Decreased Sensitivity to Ethanol Reward in Adolescent Mice as Measured by Conditioned Place Preference

Background:  Many preclinical studies have demonstrated age-related differential sensitivity to various effects of ethanol between adolescent and adult animals. However, published data addressing possible differences in ethanol's motivational effects are sparse, particularly in mice. The present study examined age-related differences in the conditioned rewarding effects of ethanol in DBA/2J mice.
Methods:  In the first experiment an unbiased place conditioning procedure was used to determine the rewarding effects of 2 g/kg ethanol in adult and adolescent DBA/2J mice. In a subsequent place conditioning experiment, the effects of 2 and 4 g/kg were assessed in adolescent mice.
Results:  Adolescents demonstrated a place preference with the high dose of 4 g/kg but not with a more moderate dose of 2 g/kg. In contrast, 2 g/kg was sufficient to produce place preference in adult mice.
Conclusions:  Adolescents are less sensitive than adults to the rewarding effects of ethanol but can experience reward with high doses. These results extend the current literature on ethanol's effects in adolescent animals.     

The effects of continuous and intermittent ethanol exposure in adolesence on the aversive properties of ethanol during adulthood

Background:  Alcohol abuse among adolescents is prevalent. Epidemiological studies suggest that alcohol abuse during the adolescent developmental period may result in long-term changes such as an increased susceptibility to alcohol-related problems in adulthood. Laboratory findings suggest that alcohol exposure during the adolescent developmental period, as compared with adulthood, may differentially impact subsequent neurobehavioral responses to alcohol. The present study was designed to examine whether ethanol exposure, continuous versus intermittent, during the adolescent developmental period would alter the aversive properties of ethanol in adult C3H mice.
Methods:  Periadolescent (PD28) male C3H mice were exposed to 64 hours of continuous or intermittent ethanol vapor. As a comparison, adult (PD70) C3H mice were also exposed to 64 hours of continuous or intermittent ethanol vapor. Six weeks after ethanol exposure, taste aversion conditioning was carried out on both ethanol pre-exposed and ethanol-naive animals using a 1-trial, 1-flavor taste-conditioning procedure.
Results:  Ethanol exposure during the periadolescent period significantly attenuated a subsequent ethanol-induced conditioned taste aversion, as compared with control animals. Adult animals exposed to chronic ethanol vapor during adolescence showed less of an aversion to an ethanol-paired flavor than ethanol-naive adults. Intermittent exposure to ethanol vapor during periadolescence produced a greater attenuation.
Conclusion:  It is suggested that ethanol exposure during the periadolescent period results in long-term neurobehavioral changes, which lessen a conditioned aversion to ethanol in adulthood. It is suggested that this age-related effect may underlie the increased susceptibility to alcohol-related problems which is negatively correlated with the age of onset for alcohol abuse.     

Specific reduction of alcohol's motivational properties by the positive allosteric modulator of the GABAB receptor, GS39783--comparison with the effect of the GABAB receptor direct agonist, baclofen

Background:  Activation of the GABA_B receptor—either by means of direct agonists (like baclofen) or positive allosteric modulators (like GS39783)—has been observed to suppress alcohol drinking and reinforcement in rats and mice. The present study was conducted to assess and compare the effect of baclofen and GS39783 on the motivational properties of alcohol.
Methods:  Selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to respond on a lever (on an fixed ratio 4 schedule of reinforcement) to orally self-administer alcohol (15%, v/v) or sucrose (3%, w/v) in daily 30-minute sessions. Once lever-responding reached stable levels, rats were exposed to sessions with a progressive ratio schedule of reinforcement. The effect of nonsedative doses of baclofen (0, 1, and 3 mg/kg, i.p.) and GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on breakpoint for alcohol and sucrose (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol and sucrose) was determined.
Results:  Baclofen administration resulted in a dose-dependent decrease in breakpoint for alcohol; this effect was not specific, as baclofen also reduced—to a comparable extent—breakpoint for sucrose. Conversely, GS39783 administration resulted in a dose-dependent and completely specific reduction in breakpoint for alcohol.
Conclusions:  The present results (i) confirm previous data on baclofen's capacity to suppress, although nonspecifically, alcohol's motivational properties, and (ii) extend to alcohol's motivational properties the capacity of GS39783 to inhibit alcohol drinking and reinforcement in rats.     

Electroacupuncture Inhibits Ethanol-Induced Locomotor Sensitization and Alters homer1A mRNA Expression in Mice

Background:  Here we investigated the effects of electroacupuncture over locomotor sensitization induced by ethanol in mice.
Methods:  Adult male Swiss mice were daily injected with ethanol (2 g/kg, i.p.) or saline for 21 days (acquisition phase). After 4 days of withdrawal, all animals were challenged with ethanol (1.4 g/kg, i.p.). The locomotor activity during 30 minutes was accessed just after the ethanol challenge. Electroacupuncture at acquisition, expression, or maintenance phases of locomotor sensitization was provided over ST-36 ( Zusanli ) or PC-6 ( Neiguan ) as well as concomitantly over these 2 acupoints. One hour after the challenge with ethanol, the animals were decapitated, the hippocampus, striatum, and prefrontal cortex were dissected, and the expression of homer1A mRNA assessed by PCR.
Results:  Electroacupuncture provided simultaneously over ST-36 and PC-6 (but not to ST-36 or PC-6 alone) inhibited the acquisition, expression, and maintenance of ethanol-induced locomotor sensitization. In addition, electroacupuncture blocked the diminution of homer1A mRNA expression triggered by ethanol in the acquisition (striatum and prefrontal cortex), expression (hippocampus), and in the maintenance (hippocampus and prefrontal cortex) phases.
Conclusion:  Electroacupuncture provided concomitantly over ST-36 and PC-6 prevents the sensitization of the mesocorticolimbic pathway induced by ethanol in mice. In addition, these effects were accompanied by changes in the expression of homer1A . We suggest that electroacupuncture effects over ethanol-induced locomotor sensitization are associated to its ability to modulate homer1A expression and glutamatergic plasticity.     

Acute Interaction of Baclofen in Combination With Alcohol in Heavy Social Drinkers

Background:  There is growing evidence that gamma-amino butyric acid-B receptor agonists may be effective in the treatment of alcohol abuse or dependence. The primary goal of this study was to determine the safety of baclofen in combination with alcohol consumption in heavy drinkers. In addition, the effects of baclofen alone, and in combination with alcohol, on subjective effects, cognitive performance effects, as well as alcohol craving, were assessed.
Methods:  Eighteen non-treatment-seeking heavy social drinkers (mean of 28 drinks per week), who did not meet the criteria for alcohol dependence participated. All individuals were tested using a double-blind double-dummy design with six 2-day inpatient phases. Baclofen (0, 40, and 80 mg) was administered 2.5 hours before alcohol (1.5 g/l body water or approximately 0.75 g/kg) or placebo beverages, given in 4 divided doses every 20 minutes.
Results:  Baclofen, either alone or in combination with alcohol, produced only modest increases in heart rate and blood pressure and no adverse effects were reported. Baclofen did not increase positive subjective effects (e.g., Stimulant effects, Drug Liking) but did increase sedation and impair performance. Even though both baclofen and alcohol impaired performance, for the most part performance was not impaired to a greater extent when baclofen was combined with alcohol. Among this population of nondependent drinkers, baclofen did not alter alcohol craving or alcohol-induced positive subjective effects.
Conclusions:  Baclofen alone has minimal abuse liability in heavy social drinkers, and baclofen is relatively well tolerated and safe when given in combination with intoxicating doses of alcohol.     

Differential effects of acute alcohol on prepulse inhibition and event-related potentials in adolescent and adult Wistar rats

Background: Previous studies have demonstrated that adolescent and adult rats show differential sensitivity to many of the acute effects of alcohol. We recently reported evidence of developmental differences in the effects of acute alcohol on the cortical electroencephalogram. However, it is unclear whether developmental differences are also observed in other neurophysiological and neurobehavioral measurements known to be sensitive to alcohol exposure. The present study determined the age‐related effects of acute alcohol on behavioral and event‐related potential (ERP) responses to acoustic startle (AS) and prepulse inhibition (PPI). Methods: Male adolescent and adult Wistar rats were implanted with cortical recording electrodes. The effects of acute alcohol (0.0, 0.75, and 1.5 g/kg) on behavioral and ERP responses to AS and PPI were assessed. Results: Acute alcohol (0.75 and 1.5 g/kg) significantly reduced the behavioral and electrophysiological response to AS in adolescent and adult rats. Both 0.75 and 1.5 g/kg alcohol significantly enhanced the behavioral response to PPI in adolescent, but not in adult rats. During prepulse + pulse trials, 1.5 g/kg alcohol significantly increased the N10 pulse response in the adolescent frontal cortex. Acute alcohol (0.75 and 1.5 g/kg) also increased the N1 ERP pulse response to prepulse stimuli in frontal and parietal cortices in adult rats, but not in adolescent rats. Conclusions: These data suggest that alcohol’s effect on behavioral and electrophysiological indices of AS do not differ between adults and adolescents whereas developmental stage does appear to significantly modify alcohol‐influenced response to PPI.     

Systemic Administration of Arecoline Reduces Ethanol-Induced Sleeping Through Activation of Central Muscarinic Receptor in Mice

Background:  Epidemiological evidence of co-use of alcohol and areca nuts suggests a potential central interaction between arecoline, a major alkaloid of areca and a muscarinic receptor agonist, and ethanol. Moreover, the central cholinergic system plays an important role in the depressant action of ethanol and barbiturates. The purpose of this study was to investigate the effects of arecoline on pentobarbital- and ethanol-induced hypnosis in mice.
Methods:  Male ICR mice were tested for locomotor activity following acute systemic administration of ethanol alone, arecoline alone, or ethanol plus arecoline. For the loss of the righting reflex (LORR) induced by pentobarbital and ethanol, sleep latency and sleeping duration were evaluated in mice treated with arecoline alone or the combination of arecoline and scopolamine or methscopolamine.
Results:  Ethanol (1.0 to 3.0 g/kg, i.p.) reduced locomotor activity significantly and a declining trend was observed after treatment with arecoline (0.25 to 1.0 mg/kg, i.p.), but there were no synergistic effects of ethanol and arecoline on locomotor activity. The experiments on LORR demonstrated that arecoline (0.125 to 1.0 mg/kg, s.c.) shortened the duration of sleeping induced by ethanol (4.0 g/kg, i.p.), but not pentobarbital (45 mg/kg, i.p.). In addition, alterations of sleep latency were not obvious in both pentobarbital- and ethanol-induced LORR. Statistical analyses revealed that scopolamine (centrally acting), but not methscopolamine (peripherally acting), could antagonize the effect of arecoline on the duration of ethanol-induced LORR in mice.
Conclusions:  These results suggest that central muscarinic receptor is a pharmacological target for the action of arecoline to modulate ethanol-induced hypnosis.     

Administration of myostatin does not alter fat mass in adult mice

Aim:   Myostatin, a member of the TGF-beta superfamily, is produced by skeletal muscle and acts as a negative regulator of muscle mass. It has also been suggested that low-dose administration of myostatin (2 μg/day) in rodents can reduce fat mass without altering muscle mass. In the current study, we attempted to further explore the effects of myostatin on adipocytes and its potential to reduce fat mass, since myostatin administration could potentially be a useful strategy to treat obesity and its complications in humans.
Methods:   Purified myostatin protein was examined for its effects on adipogenesis and lipolysis in differentiated 3T3-L1 adipocytes as well as for effects on fat mass in wild-type, myostatin null and obese mice.
Results:   While myostatin was capable of inhibiting adipogenesis in 3T3-L1 cells, it did not alter lipolysis in fully differentiated adipocytes. Importantly, pharmacological administration of myostatin over a range of doses (2–120 μg/day) did not affect fat mass in wild-type or genetically obese (ob/ob, db/db) mice, although muscle mass was significantly reduced at the highest myostatin dose.
Conclusions:   Our results suggest that myostatin does not reduce adipose stores in adult animals. Contrary to prior indications, pharmacological administration of myostatin does not appear to be an effective strategy to treat obesity in vivo .     

Age- and sex-dependent effects of footshock stress on subsequent alcohol drinking and acoustic startle behavior in mice selectively bred for high-alcohol preference

Background: Exposure to stress during adolescence is known to be a risk factor for alcohol‐use and anxiety disorders. This study examined the effects of footshock stress during adolescence on subsequent alcohol drinking in male and female mice selectively bred for high‐alcohol preference (HAP1 lines). Acoustic startle responses and prepulse inhibition (PPI) were also assessed in the absence of, and immediately following, subsequent footshock stress exposures to determine whether a prior history of footshock stress during adolescence would produce enduring effects on anxiety‐related behavior and sensorimotor gating. Methods: Alcohol‐naïve, adolescent (male, n = 27; female, n = 23) and adult (male, n = 30; female, n = 30) HAP1 mice were randomly assigned to a stress or no stress group. The study consisted of 5 phases: (1) 10 consecutive days of exposure to a 30‐minute footshock session, (2) 1 startle test, (3) one 30‐minute footshock session immediately followed by 1 startle test, (4) 30 days of free‐choice alcohol consumption, and (5) one 30‐minute footshock session immediately followed by 1 startle test. Results: Footshock stress exposure during adolescence, but not adulthood, robustly increased alcohol drinking behavior in both male and female HAP1 mice. Before alcohol drinking, females in both the adolescent and adult stress groups showed greater startle in phases 2 and 3; whereas males in the adolescent stress group showed greater startle only in phase 3. After alcohol drinking, in phase 5, enhanced startle was no longer apparent in any stress group. Males in the adult stress group showed reduced startle in phases 2 and 5. PPI was generally unchanged, except that males in the adolescent stress group showed increased PPI in phase 3 and females in the adolescent stress group showed decreased PPI in phase 5. Conclusions: Adolescent HAP1 mice appear to be more vulnerable to the effects of footshock stress than adult mice, as manifested by increased alcohol drinking and anxiety‐related behavior in adulthood. These results in mice suggest that stress exposure during adolescence may increase the risk for developing an alcohol‐use and/or anxiety disorder in individuals with a genetic predisposition toward high alcohol consumption.     

Place conditioning: age-related changes in the rewarding and aversive effects of alcohol

BACKGROUND: Alcohol abuse levels are very high in adolescents, creating a significant societal issue. It has been shown that people who begin alcohol use as adolescents are more likely to become addicts than people who initiate alcohol use as adults. It is important to note that the development of addiction in humans is more rapid with initiation in adolescence than in adulthood. METHODS: To determine changes in the reinforcing efficacy of alcohol as a function of adolescent development, we used a place-conditioning paradigm. In this study, we assessed the ability of ethanol to support a conditioned place preference (CPP) or aversion. Animals [postnatal days (PND) 25, 35, 45, and 60] were tested for alcohol-induced conditioning in response to a range of ethanol doses (0.2, 0.5, 1.0, and 2.0 g/kg intraperitoneally) or saline. RESULTS: In general, there was a trend for alcohol to produce an aversion to the ethanol-paired compartment at higher doses. These patterns differed significantly as a function of age. Younger animals (PND 25) exhibited a CPP to a low dose and an aversion at high doses. Late-adolescent (PND 45) animals exhibited a CPP at two moderate doses but a conditioned place aversion at the highest dose. PND 35 and 60 animals did not exhibit a CPP at any examined dose, and PND 60 animals exhibited a progressive aversion with increasing dose. CONCLUSIONS: The data show that the developmental processes of adolescence influence general responsiveness to alcohol. Specifically, late-adolescent animals (PND 45) seem to prefer doses of alcohol that are either not reinforcing (0.5 g/kg) or are aversive (1.0 g/kg) at other ages. These processes need to be examined thoroughly to understand the development of addiction in adolescence. This is especially important given that alcohol abuse in adolescence may interfere with the usual pattern of brain development as it relates to alcohol reinforcement.     

Adolescent C57BL/6J mice show elevated alcohol intake, but reduced taste aversion, as compared to adult mice: a potential behavioral mechanism for binge drinking

Background: Binge alcohol drinking during adolescence is a serious health problem that may increase future risk of an alcohol use disorder. Although there are several different procedures by which to preclinically model binge‐like alcohol intake, limited‐access procedures offer the advantage of achieving high voluntary alcohol intake and pharmacologically relevant blood alcohol concentrations (BACs). Therefore, in the current study, developmental differences in binge‐like alcohol drinking using a limited‐access cycling procedure were examined. In addition, as alcohol drinking has been negatively correlated with sensitivity to the aversive properties of alcohol, we examined developmental differences in sensitivity to an alcohol‐induced conditioned taste aversion (CTA). Methods: Binge‐like alcohol consumption was investigated in adolescent (4 weeks) and adult (10 weeks) male C57BL/6J mice for 2 to 4 h/d for 16 days. Developmental differences in sensitivity to an alcohol‐induced CTA were examined in adolescent and adult mice, with saline or alcohol (3 or 4 g/kg) repeatedly paired with the intake of a novel tastant (NaCl). Results: Adolescent mice showed a significant increase in alcohol intake as compared to adults, with adolescents achieving higher BACs and increasing alcohol consumption over successive cycles of the binge procedure. Conversely, adolescent mice exhibited a dose‐dependent reduction in sensitivity to the aversive properties of alcohol, as compared to adult mice, with adolescent mice failing to develop a CTA to 3 g/kg alcohol. Finally, extinction of an alcohol CTA was observed following conditioning with a higher dose of alcohol in adolescent, versus adult, mice. Conclusions: These results indicate that adolescent mice consume more alcohol, per kilogram body weight, than adults in a binge‐like model of alcohol drinking and demonstrate a blunted sensitivity to the conditioned aversive effects of alcohol. Overall, this supports a behavioral framework by which heightened binge alcohol intake during adolescence occurs, in part, via a reduced sensitivity to the aversive properties of alcohol.     

Acute alcohol impairs conditioning of a behavioural reward-seeking response and inhibitory control processes—implications for addictive disorders

Aims   To investigate whether acute alcohol would affect performance of a conditioned behavioural response to obtain a reward outcome and impair performance in a task measuring inhibitory control to provide new knowledge of how the acute effects of alcohol might contribute to the transition from alcohol use to dependence.
Design   A randomized controlled between-subjects design was employed.
Settings   The laboratory of experimental psychology at the University of Sussex.
Participants   Thirty-two light to moderate social drinkers recruited from the undergraduate and postgraduate population.
Measurements   After the administration of alcohol (0.8 g/kg) or placebo participants underwent an instrumental reward-seeking procedure, with abstract stimuli serving as S+ (always predicting a win of 10 pence) and S− (always predicting a loss of 10 pence). In addition, a Stop Signal task was administered before and after the administration of alcohol.
Findings   Participants of the alcohol group performed the behavioural response to obtain the reward outcome more often than placebo subjects in trials associated with loss of money. This finding was observed, although alcohol was not affecting explicit knowledge of stimulus–response outcome contingencies and acquisition of conditioned attentional and emotional responses. In addition, alcohol increased Stop Signal reaction time indicating disinhibiting effects of alcohol, and this was associated positively with response probability to the S−.
Conclusions   These results demonstrate that alcohol is affecting inhibitory control of behavioural responses to external signals even when associated with punishment, contributing in this way to the transition from alcohol use to dependence.     

Regulation of motivation to self-administer ethanol by mGluR5 in alcohol-preferring (P) rats

Background:  Emerging evidence indicates that Group I metabotropic glutamate receptors (mGluR1 and mGluR5) differentially regulates ethanol self-administration in several rodent behavioral models. The purpose of this work was to further characterize involvement of Group I mGluRs in the reinforcing effects of ethanol using a progressive ratio schedule of reinforcement.
Methods:  Alcohol-preferring (P) rats were trained to self-administer ethanol (15% v/v) versus water on a concurrent schedule of reinforcement, and the effects of the Group I mGluR antagonists were evaluated on progressive ratio performance. The rats were then trained to self-administer sucrose (0.4% w/v) versus water, and the effects of the antagonists were tested on progressive ratio performance.
Results:  The mGluR1 antagonist, 3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl ( cis -4-methoxycyclohexyl) methanone (JNJ 16259685; 0 to 1 mg/kg) and the mGluR5 antagonist, 6-methyl-2-(phenylethynyl) pyridine (MPEP; 0 to 10 mg/kg) dose-dependently reduced ethanol break point. In separate locomotor activity assessments, the lowest effective dose of JNJ 16259685 (0.3 mg/kg) produced a motor impairment, whereas the lowest effective dose of MPEP (3 mg/kg) did not. Thus, the reduction in ethanol break point by mGluR1 antagonism was probably a result of a motor impairment. JNJ 16259685 (0.3 mg/kg) and MPEP (10 mg/kg) reduced sucrose break point and produced motor impairments. Thus, the reductions in sucrose break point produced by both Group I antagonists were probably because of nonspecific effects on motor activity.
Conclusions:  Together, these results suggest that glutamate activity at mGluR5 regulates motivation to self-administer ethanol.     

Adolescent- and adult-initiated alcohol exposure in mice differentially promotes tumorigenesis and metastasis of breast cancer

Background

Alcohol exposure increases the risk of breast cancer. Alcohol consumption by adolescents is a serious social and public health issue. This study investigated the impact of adolescent alcohol consumption on mammary tumorigenesis and progression and compared it to that of adult alcohol exposure in animal models.

Methods

Female adolescent (5 weeks) and adult (8 weeks) MMTV-Wnt1 mice were exposed to alcohol either chronically or acutely. For chronic alcohol exposure, animals were fed a liquid diet containing 6.7% ethanol for 23 weeks. For acute exposure, animals were treated with ethanol (2.5 g/kg, 25% w/v) via intraperitoneal (IP) injection for 15 days.

Results

In control animals, the tumor latency was 18.5 to 22 weeks. Both chronic and acute alcohol exposure in adolescent mice significantly shortened the tumor latency to 9.5 and 8.4 weeks, respectively. However, adult-initiated alcohol exposure had little effect on the tumor latency. Both adolescent- and adult-initiated alcohol exposure significantly increased lung metastasis. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased the breast cancer stem cell population. Adolescent-initiated alcohol exposure significantly altered the proliferation of mammary epithelial cells, ductal growth, and the formation of terminal end buds in the mammary glands. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased estradiol levels in the blood. Acute adolescent alcohol exposure also significantly increased blood progesterone levels. Furthermore, adolescent-initiated alcohol exposure activated PAK1 and p38γ MAPK, critical regulators of mammary tumorigenesis and aggressiveness, respectively, while adult-initiated alcohol exposure activated only p38γ MAPK. In addition, both adolescent and adult alcohol exposure significantly decreased the levels of a prognostic marker miR200b.

Conclusions

Adolescent-initiated alcohol exposure enhanced both tumorigenesis and aggressiveness of mammary tumors, while adult-initiated alcohol exposure mainly promoted tumor metastasis. Thus, adolescent mice were more sensitive than adult mice in response to alcohol-induced tumor promotion.     

Ethanol-induced behavioral sensitization in adolescent and adult mice: role of the nNOS gene

Background: In the brain, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) has a role in synaptic plasticity. Recent evidence suggests the role of NO in a variety of effects produced by alcohol in the central nervous system. The current study investigated the role of the nNOS gene in the development of behavioral sensitization to ethanol in adolescent and adult mice. Methods: Adolescent and adult wild type (WT; B6;129SF2) and nNOS knockout (KO; B6;129S4‐Nos1) mice of both sexes received saline or ethanol (1.5 g/kg; intraperitoneally) for 5 consecutive days, and locomotor activity was recorded daily. The locomotor response to challenge ethanol and saline injections was investigated at various time points following withdrawal from ethanol. Results: Adolescent WT but not nNOS KO mice developed a long‐lasting sensitized response to ethanol as well as context‐dependent hyperlocomotion (in response to saline) from adolescence through adulthood; sex‐dependent differences were not observed. Compared to adolescent WT mice, adult WT males developed a short‐term sensitized response to ethanol and context‐dependent hyperlocomotion; adult WT females showed only short‐term context‐dependent hyperlocomotion. Adult nNOS KO males (like their adolescent counterparts) did not develop behavioral sensitization; no significant differences between adult nNOS KO and WT females were observed. Blood ethanol concentrations did not show genotype‐ or sex‐dependent differences. Conclusions: (1) The nNOS gene is required for the development of behavioral sensitization to ethanol in adolescent male and female mice. (2) Adolescent exposure to ethanol results in long‐lasting behavioral sensitization through adulthood, while adult exposure to ethanol results in a shorter behavioral sensitization. (3) Sex‐dependent differences are observed when ethanol exposure begins in adulthood but not in adolescence. (4) Ethanol‐induced behavioral sensitization in adulthood is nNOS‐dependent in males but not in females. Taken together, results suggest genotype‐, ontogeny‐, and sex‐dependent differences in the development of behavioral sensitization to ethanol.     

Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response

Background /Aims:  Expression of Hamp1 , the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice ( Hfe ^−/− ). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe ^−/− mice.
Methods:  Hfe ^−/− and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1α) was measured by western blot.
Results:  Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe ^−/− mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1α protein levels were elevated in alcohol-fed wild-type animals compared with controls.
Conclusion:  Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.     

Effects of Pregnanolone and Dehydroepiandrosterone on Ethanol Intake in Rats Administered Ethanol or Saline during Adolescence

Background: Adolescent alcohol use may contribute to long‐term changes in the receptors and neuroactive steroids that may mediate its effects and to subsequent alcohol abuse and dependence as an adult. Therefore, in this study, ethanol preference and intake as an adult were examined after adolescent ethanol or saline administration. In addition, ethanol intake in the same groups was examined after administration of 2 neuroactive steroids with modulatory effects at GABA_A receptors. Methods: Two groups of male Long‐Evans rats were administered 15 intraperitoneal (i.p.) injections of either ethanol (2 g/kg, 20% v/v) or saline between postnatal days 35 and 63. Starting on postnatal day 75, both groups were trained to consume 10% ethanol using a saccharin‐fading procedure, and ethanol intake and preference were measured after a series of manipulations involving food deprivation, changes in the duration of access to ethanol, and changes in the concentrations of ethanol presented. Following these manipulations, pregnanolone (1 to 10 mg/kg) and dehydroepiandrosterone (DHEA, 1 to 100 mg/kg) were administered prior to preference sessions with an 18% ethanol solution. Results: Adult ethanol preference and intake did not differ significantly in subjects treated with either saline or ethanol as adolescents during training, the substitution of other ethanol concentrations (3.2 to 32%), ad‐lib feeding, or moderate food deprivation. Pregnanolone administration altered the intake of both adolescent‐treated groups after the first injection of 3.2 mg/kg and after repeated injections with 10 mg/kg, a dose that produced sedation. In contrast, multiple doses of DHEA consistently decreased intake of an 18% ethanol concentration in both groups after repeated injections and 3 doses of DHEA (10, 32, and 56 mg/kg) administered with various ethanol concentrations dose‐dependently shifted the ethanol‐concentration curves for the volume and dosage of ethanol consumed downward. Conclusions: These results indicate that chronic intermittent ethanol (CIE) administration of 2 g/kg during adolescence did not alter preference or overall consumption of ethanol in outbred rats trained to drink ethanol as an adult under the conditions tested, and that DHEA may be more effective than pregnanolone at significantly decreasing ethanol consumption.     

A Study Examining Intravenous Ethanol-Conditioned Place Preference in C57BL/6J Mice

The reinforcing effects of intravenous (IV) ethanol were examined in C57BL/6J (C57) mice with a conditioned-place-preference (CPP) paradigm. Before CPP testing, adult mice underwent jugular catheterization. On the following day, subjects were acclimated to a two-compartment CPP chamber. A 15-min nondrug pretest was conducted to determine compartment preference. For the treatment group, IV ethanol [30% (v/v), 3.4 μl/min, 25 min] was paired with the nonpreferred compartment, whereas IV saline was paired with the preferred compartment. The control group received IV saline in both compartments. Two conditioning sessions were conducted per day (0900 and 1500), and the order of the infusions was counterbalanced across subjects. The drug-free posttest was identical to the pretest, except that it occurred on the day after the final drug/compartment pairing. The entire procedure required 6 days. After just two pairings with ethanol, with a cumulative ethanol dose of only 0.82 g/kg/day, significant CPP was noted in the treatment group, whereas no change in compartment preference was noted for the control group. A separate group of C57 mice were trained to discriminate intraperitoneal ethanol (1.5 g/kg) from saline using a two-lever drug discrimination paradigm. After training was complete, these mice also underwent jugular catheterization. Substitution testing was conducted with IV ethanol [30% (v/v), 6.4 μl/min, 12 min] and saline. The results indicate that the subjective effects of ethanol did not differ according to the route of administration. Together, these experiments provide evidence that ethanol is rewarding for C57 mice, as indexed by ethanol CPP, and that the subjective effects of intravenously and intraperitoneally administered ethanol are similar.     

Prefrontal cortex volumes in adolescents with alcohol use disorders: unique gender effects

Background:  Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders.
Methods:  Participants were adolescents aged 15 to 17 who met criteria for AUD ( n  = 14), and demographically similar healthy controls ( n  = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups.
Results:  After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes ( p  = 0.09) than controls, and significant interactions between group and gender were observed ( p  < 0.001 to p  < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes.
Conclusions:  Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.     

Alcohol consumption before sleep is associated with severity of sleep-disordered breathing among professional Japanese truck drivers

Background:  Alcohol consumption as well as overweight is known to aggravate the severity of sleep-disordered breathing (SDB), but little is known about alcohol consumption in truck drivers. The aim of this study was to examine the relationship between alcohol consumption and SDB among truck drivers.
Methods:  We conducted a cross-sectional study of 1,465 men aged 20–69 years who were registered with the Japanese Trucking Association. The 3% oxygen desaturation index (3%ODI) was selected as an indicator of SDB, representing the number of desaturation events per hour of recording time in which blood oxygen fell by ≥3% based on overnight pulse-oximetry. Participants completed a self-administered questionnaire including alcohol consumption on the same night for SDB assessment.
Results:  The prevalence of 3%ODI ≥5, ≥10, and ≥15/h was 25.4%, 11.1%, and 6.6% respectively. The multivariable odds ratios (OR) of 3%ODI ≥ 10/h were 1.5(0.9–2.5) for 0.5 to <1.0 g of alcohol intake/kg and 3.4(1.8–6.6) for ≥1.0 g of alcohol intake/kg compared with non-drinkers. Similar associations with alcohol consumption were observed for 3%ODI ≥5 and ≥15/h. The relation between alcohol consumption (≥1.0 g of alcohol intake/kg) and 3%ODI ≥ 10/h tended to be more evident among men with body mass index (BMI) <23.4 kg/m² than those with BMI ≥ 23.4 kg/m² [11.4 (3.2–41) vs. 1.2 (0.6–2.7), p  = 0.18 for interaction]. A similar trend was observed for 3%ODI ≥ 5/h.
Conclusions:  The prevalence of undiagnosed SDB and the significant association of alcohol consumption with SDB severity emphasize the need for SDB screening and alcohol modification as well as weight control to prevent and control SDB among truck drivers.