-like behavior Economidou et al. While few studies have addressed sex differences in the extended amygdala, two studies investigating sex differences in CRF expression have shown sex-specific expression patterns in the CeA. Together these data demonstrate that alcohol and stress generate sexually divergent adaptations of similar targets, which may vary by developmental stage.

Of importance is the impact of such neuroadaptations on neuronal activity in the region. Given the aforementioned sex differences in the effects of stress and alcohol on CeA CRF neurons, associated changes in neuronal activity would be expected to display different patterns in males and females. To date, only two studies have tested sex differences in the electrophysiological impact of alcohol and stress on CeA neurons. Specifically, females required longer exposure to intermittent ethanol vapor to display the same phenotypes as males, which included increased glutamate release and increased EPSC amplitude in the BLA.

While these differential sensitivities would suggest greater amygdala neuroadaptation to stressors for females and to alcohol for males, the broader molecular and behavioral impacts of these findings remain to be determined. Activation of the CB1 receptor, considered anxiolytic, also produced sex-specific effects, inhibiting EPSPs ificantly in neurons from msPs of both sexes, but only in Wistar male neurons. Yet CB1 inhibition alone did not alter CeM electrophysiological properties in rats of either sex or genetic background, suggesting that behavioral effects of cannabinoid system manipulation on alcohol drinking may be driven by brain regions outside the CeA or by neuroadaptations caused by extensive alcohol drinking history.

These initial studies strongly support the need for additional investigations to elucidate how sex regulates neuronal adaptation to alcohol and stressors, in order to understand the myriad factors regulating sex differences in behavioral responses to alcohol, stressors and their interaction. As discussed above, sex differences exist in physiological responses to stress and to alcohol exposure, and are predictive of sex differences in behavioral responses to these two challenges.

The effects of stress on alcohol-motivated behavior reviewed in H. In contrast, animal models of drug-motivated behavior consistently show females take and seek alcohol and other drugs in larger amounts than males J. However, studies examining sex differences in stress-induced alcohol-related behaviors are inconsistent, likely due to variations in experimental factors, as listed above. Only a handful of studies have measured the behavioral consequences of experimenter-administered alcohol as a function of stress exposure and sex.

Similarly, sex differences were not observed in the effects of adolescent or adult exposure to footshock stress on alcohol CPP in mice Song et al. Taken together, it appears that age at stress exposure and behavioral testing, as well as species of rodent, contribute to the ability to detect sex- and stress-dependent effects on behavioral responses to noncontingent administration of alcohol. A of studies using limited, intermittent, or continuous home cage access to alcohol have examined the effects of stress, given at various times during development, on alcohol drinking and preference.

Animals exposed to acute stress in adulthood also show varying . Clearly, sex- and stress-related alterations in voluntary drinking vary ificantly as a function of the parameters used. Only two studies have examined sex differences in the effects of stress in altering alcohol-motivated behavior using operant self-administration and reinstatement of alcohol seeking techniques Bertholomey et al. A of studies discussed below have examined sex- and estrous cycle-related alterations in alcohol self-administration, finding enhanced drinking in females.

In contrast, a contemporaneous study showed not only that female Sprague-Dawley rats displayed enhanced alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking compared to males, but that these effects were additive when cues and yohimbine were given in combination Bertholomey et al. Further, alcohol drinking and cue-related seeking were enhanced in female, but not male, rats exposed chronically to CORT in adolescence p30—50 and tested in adulthood, suggesting that both acute and chronic stressors may contribute to an increased vulnerability in females.

Importantly, both plasma CORT and estradiol E2 levels were positively correlated with responding during reinstatement, indicating that physiological markers of the stress response as well as circulating ovarian hormones contribute to the increased sensitivity to stress-related alcohol-motivated behavior in females Bertholomey et al. Taken together, the impact of sex differences on stress modulation of alcohol drinking and seeking is inconsistent and complex, and substantial research is still needed to parse the role of each of the potential sources of sex differences on the behavioral response to stress and alcohol.

Nonetheless, the consistent finding that females consume more alcohol than males, and tend to be more sensitive to stress, points to the importance of assessing overlapping stress and gonadal hormone systems when measuring behavioral responses to stress in males and females. Typically, the first step in determining the cause of sex differences in behavior is to determine if the activational effects of circulating gonadal hormones are sufficient to explain the observation J. Becker et al. Numerous studies have investigated whether estrous cycle-related alterations in ovarian hormones namely estradiol and progesterone , or plasma levels of gonadal hormones measured on the day of a behavioral test mediate observed differences.

Studies investigating these questions using slightly different models have been surprisingly equivocal with respect to alcohol-related behavior. Conversely, removal of estradiol and progesterone via OVX has reduced alcohol drinking more consistently Almeida et al. Despite some conflicting findings, the overall consensus is that testosterone is responsible for reduced alcohol drinking in males and ovarian hormones are responsible for increased drinking in females. However, these can be difficult to reconcile as GDX, hormone replacement, and sham controls for both sexes were often not compared in the same study.

Further, none of these studies examined the role of gonadal hormones in altering stress-related increases in alcohol reinforcement. Consistent with findings, females self-administered ificantly more alcohol than males, and GDX increased self-administration in males and decreased self-administration in females, relative to gonadally intact sham surgery controls. Furthermore, replacing estradiol in females increased alcohol self-administration, while testosterone replacement reduced self-administration in males, relative to sham levels of responding.

While circulating hormone levels could shift the degree of alcohol self-administration within sex, GDX in both sexes was not sufficient to eliminate sex differences, as OVX females still self-administered ificantly more alcohol than GDX males. Therefore, the activational effects of hormones cannot fully explain sex differences in alcohol self-administration. Therefore, differences between males and females in this alcohol craving-like response does not appear to be mediated by the activational effects of hormones. Nonetheless, it is possible that within sex, circulating hormones modulate individual differences in the degree of reinstatement, as suggested by prior correlational findings, but that the range of reinstatement response is greater in females regardless of hormonal state.

Together these studies indicate that while hormone supplementation can alter parameters of alcohol self-administration, adult GDX does not directly modulate the motivation to work for alcohol in an operant setting, in contrast with some findings discussed above for alcohol drinking in a free-access setting. Future studies will need to investigate how either organizational or genetic effects of sex alter neurodevelopment in a way that le to increased risk for alcohol-motivated behaviors, such as alcohol seeking and drinking, as well as stress-induced craving in females.

Identification of these mechanisms may lead to improved, sex-specific treatments for AUDs. Limitations exist in assessing treatment options in females given the need to better understand the molecular bases of sex differences in stress-alcohol interactions. However, components of the stress response — including HPA axis and adrenergic system activity — represent common targets implicated by both preclinical and clinical studies as possible points of differentiation between the sexes. Human studies have shown neuroadaptations in the HPA axis with chronic drug and alcohol abuse, as well as emotional changes during abstinence, which impact responses to stress and increase the risk of relapse Back et al.

The studies presented herein demonstrate evidence of sex differences in these HPA axis neuroadaptations, as assessed in human laboratory studies, as well as sex differences in treatment efficacy of medications targeting this stress pathophysiology. Because investigation of sex differences in AUD has been somewhat sparse, even at the clinical level, studies described herein demonstrate sex differences in mechanisms that may similarly drive craving and relapse in both alcohol- and cocaine-dependent individuals, to identify putative targets for future preclinical studies.

These patients also displayed higher severity of alcohol and other drug abuse, with elevated stress- and cue-induced craving, heightened anxiety and HPA axis dysregulation compared to those with less alcohol abuse severity Fox et al. Women with cocaine use disorder CUD exhibited ificantly lower ACTH, cortisol and blood pressure responses following exposure to personalized stress, drug-cue, and neutral imagery, as compared to CUD men Fox et al.

Patients with AUD similarly display HPA axis alterations, as well as sexual dimorphism in the interaction between alcohol use and stress. Across all three groups, females showed ificantly lower levels of ACTH compared to males. Collectively, these findings suggest that stress and drug cues increase craving and anxiety, and that chronic drug use is associated with an altered HPA axis response to stress, marked by basal hyperactivity and blunted phasic response to stress, that is more severe in females. While it remains unknown whether HPA axis dysfunction predisposes individuals to SUDs or develops consequent to the SUD, these states have been shown to potently predict relapse, suggesting that improved understanding of the molecular mechanisms triggering these adaptations are important preclinical avenues of investigation to identify better treatments and reduce relapse in both sexes.

Conversely, knowledge about medication responses in clinical trials addressing stress-alcohol interactions will provide additional indicators of sex differences that must be further elucidated by preclinical investigations. As ificant sex differences have been observed in SUD-related adaptation of these pathways, however, special attention must be paid to the development of sex-specific treatment targets. Whereas much experimental evidence has focused on treatments in male-only or male-biased populations, studies investigating multiple medications aimed at improving the HPA axis dysregulation found in SUDs in sex-balanced populations have yielded some sex-specific effects.

However, population sizes in these preliminary studies precluded the performance of sufficiently powered sex-specific analyses. Guanfacine has also demonstrated enhanced efficacy vs. Importantly, this effect was not observed in men. Together these studies not only implicate the adrenergic system as a medication target to treat females more successfully than males, but also highlight the need for preclinical investigations to elucidate sex differences in stress- and alcohol-induced adrenergic circuit adaptations that may underlie this differential treatment efficacy.

Given the a priori sex difference in hormone status that likely impacts neuronal activity, as discussed above, elevating progesterone levels has been explored as a therapeutic approach that may generate a sexually dimorphic response. While main treatment effects were observed regardless of sex, progesterone treatment provided the added benefit of decreasing ratings of negative emotion and increasing ratings of relaxed mood following stress exposure in women but not men Fox et al. One metabolite of progesterone that may produce different treatment responses in males and females is the neuroactive steroid allopregnanolone ALLO.

ALLO is found in higher concentrations in the female mouse brain, but increased after alcohol drinking only in male mice Finn et al. Together these studies suggest elevation of neuroactive steroids like ALLO may represent a biomarker of treatment efficacy in men and women, warranting future preclinical and clinical research into steroids like ALLO that may be useful biomarkers for long-term treatment efficacy in both sexes. AUD, although currently more prevalent in males, afflicts both sexes, and the gender gap in disease prevalence is narrowing.

Yet preclinical studies including females, which provide a fuller understanding of brain mechanisms underlying these disorders, continue to lag far behind the vast body of literature focusing solely on male subjects. The data reviewed above demonstrate ificant sex differences in the impact of stressors on AUD in both preclinical animal models and human studies. Importantly, observed sex differences in the brain mechanisms supporting alcohol-stress interactions, in the behavioral impact of past stress on alcohol use, and in drug treatment efficacy highlight the need for continued pursuit of knowledge in the preclinical realm to understand the neural basis of sex differences in stress responses and alcohol use, so that better therapeutic approaches may be developed for both sexes.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the National Institute of Alcohol Abuse and Alcoholism, or the Pennsylvania Department of Health. National Center for Biotechnology Information , U. Author manuscript; available in PMC Nov 1. Marian L.

Bertholomey , 3 and Mary M.

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