Brain Alcohol Levels Research Articles

Chronic alcohol-induced liver injury correlates with memory deficits: Role for neuroinflammation.

Alcohol use disorder (AUD) affects over 15 million adults over age 18 in the United States, with estimated costs of 220 billion dollars annually - mainly due to poor quality of life and lost productivity, which in turn is intricately linked to cognitive dysfunction. AUD-induced neuroinflammation in the brain, notably the hippocampus, is likely to contribute to cognitive impairments. The neuroinflammatory mechanisms mediating the impact of chronic alcohol on the central nervous system, specifically cognition, require further study. We hypothesized that chronic alcohol consumption impairs memory and increases the inflammatory cytokines TNFα, IL6, MCP1, and IL1β in the hippocampus and prefrontal cortex regions in the brain. Using the chronic-binge Gao-NIAAA alcohol mouse model of liver disease, representative of the drinking pattern common to human alcoholics, we investigated behavioral and neuroinflammatory parameters. Our data show that chronic alcohol intake elevated peripheral and brain alcohol levels, induced serum alanine aminotransferase (ALT, a marker of liver injury), impaired memory and sensorimotor coordination, and increased inflammatory gene expression in the hippocampus and prefrontal cortex. Interestingly, serum ALT and hippocampal IL6 correlated with memory impairment, suggesting an intrinsic relationship between neuroinflammation, cognitive decline, and liver disease. Overall, our results point to a likely liver-brain functional partnership and suggest that future strategies to alleviate hepatic and/or neuroinflammatory impacts of chronic AUD may result in improved cognitive outcomes.

Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone

Binge alcohol drinking has emerged as a typical phenomenon in young people. This pattern of drinking, repeatedly leading to extremely high blood and brain alcohol levels and intoxication is associated with severe risks of neurodegeneration and cognitive damage. Mechanisms involved in excitotoxicity and neuroinflammation are pivotal elements in alcohol-induced neurotoxicity. Evidence has demonstrated that PPARγ receptor activation shows anti-inflammatory and neuroprotective properties. Here we examine whether treatment with the PPARγ agonist pioglitazone is beneficial in counteracting neurodegeneration, neuroinflammation and cognitive damage produced by binge alcohol intoxication. Adult Wistar rats were subjected to a 4-day binge intoxication procedure, which is commonly used to model excessive alcohol consumption in humans. Across the 4-day period, pioglitazone (0, 30, 60mg/kg) was administered orally twice daily at 12-h intervals. Degenerative cells were detected by fluoro-jade B (FJ-B) immunostaining in brain regions where expression of pro-inflammatory cytokines was also determined. The effects of pioglitazone on cognitive function were assessed in an operant reversal learning task and the Morris water maze task. Binge alcohol exposure produced selective neuronal degeneration in the hippocampal dentate gyrus and the adjacent entorhinal cortex. Pioglitazone reduced FJ-B positive cells in both regions and prevented alcohol-induced expression of pro-inflammatory cytokines. Pioglitazone also rescued alcohol-impaired reversal learning in the operant task and spatial learning deficits in the Morris water maze. These findings demonstrate that activation of PPARγ protects against neuronal and cognitive degeneration elicited by binge alcohol exposure. The protective effect of PPARγ agonist appears to be linked to inhibition of pro-inflammatory cytokines.

Binge alcohol-induced alterations in BDNF and GDNF expression in central extended amygdala and pyriform cortex on infant rats

Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome termed fetal alcohol spectrum disorder (FASD) in the offspring, which includes cognitive deficits and emotional/social disturbances. These alterations are thought to be caused, at least in part, by alcohol-induced imbalance in neurotrophic factor levels, which are critically involved in normal neurodevelopment. Our goal was to study whether brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) expression were affected by alcohol in central extended amygdala (CEXA) and pyriform cortex (Pyr), structures strongly involved in emotional/social behaviors. Further, we evaluated how these changes could be related to blood and brain alcohol concentrations. Postnatal day (PND) pups at 7, 15 and 20-days old were administered alcohol (2.5g/kg s.c. at 0 and 2h) or saline. Immunohistochemistry was used to detect the expression of BDNF and GDNF at 2, 12 and 24h after drug administration. Also, gas chromatography was bused to measure blood alcohol levels (BALs) and brain alcohol levels (BrALs) at each hour, from 2 to 8h after the second alcohol administration. Results showed: (1) alcohol-induced enhancement of BDNF positive cells on PND 7 and 20, a decrease on PND 15 in the CEXA, and no changes in the Pyr on PND 7 and 20, but a diminished on PND 15; (2) GDNF positive cells rise after alcohol administration for the three ages in the CEXA and Pyr except on PND 15, where there was a decline; and (3) pharmacokinetics analysis demonstrated age-related differences showing equal BALs on PND 7 and 20 but higher BALs on PND 15. In contrast, BrALs were higher on PND 7 than 15 and 20. Hence, BALs may not be predictive of BrALs in postnatal rats. Furthermore, we did not find a relationship between age in pharmacokinetic differences and neurotrophins response. In conclusion, the CEXA and Pyr are brain structures sensitive to alcohol-induced imbalance in neurotrophic factors expression; and BALs are not a mirror of BrALs.

Operant behavior and alcohol levels in blood and brain of alcohol-dependent rats.

The purpose of the present investigation was to more clearly define blood-alcohol parameters associated with alcohol dependence produced by alcohol vapor inhalation and alcohol-containing liquid diet. Alcohol levels in blood and brain were compared during and after 4 hours of acute alcohol vapor exposure; also, brain-alcohol levels were assessed in alcohol-exposed (14-day alcohol vapor) and alcohol-naïve rats during and after 4 hours of acute alcohol vapor exposure. A separate group of rats were implanted with i.v. catheters, made dependent on alcohol via vapor inhalation, and tested for operant alcohol responding; blood-alcohol levels (BALs) were measured throughout operant alcohol drinking sessions during alcohol withdrawal. A final group of rats consumed an alcohol-liquid diet until they were dependent, and those rats were then tested for operant behavior at various withdrawal time points; BALs were measured at different withdrawal time points and after operant sessions. Blood- and brain-alcohol levels responded similarly to vapor, but brain-alcohol levels peaked at a higher point and more slowly returned to zero in alcohol-naïve rats relative to alcohol-exposed rats. Alcohol vapor exposure also produced an upward shift in subsequent operant alcohol responding and resultant BALs. Rats consumed large quantities of alcohol-liquid diet, most of it during the dark cycle, sufficient to produce high blood-alcohol levels and elevated operant alcohol responding when tested during withdrawal from liquid diet. These results emphasize that the key determinants of excessive alcohol drinking behavior are the BAL range and pattern of chronic high-dose alcohol exposure.

Characterizing the ontogeny of ethanol-associated increases in corticosterone

The following experiments were conducted as adjuncts to previous work in an effort to characterize the ontogenetic profile of the elevations in corticosterone after ethanol challenge. In Experiment 1, female and male Sprague–Dawley rats were administered intraperitoneally either a 1.5- or a 4.5-g/kg dose of ethanol on postnatal day (PND) 16, 26, 36, or 56. Blood samples were collected at 40, 80, or 160 min after ethanol injection and analyzed by means of radioimmunoassay for corticosterone levels and correlated with brain alcohol levels (BrALs) determined from brain samples collected at the same time intervals. In Experiment 2, the ethanol dose was varied ontogenetically to equate functional impairment across age, with the use of intraperitoneal doses of ethanol of 3.2, 2.6, or 2.2 g/kg, to induce equivalent amounts of ethanol-induced motor impairment in infant (PND 22), adolescent (PND 28), or adult (PND 60) rats, respectively. Animals were tested on a swim task 15 min after injection, with blood and brain samples collected immediately after the swim and analyzed for corticosterone levels and BrALs as in Experiment 1. Reminiscent of previous reports of an age-related increase in sensitivity to the hypnotic and motor-impairing effects of ethanol, the corticosterone response to an ethanol challenge increased at least through adolescence, with sex differences emerging by PND 26 and becoming more pronounced in adulthood. To the extent that corticosterone release is involved in the reinforcing effects of drugs, ontogenetic differences in the response of the hypothalamic–adrenal–pituitary (HPA) axis to ethanol could contribute to the excessive alcohol consumption often observed during adolescence.

Characterizing the ontogeny of ethanol-associated increases in corticosterone

The following experiments were conducted as adjuncts to previous work in an effort to characterize the ontogenetic profile of the elevations in corticosterone after ethanol challenge. In Experiment 1, female and male Sprague–Dawley rats were administered intraperitoneally either a 1.5- or a 4.5-g/kg dose of ethanol on postnatal day (PND) 16, 26, 36, or 56. Blood samples were collected at 40, 80, or 160 min after ethanol injection and analyzed by means of radioimmunoassay for corticosterone levels and correlated with brain alcohol levels (BrALs) determined from brain samples collected at the same time intervals. In Experiment 2, the ethanol dose was varied ontogenetically to equate functional impairment across age, with the use of intraperitoneal doses of ethanol of 3.2, 2.6, or 2.2 g/kg, to induce equivalent amounts of ethanol-induced motor impairment in infant (PND 22), adolescent (PND 28), or adult (PND 60) rats, respectively. Animals were tested on a swim task 15 min after injection, with blood and brain samples collected immediately after the swim and analyzed for corticosterone levels and BrALs as in Experiment 1. Reminiscent of previous reports of an age-related increase in sensitivity to the hypnotic and motor-impairing effects of ethanol, the corticosterone response to an ethanol challenge increased at least through adolescence, with sex differences emerging by PND 26 and becoming more pronounced in adulthood. To the extent that corticosterone release is involved in the reinforcing effects of drugs, ontogenetic differences in the response of the hypothalamic–adrenal–pituitary (HPA) axis to ethanol could contribute to the excessive alcohol consumption often observed during adolescence.

Ethanol effects on three strains of zebrafish: model system for genetic investigations

The effects of acute and chronic ethanol administration on the wild-type (WT), long-fin striped (LFS), and blue long-fin (BLF) strains of zebrafish were investigated. In the LFS strain, acute exposure to 0.25% (v/v) ethanol inhibited the startle reaction and increased both the area occupied by a group of subjects and the average distance between each fish and its nearest neighbor. Similar effects were found in the WT fish although higher concentrations of ethanol were required. No effects on the behavior of the BLF fish were observed with up to 1.0% (v/v) ethanol. Brain alcohol levels were comparable among the three strains precluding a pharmacokinetic explanation for the behavioral results. In LFS zebrafish, behavioral tolerance was observed after 1 week of continual exposure to ethanol. Conversely, chronic ethanol exposure of the WT fish for up to 2 weeks did not result in the development of tolerance, but rather appeared to increase the disruptive action of the drug. The present results suggest the observed strain differences in the effects of ethanol reflect genotypic differences in both the response of the central nervous system (CNS) to ethanol as well as the ability of the CNS to adapt to ethanol exposure. Although preliminary, the present study indicates that the zebrafish is an excellent model system to investigate the genetic determinants involved in regulating the responses to ethanol.

Acute, Rapid, and Chronic Tolerance During Ontogeny: Observations When Equating Ethanol Perturbation Across Age

Sensitivity to the motor-impairing and hypnotic effects of ethanol (EtOH) increases notably during development. Less is known, however, about the ontogeny of EtOH tolerance and the ontogenetic relationship among different types of tolerance. Consequently, we compared the ontogenetic development of acute, rapid, and chronic tolerance to EtOH-induced motor impairment and hypothermia in a swim task. Preweanling, adolescent, and adult female and male Sprague-Dawley rats were given chronic saline (control group), five daily EtOH exposures before EtOH on test day (chronic group), one EtOH exposure before test day (rapid group), or EtOH exposure only on test day (acute groups). Separate groups of animals in the acute groups were tested at 15, 60, or 105 min after injection to estimate acute tolerance development via calculating slopes of the linear regression of impairment relative to brain alcohol levels at each postinjection interval. Initial EtOH perturbation of swim performance was equated across age by varying EtOH dose. Acute tolerance was evident to the motor-impairing effects of EtOH at all ages. When impairment was indexed relative to brain alcohol levels, rapid and chronic tolerance to the motor-impairing effects of EtOH on latency to reach the start was seen across age, although this tolerance tended to be more pronounced in adults. Somewhat different ontogenetic patterns of tolerance development were observed with EtOH-induced hypothermia, a dependent measure for which EtOH perturbation was not equated across age. The degree of initial perturbation by EtOH seems to be an important predictor of tolerance expression during ontogeny. That is, ontogenetic profiles of tolerance development differ significantly when EtOH-induced motor impairment is equated across age rather than dose of EtOH administered. The role of target response measures and context stress should also be considered when exploring ontogenetic expression of EtOH tolerance.

Acute, Rapid, and Chronic Tolerance During Ontogeny: Observations When Equating Ethanol Perturbation Across Age

Background: Sensitivity to the motor-impairing and hypnotic effects of ethanol (EtOH) increases notably during development. Less is known, however, about the ontogeny of EtOH tolerance and the ontogenetic relationship among different types of tolerance. Consequently, we compared the ontogenetic development of acute, rapid, and chronic tolerance to EtOH-induced motor impairment and hypothermia in a swim task. Methods: Preweanling, adolescent, and adult female and male Sprague-Dawley rats were given chronic saline (control group), five daily EtOH exposures before EtOH on test day (chronic group), one EtOH exposure before test day (rapid group), or EtOH exposure only on test day (acute groups). Separate groups of animals in the acute groups were tested at 15, 60, or 105 min after injection to estimate acute tolerance development via calculating slopes of the linear regression of impairment relative to brain alcohol levels at each postinjection interval. Initial EtOH perturbation of swim performance was equated across age by varying EtOH dose. Results: Acute tolerance was evident to the motor-impairing effects of EtOH at all ages. When impairment was indexed relative to brain alcohol levels, rapid and chronic tolerance to the motor-impairing effects of EtOH on latency to reach the start was seen across age, although this tolerance tended to be more pronounced in adults. Somewhat different ontogenetic patterns of tolerance development were observed with EtOH-induced hypothermia, a dependent measure for which EtOH perturbation was not equated across age. Conclusions: The degree of initial perturbation by EtOH seems to be an important predictor of tolerance expression during ontogeny. That is, ontogenetic profiles of tolerance development differ significantly when EtOH-induced motor impairment is equated across age rather than dose of EtOH administered . The role of target response measures and context stress should also be considered when exploring ontogenetic expression of EtOH tolerance.

Ethanol in Human Brain by Magnetic Resonance Spectroscopy: Correlation With Blood and Breath Levels, Relaxation, and Magnetization Transfer

Background: Proton magnetic resonance spectroscopy (1H MRS) allows measurement of alcohol in the human brain after alcohol consumption. However, the quantity of alcohol that can be detected in the brain by 1H MRS pulse sequences has been controversial, with values ranging from about 24% to 94% of the temporally concordant blood alcohol concentrations. The quantitation of brain alcohol is critically affected by the kinetics of alcohol uptake and elimination, by the relaxation times of the protons that give rise to the brain alcohol signal, and by the specifics of both pulse sequence timing and radio frequency pulse applications. Methods: We investigated these factors in 20 light-drinking subjects after oral administration of approximately 0.85 g/kg body weight of alcohol by localized 1H MRS and measurements of blood and breath alcohol concentrations obtained at the same time. Specifically, we measured transverse and longitudinal relaxation times of brain alcohol and its signal saturation on application of on- or off-resonance radio frequency pulses. All 1H MRS measurements were performed at a time after brain and blood alcohol concentrations had equilibrated. Results: 1H MRS measures of brain alcohol were correlated highly with both breath and blood alcohol concentrations after equilibration in brain tissue. The measured 1H MRS relaxation times of brain alcohol were shorter than given in previous reports that were limited by smaller subject numbers, improper use of 1H MRS methods, and estimates rather than measurements. The brain alcohol signal decreased by about 30% on application of on- or off-resonance saturation pulses. Conclusions: 1H MRS allows direct measurement of brain alcohol, formerly only possible indirectly through inferences from breath alcohol levels. Quantitation of brain alcohol levels need to take into account measured relaxation times and alcohol signal attenuation due to presence and timing of standard radio frequency MRS pulses. Saturation experiments give evidence for the existence of more than one compartment of brain alcohol characterized by different molecular environments. They suggest that a fraction of brain alcohol is invisible to 1H MRS.

Ethanol in Human Brain by Magnetic Resonance Spectroscopy: Correlation With Blood and Breath Levels, Relaxation, and Magnetization Transfer

Proton magnetic resonance spectroscopy (1H MRS) allows measurement of alcohol in the human brain after alcohol consumption. However, the quantity of alcohol that can be detected in the brain by 1H MRS pulse sequences has been controversial, with values ranging from about 24% to 94% of the temporally concordant blood alcohol concentrations. The quantitation of brain alcohol is critically affected by the kinetics of alcohol uptake and elimination, by the relaxation times of the protons that give rise to the brain alcohol signal, and by the specifics of both pulse sequence timing and radio frequency pulse applications. We investigated these factors in 20 light-drinking subjects after oral administration of approximately 0.85 g/kg body weight of alcohol by localized 1H MRS and measurements of blood and breath alcohol concentrations obtained at the same time. Specifically, we measured transverse and longitudinal relaxation times of brain alcohol and its signal saturation on application of on- or off-resonance radio frequency pulses. All 1H MRS measurements were performed at a time after brain and blood alcohol concentrations had equilibrated. 1H MRS measures of brain alcohol were correlated highly with both breath and blood alcohol concentrations after equilibration in brain tissue. The measured 1H MRS relaxation times of brain alcohol were shorter than given in previous reports that were limited by smaller subject numbers, improper use of 1H MRS methods, and estimates rather than measurements. The brain alcohol signal decreased by about 30% on application of on- or off-resonance saturation pulses. 1H MRS allows direct measurement of brain alcohol, formerly only possible indirectly through inferences from breath alcohol levels. Quantitation of brain alcohol levels need to take into account measured relaxation times and alcohol signal attenuation due to presence and timing of standard radio frequency MRS pulses. Saturation experiments give evidence for the existence of more than one compartment of brain alcohol characterized by different molecular environments. They suggest that a fraction of brain alcohol is invisible to 1H MRS.

Ontogeny of ethanol elimination and ethanol-induced hypothermia

Ontogeny of ethanol elimination rates and ethanol-induced hypothermia were examined as possible mechanisms contributing to the marked reduction in ethanol sensitivity early in life (Little et al., 1996; Silveri & Spear, 1998) and the notable gender difference in ethanol sleep-time seen in adult animals (Silveri & Spear, 1998). Elimination rates and brain/blood ethanol levels were determined following doses of 1.5 or 4.5 g/kg ethanol in male and female Sprague–Dawley rats at postnatal days (P)16, 26, 36, or 56. Animals were sacrificed at 40, 80, or 160 min post-injection, with ethanol elimination rates estimated from the slope of the regression of blood and brain alcohol levels across the three sampling periods. P16 animals exhibited the slowest rate of ethanol metabolism, while no gender effects were evident at any age. Observed ontogenetic increases in ethanol hypothermia were not systematically related to the ontogeny of ethanol metabolism. Factors other than ontogenetic changes in ethanol metabolism, hypothermia, or the distribution of ethanol between brain and blood must underlie the relative insensitivity to ethanol often reported in young and adolescent organisms, a fruitful area for future studies given the frequent use and misuse of alcohol by human adolescents.

Ontogeny of Rapid Tolerance to the Hypnotic Effects of Ethanol

Alcohol use typically begins during adolescence. Little is known regarding the antecedents and impact of this early alcohol use, although age-related changes in the neural systems modulating alcohol sensitivity could contribute to the propensity of adolescents to consume alcohol. We have previously observed a marked ontogenetic decline in acute tolerance to ethanol (EtOH), with preweanling pups exhibiting the most acute tolerance (Silveri and Spear, 1998). The objective of this study was to assess whether rapid tolerance shows a similar ontogenetic profile. In Experiment I of the present study, female and male Sprague-Dawley preweanling rats at postnatal day (P) 16 or young adults at P56 were examined. On Day 1, preweanlings were pretreated with saline, 1.5, 3.5, or 5.0 g/kg EtOH and adults were pretreated with saline or 3.5 g/kg EtOH. This was followed by challenge with 3.5 g/kg EtOH and assessment of ethanol-induced sleep time on Day 2. In Experiment II, adolescents at P36 were pretreated with saline, 3.5, or 5.0 g/kg EtOH on Day 1 before Day 2 assessment of sleep time after 3.5 g/kg EtOH. Upon awakening, animals were killed and whole brains removed and analyzed for brain alcohol levels (BrALs). Rapid tolerance was observed in P36 and P56 animals, with EtOH-pretreated animals exhibiting significantly shorter sleep times than age-matched animals treated with saline. In contrast, no evidence for rapid tolerance was seen after any pretreatment dose at P16. Interestingly, although EtOH-pretreated adults woke at higher BrALs than saline-treated adults, this pattern was not evident in the adolescents, which suggests that at this age, metabolic tolerance may play a prominent role in the expression of rapid tolerance. Thus, it seems as though the ability to develop rapid tolerance to EtOH hypnosis emerges during adolescence and continues into adulthood. Together with previous findings that adolescent animals also display substantial acute tolerance to alcohol (Silveri and Spear, 1998), the propensity of adolescents for developing these two forms of tolerance may have important implications for the increased voluntary consumption of alcohol at this age relative to other ages.

Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny.

Sensitivity to the hypnotic effects of ethanol was examined in Sprague-Dawley male and female rats at 16, 26, 36, 46, 56, or 96 days postnatally. Following administration of 3.5, 4.0, 4.5, or 5.0 g/kg of a 17% v/v ethanol solution, sleep times were recorded and blood alcohol levels (BALs) and brain alcohol levels (BrALs) were measured upon awakening. In addition to examining ethanol sleep time during ontogeny, data were used to estimate acute tolerance (indexed by the slope of the linear regressions of waking BALs and BrALs as a function of dose) and initial brain sensitivity to ethanol (indexed by calculating the y-intercept from the linear regression of BrALs as a function of sleep time). The results showed a marked increase in sensitivity to ethanol hypnosis during ontogeny, with young animals exhibiting shorter ethanol-induced sleep times and high waking BALs and BrALs. This ontogenetic increase in ethanol sensitivity was associated with a developmental decline in acute tolerance, with acute tolerance being most pronounced at postnatal day (P) 16 and evident only up to P36. Initial sensitivity conversely increased with age, with P16 pups showing lower initial brain sensitivity to ethanol than at all other ages. Gender differences emerged in adulthood, with males sleeping significantly longer than females at P56 and P96. These findings suggest that the marked insensitivity of young animals to the hypnotic effects of ethanol is related to both pronounced acute tolerance, as well as reduced initial brain sensitivity to ethanol early in life.

Decreased Sensitivity to the Hypnotic Effects of Ethanol Early in Ontogeny

Sensitivity to the hypnotic effects of ethanol was examined in Sprague-Dawley male and female rats at 16, 26, 36, 46, 56, or 96 days postnatally. Following administration of 3.5, 4.0, 4.5, or 5.0 g/kg of a 17% v/v ethanol solution, sleep times were recorded and blood alcohol levels (BALs) and brain alcohol levels (BrALs) were measured upon awakening. In addition to examining ethanol sleep time during ontogeny, data were used to estimate acute tolerance (indexed by the slope of the linear regressions of waking BALs and BrALs as a function of dose) and initial brain sensitivity to ethanol (indexed by calculating the y-intercept from the linear regression of BrALs as a function of sleep time). The results showed a marked increase in sensitivity to ethanol hypnosis during ontogeny, with young animals exhibiting shorter ethanol-induced sleep times and high waking BALs and BrALs. This ontogenetic increase in ethanol sensitivity was associated with a developmental decline in acute tolerance, with acute tolerance being most pronounced at postnatal day (P) 16 and evident only up to P36. Initial sensitivity conversely increased with age, with P16 pups showing lower initial brain sensitivity to ethanol than at all other ages. Gender differences emerged in adulthood, with males sleeping significantly longer than females at P56 and P96. These findings suggest that the marked insensitivity of young animals to the hypnotic effects of ethanol is related to both pronounced acute tolerance, as well as reduced initial brain sensitivity to ethanol early in life.

Effect of NMDA receptor antagonists on rapid tolerance to ethanol

Hypothermia and motor impairment (tilt-plane test) were used to assess whether N-methyl-D-aspartate (NMDA) receptors play a role in the development of rapid tolerance to ethanol, i.e, tolerance to a second dose of ethanol given 24 h after the effect of the first dose of ethanol has disappeared. Results showed that (+)-MK-801 and ketamine blocked the development of rapid tolerance to ethanol on both tests. Since these drugs did not modify blood or brain alcohol levels in any of the groups, the blockade of ethanol rapid tolerance cannot be attributed to changes in pharmacokinetics of ethanol. These data suggest that the role of NMDA receptors in ethanol tolerance may be similar to their role in memory and learning, involving a facilitation of transmission in certain synapses.

Alcohol and alcoholism in traffic and other accidental deaths.

To assess the role of alcohol and alcoholism in motor vehicle and other accidental deaths, New Jersey State Medical Examiner cases from Essex County aged 16 or older during a 4-year period, October 1981 to September 1985, were analyzed. Cases were classified as alcoholics according to the following criteria: (1) autopsy findings of liver change or pancreatitis due to alcoholism or (2) any case record report of drinking problems. There were 467 age-eligible cases whose certified manner of death was an accident for which the decedent may have had some responsibility. The study sample of 300 cases with blood or brain alcohol levels (BALs) obtained within 6 h after injury, including 96 motor vehicle drivers, 78 pedestrians in motor vehicle accidents, 38 fire victims, and 33 fall victims. In the study sample, 23% were classified as alcoholics, 47% had positive BALs, and 36% had levels of 0.10% or more. Alcoholics much more often than nonalcoholics had positive BALs and levels of 0.20% or more. Accidental nontraffic deaths were significantly more often associated with both alcohol use and alcoholism than were traffic deaths.

Acute alcohol intoxication disrupts brightness but not olfactory conditioning in preweanling rats.

The present experiments tested the effect of acute alcohol administration on Pavlovian conditioning of 21-day-old rats using conditioned stimuli of two different sensory modalities--olfaction, an early developing sensory capacity functional at birth, and vision, a later developing sensory system not becoming functional until approximately 15 days of age. Conditioning and testing were conducted between 30 and 60 min following gastric infusion with either physiological saline or a mildly intoxicating alcohol dose (1.5 g/kg body weight). Brain alcohol levels were observed to remain at a peak and stable concentration during this period (Experiment 1). Alcohol impaired acquisition or expression of conditioned aversions to a visual cue paired with footshock when presented either as a single-element conditioned stimulus or as part of an odor/visual compound stimulus (Experiment 2), but it had no discernible effect on conditioned aversions to an olfactory stimulus that had similarly been paired with footshock (Experiments 2 and 3). The results suggest that alcohol may impair some aspects of learning but spare others, depending perhaps on the particular sensory modality to be conditioned.

Adrenalectomy reduces alcohol-stimulated activity: Blood and brain alcohol content

It has been shown that adrenal glucocorticoids have a permissive role in some of the actions of alcohol. To determine if an intact adrenal was necessary for the stimulation of locomotor activity, 24 female C3H mice were tested for open field activity with ethanol or saline. Two weeks after adrenalectomy or sham surger, animals were tested for activity again with ethanol or saline. One week later, alcohol disappearance curves were generated for blood and brain. Adrenalectomy reduced estimated peak alcohol levels in alcohol-stimulated locomotor activtiy. In addition, adrenalectomy significantly reduced estimated peak alcohol levels in blood and brain but significantly reduced the disappearance rate for alcohol only in brain. These data suggest that adrenalectomy significantly changes alcohol distribution, with greater impact on brain alcohol levels than on blood levels, and that this may be responsible, at least in part, for the reduction in stimulated locomotor activity.