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Previous work, using membrane receptor binding techniques, demonstrated an increase in hippocampal MK-801 binding sites in mice after chronic ethanol ingestion. The current studies, using quantitative autoradiography, demonstrate that chronic ethanol ingestion also produces increases in MK-801 binding in cerebral cortex, striatum and thalamus, as well as in hippocampus. The persistence of changes in MK-801 binding paralleled the time-course for ethanol withdrawal seizure susceptibility. These results support the hypothesis that an increase in the number of NMDA receptor/channel complexes in hippocampus, and possibly other brain regions, plays a role in the generation or expression of ethanol withdrawal seizures.

Since serotonin (5-HT) reportedly is involved in aberrant drinking of ethyl alcohol, the present study examined a possible role of the concentration of 5-HT in systems originating in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN) or both nuclei. The preference for alcohol offered in concentrations increased over 10 days from 3% to 30% was determined for each Sprague-Dawley rat. After the rats were anesthetized with sodium pentobarbital, either 10 microg 5,7-DHT or artificial cerebrospinal fluid (CSF) was micro-injected stereotaxically into the DRN, MRN or both nuclei. After 10 days, a second alcohol preference test was offered to the animals. Then the rats were decapitated, each brain removed, and the block of tissue containing injection sites was saved for histological analysis. The remaining portion was dissected into separate regions for analysis by HPLC of 5-HT, 5-hydroxyindoleacetic-acid (5-HIAA), norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The 5,7-DHT lesion of the DRN depleted the levels of 5-HT and 5-HIAA by 50-55% in the midbrain and pons and by 70-80% in the frontal cortex, whereas, the 5,7-DHT lesion of MRN reduced 5-HT in all regions except the corpus striatum. The depletion of 5-HT was lower in MRN-lesioned than in DRN-lesioned rats in the frontal cortex and nucleus accumbens. The combined lesion of both DRN and MRN produced a massive decline of >90% of 5-HT and 5-HIAA in all structures except the pons where 5-HT was reduced by 70%. Whereas the level of NE was reduced mainly in the frontal cortex, the levels of DA and its metabolites were essentially unaffected by the 5,7-DHT lesions. Although single or combined lesions of the DRN and MRN failed to alter the intake of alcohol of the rats, the combined serotonergic lesions increased significantly the ingestion of water but not food. Correlational analyses in the sham groups showed a negative association between the intake of alcohol and cortical dopamine and possible hippocampal 5-HT and NE as well as between the ingestion of food and of 5-HT in the frontal cortex. Taken together, these observations in the Sprague-Dawley rat suggest that lower levels of these monoamines in certain regions of the brain may play a role in the maintenance of the basal intake of alcohol but not in the drinking after the injection of 5,7-DHT. Explanations of our findings include: (1) a compensatory neurochemical change in pre- or postsynaptic 5-HT receptors subsequent to the dysfunction of serotonergic neurons in the forebrain; (2) a unique characteristic of the Sprague-Dawley strain of rat; and (3) residual quanta of 5-HT which sustains the pattern of alcohol drinking.

Groups of rats were maintained on a daily regimen of 22 h of water deprivation followed by a 2-h opportunity to take either water or a sweetened ethanol solution (ES). In one experiment, it was shown that previous morphine (M) dependence had no effect on initial daily intakes of fluids. After stable ES intakes were achieved, a variety of pharmacological manipulations were assessed for their effects on intake of the ES. Nalmefene, an opioid antagonist, dose-relatedly decreased intakes of ES, and was effective across days of injections. Fluoxetine (FX), a serotonergic reuptake inhibitor, also reduced ES intakes dose relatedly, and across days of injections, but the reduction was not as great as that seen with opioid antagonists. A small dose of M increased ES intakes when given in combination with an ineffective dose of FX, just as it does by itself. However, M had no effect on ES intakes in combination with an effective dose of FX. Pimozide (PIM), a dopaminergic antagonist, dose-relatedly decreased intakes of ES and water, and responding for positively reinforcing intracranial stimulation (ICS). When given in combination, M blunted PIM's reduction of ES intake, but had no effect on PIM's ability to decrease either intake of water or responding for ICS. Amphetamine did not reliably affect rats' intakes of ES across a range of doses. The data, in addition to previous work, lead to the idea that endogenous opioid systems are more salient, with respect to intake of alcoholic beverages, than the other tested neurotransmitter systems. Furthermore, the collective data suggest that a long-lasting opioid antagonist may be an effective pharmacological adjunct to other treatments for alcohol abuse and alcoholism.

The population of most countries is increasing and the United Nations predicts that by the year 2050 those over the age of 60 years old will increase from 900 million individuals to approximately 2.1 billion individuals (United Nations, 2015). The increase in the number of older individuals will place a strain on many national health care systems making it important to investigate behaviors in the aged that may negatively impact general health in this demographic. Recent work has shown that older adults consume alcohol, often at levels that exceed the legal limit of intoxication. Unfortunately, consumption of high levels of ethanol in the older population is associated with many health consequences and may negatively impact the brain. Given ethical constraints found in many biomedical studies, animal models are needed to investigate the possible negative impact of high ethanol use in aged populations. However, few studies have investigated the effect of ethanol exposure in aged animals compared to ethanol exposure in younger animals and consequently the impact of ethanol in the aged population is not well understood. The current review summarizes initial work establishing the impact of ethanol in aged animals. The reviewed research studies support the working hypothesis that ethanol exposure produces significantly greater effects in aged animals compared to younger animals on many, if not all, behavioral tasks. In addition, the review proposes several initial, promising avenues of research to explore the neurobiological mechanisms that underly greater effects on ethanol-induced ataxia, cognition and sleep time. It is hoped that this effort will not only lead to a better understanding of behaviors impacted by ethanol in aged animals, but also improve the understanding brain mechanisms of the reported increased sensitivity to ethanol in the aged population.

Rats that were selectively bred for differences in alcohol‐induced sleep time (alcohol neurosensitivity) were tested for differences in formation and extinction of alcohol‐ and LiCl‐induced conditioned taste aversions. Male rats bred for high, control, or low alcohol sensitivity (HAS, CAS, and LAS rats, respectively) were deprived of water and given daily 30 min access to water for a baseline period of 7 days. Rats were then given a novel 0.125% sodium saccharin solution, followed by an intraperitoneal injection of either saline, 2 g/kg of ethanol (at 10% w/v), or 50.9 mg/kg of LiCl(0.15 M) on 3 conditioning days. Each saccharin exposure was followed by a recovery day of BCCBSS to water. The ethanol‐induced saccharin aversion extinguished more rapidly in LAS rats than in CAS or HAS rats (p < 0.05), but LiCl conditioned equivalent aversions in each group. Also, ethanol injection results in large differences in observed resting behavior in these rats (HAS > CAS > LAS), but LiCl injection produced no reliable group differences in resting. The weaker alcohol‐Induced M e aversion in LAS rats accords with their previously measured higher oral consumption of alcohol (Kulkosky et al., Alcoholism 17: M‐651, 1993) and the idea that alcohol intake is limited by an expectancy of postingestive consequences. The weaker ethanol induced aversion in LAS rats reflects selective breeding of an alcohol‐specific trait and not a general difference In aversive conditioning or chemical neurosensitivity.

In humans and in animal models the most frequently observed alcohol‐related birth defect (ARBD) is intrauterine growth retardation (IUGR). The central nervous system (CNS) is sensitive to the growth inhibitory effects of in utero ethanol exposure and neonatal CNS alterations with associated behavioral deficits are a likely result of maternal ethanol consumption. Presently, little information exists as to the biochemical mechanism by which ethanol inhibits fetal CNS growth. Further, it is unknown if there are genetic differences in maternal or fetal responses to ethanol. Ongoing research using a chick model indicates that pharmacologically appropriate doses of ethanol (< 30 mm) inhibit brain growth and reduce CNS 3′,5′‐cyclic adenosine monophosphate (cyclic AMP) with an associated 50% decrease in the binding of cyclic AMP by the regulatory subunit (RII) of protein kinase A. Furthermore, there is a specific loss of phosphorylation of RII by kinase catalytic subunit as a result of ethanol exposure. Because tissue cyclic AMP content and the degree of RII phosphorylation are important parameters for the regulation of protein kinase A catalytic activity, it is hypothesized that these alterations may be biochemical transformations that underlie ethanol‐induced growth suppression.

Chronic alcohol abuse is a ubiquitous health and societal problem, with a growing prevalence in the older population. Alcoholism is a source of substantial deterioration in brain tissue and has been consistently observed in vivo and postmortem in white matter. To quantify the potential compounded effect of age and alcoholism, we used conventional structural MRI and diffusion tensor imaging (DTI) to examine the macrostructural and microstructural integrity of the corpus callosum, one of the most prominent white matter structures of the brain, in 131 adults, age 27-75 years. Compared with the 74 controls, the 40 alcoholic men and 17 alcoholic women, who were abstinent from alcohol for an average of 3 months, showed similar patterns and extents of callosal shrinkage, which was greatest in the genu and body and less prominent in the splenium. Microstructural integrity was measured with DTI as fractional anisotropy, an index of intravoxel orientational coherence of white matter fibers, and bulk mean diffusivity, an index of the amount of intravoxel water motility. The macrostructural shrinkage was accompanied by abnormalities in anisotropy and diffusivity of the microstructural environment of these callosal regions, indicative of disruption of structural constituents of local brain white matter. Correlational analyses revealed an age-alcohol interaction, where older alcoholics had smaller genu and splenium and higher diffusivity in these regions than younger alcoholics. Significant correlations between regional MRI and DTI measures and performance on working memory, visuospatial ability, and gait and balance provided evidence for the functional ramifications of the callosal abnormalities in the alcoholics. Thus, despite abstinence from alcohol, the interaction of age and recent alcoholism history exerted a compounded untoward effect on callosal macrostructure and microstructure.

Young and aged rats were treated chronically with ethanol or scopolamine. Muscarinic receptors were measured in cerebral cortex, hippocampus and striatum. Following scopolamine treatment muscarinic receptor density in cerebral cortex, hippocampus and striatum of young rats increased by 34, 57 and 27%, respectively; in brains of aged rats the increase was 41% in cerebral cortex, 43% in hippocampus and nil in striatum. Affinity of muscarinic receptors was not changed by scopolamine treatment. Following chronic ethanol administration there was a 48% increase in cortical muscarinic receptor density in young, but not aged rats. The density of muscarinic receptors in hippocampus and striatum of both young and aged rats was not affected by ethanol treatment. Affinity of receptors in hippocampus of aged, ethanol-treated rats was increased compared to age-matched controls. Adaptative responses of the muscarinic receptor/transducer system to neurotransmitter availability are present in both young and aged rats, both the ethanol-induced response is present only in young animals. This suggests differences in the mechanism of action of ethanol and receptor agonists and antagonists in modulating receptor plasticity.

The purpose of the current study was to ascertain whether ethyl nitrite could be detected in vitro from the reaction of ethanol with peroxynitrite, as well as after administration of ethanol to mice. Ethyl nitrite analyte was determined by using gas chromatography--mass spectrometry with headspace analysis with the use of a solid-phase microextraction device. Peroxynitrite was allowed to react with ethanol under a variety of conditions in vitro. Ethyl nitrite was generated when peroxynitrite was allowed to react with ethanol. Male, inbred short-sleep mice were injected intraperitoneally with either ethanol [5.2 g/kg; 15.0% (weight/volume) ethanol in saline] or a 50:50 mixture of deuterium-labeled ethanol (D5-ethanol) and ethanol. Blood samples, as well as whole brain and liver sections, were obtained from mice 30 min later for determination of ethanol, D5-ethanol, ethyl nitrite, and deuterium-labeled ethyl nitrite (D5-ethyl nitrite). Time courses for the appearance of ethyl nitrite in blood samples, as well as in whole brain and liver sections, obtained from mice were carried out. After ethanol administration, ethyl nitrite was detected and quantitated in mouse blood, brain, and liver. A small fraction of ethyl nitrite was present. When a 50:50 mixture of ethanol and D5-ethanol was given to animals, both ethyl nitrite and D5-ethyl nitrite were found in blood and brain in approximately the same ratio as that of ethanol and D5-ethanol. The level of D5-ethyl nitrite in liver was more than twice that of ethyl nitrite, indicating a possible isotope effect in the metabolism of ethyl nitrite. Ethyl nitrite is a new metabolite of ethanol in vivo. The mechanism of ethyl nitrite formation is most likely the reaction of ethanol with peroxynitrite generated in vivo from nitric oxide.