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In human adolescents, sociable males frequently drink to enhance positive emotional states, whereas anxious females often drink to avoid negative affective states. This study used a rat model of adolescence to provide information regarding possible sex differences in contributors to social drinking. The effects of ethanol (0, 0.5, and 0.75g/kg) on play fighting and social preference were assessed on P30, P32, and P34 using a within-subject design. Then animals were tested in a social drinking paradigm (P37-P40), with this testing revealing high drinkers and low drinkers. Sex differences in sensitivity to ethanol emerged among high and low drinkers. High socially drinking males, but not females, when tested prior to drinking sessions, showed significant increases in play fighting at both doses. In low drinking males, play fighting was increased by 0.5g/kg ethanol, whereas the higher dose of 0.75g/kg produced significant decreases in play fighting. High drinking females initially showed low levels of social preference than high drinking males and low drinking females and were extremely sensitive to ethanol-induced enhancement of this social measure. Low social drinkers, both males and females, were more sensitive to the suppressing effects of ethanol on social preference following 0.75g/kg ethanol. These findings indicate that during adolescence enhanced sensitivity to the facilitating effects of ethanol on play fighting is associated with heavy drinking among males, whereas low social preference together with high sensitivity to ethanol-induced enhancement of social preference is related to high social drinking in females.

In human adolescents, sociable males frequently drink to enhance positive emotional states, whereas anxious females often drink to avoid negative affective states. This study used a rat model of adolescence to provide information regarding possible sex differences in contributors to social drinking. The effects of ethanol (0, 0.5, and 0.75g/kg) on play fighting and social preference were assessed on P30, P32, and P34 using a within-subject design. Then animals were tested in a social drinking paradigm (P37-P40), with this testing revealing high drinkers and low drinkers. Sex differences in sensitivity to ethanol emerged among high and low drinkers. High socially drinking males, but not females, when tested prior to drinking sessions, showed significant increases in play fighting at both doses. In low drinking males, play fighting was increased by 0.5g/kg ethanol, whereas the higher dose of 0.75g/kg produced significant decreases in play fighting. High drinking females initially showed low levels of social preference than high drinking males and low drinking females and were extremely sensitive to ethanol-induced enhancement of this social measure. Low social drinkers, both males and females, were more sensitive to the suppressing effects of ethanol on social preference following 0.75g/kg ethanol. These findings indicate that during adolescence enhanced sensitivity to the facilitating effects of ethanol on play fighting is associated with heavy drinking among males, whereas low social preference together with high sensitivity to ethanol-induced enhancement of social preference is related to high social drinking in females.

Prenatal alcohol exposure can interfere with endocrine function and have sex-specific effects on behavior. Disrupted development of the pituitary gland, which has been observed in rodent studies, may account for some of these effects. To determine if gestational exposure to alcohol produces measureable changes in the pituitary in human adolescents, we manually traced the pituitary in T1-weighted structural magnetic resonance images (MRI) from adolescents with (15 males, 11 females) and without (16 males, 11 females) heavy prenatal alcohol exposure. Pituitary gland volume and maximum signal intensity were examined for group differences. Control female adolescents presented with significantly greater pituitary volume compared to males, as has been previously reported. However, this sexual dimorphism was absent in adolescents with histories of prenatal alcohol exposure. Alcohol-exposed adolescents, regardless of sex, demonstrated reduced pituitary maximum signal intensity compared to controls. The lack of a sex difference in pituitary volumes within the alcohol-exposed group suggests such exposure may interfere with adolescent typical sexual dimorphism of the pituitary. Signal intensity in the posterior pituitary may reflect vasopressin storage. Our findings suggest vasopressin activity should be evaluated in alcohol-exposed adolescents.

Prenatal alcohol exposure can interfere with endocrine function and have sex-specific effects on behavior. Disrupted development of the pituitary gland, which has been observed in rodent studies, may account for some of these effects. To determine if gestational exposure to alcohol produces measureable changes in the pituitary in human adolescents, we manually traced the pituitary in T1-weighted structural magnetic resonance images (MRI) from adolescents with (15 males, 11 females) and without (16 males, 11 females) heavy prenatal alcohol exposure. Pituitary gland volume and maximum signal intensity were examined for group differences. Control female adolescents presented with significantly greater pituitary volume compared to males, as has been previously reported. However, this sexual dimorphism was absent in adolescents with histories of prenatal alcohol exposure. Alcohol-exposed adolescents, regardless of sex, demonstrated reduced pituitary maximum signal intensity compared to controls. The lack of a sex difference in pituitary volumes within the alcohol-exposed group suggests such exposure may interfere with adolescent typical sexual dimorphism of the pituitary. Signal intensity in the posterior pituitary may reflect vasopressin storage. Our findings suggest vasopressin activity should be evaluated in alcohol-exposed adolescents.

Background: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects.Methods: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2‐deoxy‐2[18F]fluoro‐d‐glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda).Results: Alcohol significantly and consistently decreased whole‐brain metabolism. The magnitude of these changes was significantly larger in male (−25 ± 6%) than in female (−14 ± 11%;p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self‐reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects.Conclusions: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

Background: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects.Methods: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2‐deoxy‐2[18F]fluoro‐d‐glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda).Results: Alcohol significantly and consistently decreased whole‐brain metabolism. The magnitude of these changes was significantly larger in male (−25 ± 6%) than in female (−14 ± 11%;p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self‐reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects.Conclusions: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.

A pattern of intact verbal abilities and impaired visuospatial abilities has led to a hypothesis of alcohol-induced right-hemisphere dysfunction in male chronic alcoholics. The applicability of this hypothesis to chronic female alcoholics was examined by administering the WAIS-R, Stark Paired Associates Tasks, and dichotic listening tasks to 15 male and 10 female alcoholics and 15 male and 10 female controls of similar age and education. Alcoholics had significantly lower Full Scale IQ scores on the WAIS-R but neither sex had a Verbal-Performance IQ difference indicative of right-hemisphere dysfunction. Male alcoholics showed deficits on both the Verbal and Visuospatial Stark Tasks, the deficit being greater on the Visuospatial Task. Male alcoholics showed an increased right-ear superiority on the verbal dichotic listening task and a decreased left-ear superiority on the musical dichotic listening task, both indicative of right-hemisphere dysfunction. The results, except for the WAIS-R, support the hypothesis that male but not female chronic alcoholics exhibit right-hemisphere dysfunction. Females, alcoholic or not, appear to be less lateralized in function.

A pattern of intact verbal abilities and impaired visuospatial abilities has led to a hypothesis of alcohol-induced right-hemisphere dysfunction in male chronic alcoholics. The applicability of this hypothesis to chronic female alcoholics was examined by administering the WAIS-R, Stark Paired Associates Tasks, and dichotic listening tasks to 15 male and 10 female alcoholics and 15 male and 10 female controls of similar age and education. Alcoholics had significantly lower Full Scale IQ scores on the WAIS-R but neither sex had a Verbal-Performance IQ difference indicative of right-hemisphere dysfunction. Male alcoholics showed deficits on both the Verbal and Visuospatial Stark Tasks, the deficit being greater on the Visuospatial Task. Male alcoholics showed an increased right-ear superiority on the verbal dichotic listening task and a decreased left-ear superiority on the musical dichotic listening task, both indicative of right-hemisphere dysfunction. The results, except for the WAIS-R, support the hypothesis that male but not female chronic alcoholics exhibit right-hemisphere dysfunction. Females, alcoholic or not, appear to be less lateralized in function.

The pharmacological profile of allopregnanolone, a neuroactive steroid that is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors, is similar to that of ethanol. Recent findings indicate that acute injection of ethanol increased endogenous allopregnanolone to pharmacologically relevant concentrations in male rats. However, there are no comparable data in mice, nor has the effect of ethanol drinking on endogenous allopregnanolone levels been investigated. Therefore, the present studies measured the effect of ethanol drinking and injection on allopregnanolone levels in male and female C57BL/6 mice. One group was given 17 days of 2-h limited access to a 10% v/v ethanol solution in a preference-drinking paradigm, while another group had access to water only. The ethanol dose consumed in 2 h exceeded 2 g/kg. Then, separate groups of mice were injected with either 2 g/kg ethanol or saline. Mice were killed 30 min after the 2-h drinking session or injection. Blood ethanol concentration was significantly higher in the ethanol-injected versus ethanol-drinking groups, even though the dose was similar. Consumption of ethanol significantly increased brain allopregnanolone levels in male but not female mice, compared with animals drinking water, but did not alter plasma corticosterone levels. In contrast, injection of ethanol did not significantly alter brain allopregnanolone levels in male or female mice and only significantly increased plasma corticosterone levels in the male mice, when compared with saline-injected animals. The sex differences in the effect of ethanol administration on endogenous allopregnanolone levels suggest that the hormonal milieu may impact ethanol's effect on GABAergic neurosteroids. Importantly, these data are the first to report the effect of ethanol drinking on allopregnanolone levels and indicate that ethanol consumption and ethanol injection can produce physiologically relevant allopregnanolone levels in male mice. These results have important implications for studies investigating the potential role of endogenous allopregnanolone levels in modulating susceptibility to ethanol abuse.

The pharmacological profile of allopregnanolone, a neuroactive steroid that is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors, is similar to that of ethanol. Recent findings indicate that acute injection of ethanol increased endogenous allopregnanolone to pharmacologically relevant concentrations in male rats. However, there are no comparable data in mice, nor has the effect of ethanol drinking on endogenous allopregnanolone levels been investigated. Therefore, the present studies measured the effect of ethanol drinking and injection on allopregnanolone levels in male and female C57BL/6 mice. One group was given 17 days of 2-h limited access to a 10% v/v ethanol solution in a preference-drinking paradigm, while another group had access to water only. The ethanol dose consumed in 2 h exceeded 2 g/kg. Then, separate groups of mice were injected with either 2 g/kg ethanol or saline. Mice were killed 30 min after the 2-h drinking session or injection. Blood ethanol concentration was significantly higher in the ethanol-injected versus ethanol-drinking groups, even though the dose was similar. Consumption of ethanol significantly increased brain allopregnanolone levels in male but not female mice, compared with animals drinking water, but did not alter plasma corticosterone levels. In contrast, injection of ethanol did not significantly alter brain allopregnanolone levels in male or female mice and only significantly increased plasma corticosterone levels in the male mice, when compared with saline-injected animals. The sex differences in the effect of ethanol administration on endogenous allopregnanolone levels suggest that the hormonal milieu may impact ethanol's effect on GABAergic neurosteroids. Importantly, these data are the first to report the effect of ethanol drinking on allopregnanolone levels and indicate that ethanol consumption and ethanol injection can produce physiologically relevant allopregnanolone levels in male mice. These results have important implications for studies investigating the potential role of endogenous allopregnanolone levels in modulating susceptibility to ethanol abuse.

For many years, researchers have avoided including females in their research because of the poorly understood influences of cycling hormones. However, we are becoming increasingly aware that sex matters, showing that it is important to conduct studies in females as well as males. This review will focus on the central nervous system (CNS) actions of alcohol (ethanol) because we have found significant sex differences in ethanol actions at the molecular as well as the behavioral level. Most recently, in our studies of ethanol dependence and withdrawal, we found that female rats displayed a shorter time for recovery from ethanol withdrawal, assessed by measuring seizure susceptibility. We now report that this finding was confirmed with a second convulsant agent. Moreover, GABAA receptor function was differentially altered in ethanol-withdrawn female compared to male rats. Studies by other investigators have reported additional significant sex differences in ethanol seeking and drinking behaviors and across several measures of ethanol dependence and withdrawal. We are gaining a better understanding of how the actions of ethanol in the CNS overlay sex differences in brain architecture and the hormonal milieu. Therefore, it is not surprising to observe sex-selective effects on cellular and behavioral outcomes from ethanol consumption. While current research is focused on characterizing sex differences in the actions of ethanol, it has not yet reached the point where we can integrate our findings into a unifying concept of how being female differentially regulates CNS responses to ethanol. This is likely a result of the complexity of ethanol actions, involving multiple neurotransmitter systems and responses covering the spectrum from drug seeking behaviors to neuropathological consequences of ethanol misuse. Regardless, the observed sex differences in ethanol withdrawal are noteworthy because they suggest that treatment of alcoholism should be managed differently in women than in men. Finally, it remains important to compare and contrast responses in males and females because recent studies of sex differences in basic physiology have made it clear that being female impacts health and disease.