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Background: Dopamine concentrations in the nucleus accumbens fluctuate on phasic (subsecond) and tonic (over minutes) timescales in awake rats. Acute ethanol increases tonic concentrations of dopamine, but its effect on subsecond dopamine transients has not been fully explored.Methods: We measured tonic and phasic dopamine fluctuations in the nucleus accumbens of rats in response to ethanol (within‐subject cumulative dosing, 0.125 to 2 g/kg, i.v.).Results: Microdialysis samples yielded significant tonic increases in dopamine concentrations at 1 to 2 g/kg ethanol in each rat, while repeated saline infusions had no effect. When monitored with fast scan cyclic voltammetry, ethanol increased the frequency of dopamine transients in 6 of 16 recording sites, in contrast to the uniform effect of ethanol as measured with microdialysis. In the remaining 10 recording sites that were unresponsive to ethanol, dopamine transients either decreased in frequency or were unaffected by cumulative ethanol infusions, patterns also observed during repeated saline infusions. The responsiveness of particular recording sites to ethanol was not correlated with either core versus shell placement of the electrodes or the basal rate of dopamine transients. Importantly, the phasic response pattern to a single dose of ethanol at a particular site was qualitatively reproduced when a second dose of ethanol was administered, suggesting that the variable between‐site effects reflected specific pharmacology at that recording site.Conclusions: These data demonstrate that the relatively uniform dopamine concentrations obtained with microdialysis can mask a dramatic heterogeneity of phasic dopamine release within the accumbens.

Background:The ventral tegmental area (VTA) is involved in regulating ethanol drinking, and the posterior VTA seems to be a neuroanatomical substrate that mediates the reinforcing effects of ethanol in ethanol‐naïve Wistar and ethanol‐naïve alcohol‐preferring (P) rats. The objective of this study was to test the hypothesis that chronic ethanol drinking increases the sensitivity of the posterior VTA to the reinforcing effects of ethanol.Methods:Two groups of female P rats (one given water as its sole source of fluid and the other given 24‐hr free‐choice access to 15% ethanol and water for at least 8 weeks) were stereotaxically implanted with guide cannulae aimed at the posterior VTA. One week after surgery, rats were placed in standard two‐lever (active and inactive) operant chambers and connected to the microinfusion system. Depression of the active lever produced the infusion of 100 nl of artificial cerebrospinal fluid (CSF) or ethanol. The ethanol‐naïve and chronic ethanol‐drinking groups were assigned to subgroups to receive artificial CSF or 25, 50, 75, or 125 mg/dl of ethanol (n= 6–9/dose/group) to self‐infuse (FR1 schedule) during the 4‐hr sessions given every other day.Results:Compared with the infusions of artificial CSF, the control group reliably (p < 0.05) self‐infused 75 and 125 mg/dl of ethanol but not the lower concentrations. The ethanol‐drinking group had significantly (p < 0.05) higher self‐infusions of 50, 75, and 125 mg/dl of ethanol than artificial CSF during the four acquisition sessions; the number of infusions of all three doses was higher in the ethanol‐drinking group than in the ethanol‐naive group. Both groups decreased responding on the active lever when artificial CSF was substituted for ethanol, and both groups demonstrated robust reinstatement of responding on the active lever when ethanol was restored.Conclusions:Chronic ethanol drinking by P rats increased the sensitivity of the posterior VTA to the reinforcing effects of ethanol.

MRI examination revealed similar brain lesions in 5 alcoholic Korsakoff patients and 5 chronic alcoholics without cognitive impairment. Not only cerebral atrophy and demyelination, but also lesions thought to be specific for the Wernicke-Korsakoff syndrome were equally prominent in both groups. The morphological abnormalities thought to be typical of Wernicke-Korsakoff syndrome are probably common features of chronic alcoholism and malnutrition. Marked atrophy of the operculae was found in all Korsakoff patients and in 3 out of 5 chronic alcoholics. Alcohol amnestic disorder may not exclusively result from diencephalic lesions, but also from temporal lesions.

Background and Purpose— Ischemic stroke induces metabolic disarray. A central regulatory site, pyruvate dehydrogeanse complex (PDHC) sits at the cross-roads of 2 fundamental metabolic pathways: aerobic and anaerobic. In this study, we combined ethanol (EtOH) and normobaric oxygen (NBO) to develop a novel treatment to modulate PDHC and its regulatory proteins, namely pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase, leading to improved metabolism and reduced oxidative damage. Methods— Sprague–Dawley rats were subjected to transient (2, 3, or 4 hours) middle cerebral artery occlusion followed by 3- or 24-hour reperfusion, or permanent (28 hours) middle cerebral artery occlusion without reperfusion. At 2 hours after the onset of ischemia, rats received either an intraperitoneal injection of saline, 1 dose of EtOH (1.5 g/kg) for 2- and 3-hour middle cerebral artery occlusion, 2 doses of EtOH (1.5 g/kg followed by 1.0 g/kg in 2 hours) in 4 hours or permanent middle cerebral artery occlusion, and EtOH+95% NBO (at 2 hours after the onset of ischemia for 6 hours) in permanent stroke. Infarct volumes and neurological deficits were examined. Oxidative metabolism and stress were determined by measuring ADP/ATP ratio and reactive oxygen species levels. Protein levels of PDHC, pyruvate dehydrogenase kinase, and pyruvate dehydrogenase phosphatase were assessed. Results— EtOH induced dose-dependent neuroprotection in transient ischemia. Compared to EtOH or NBO alone, NBO+EtOH produced the best outcomes in permanent ischemia. These therapies improved brain oxidative metabolism by decreasing ADP/ATP ratios and reactive oxygen species levels, in association with significantly raised levels of PDHC and pyruvate dehydrogenase phosphatase, as well as decreased pyruvate dehydrogenase kinase. Conclusions— Both EtOH and EtOH+NBO treatments conferred neuroprotection in severe stroke by affecting brain metabolism. The treatment may modulate the damaging cascade of metabolic events by bringing the PDHC activity back to normal metabolic levels.

Impairment of motor coordination, or ataxia, is a prominent effect of alcohol ingestion in humans. To date, many models have been created to examine this phenomenon in animals. Evidence suggests that the tasks thought to measure this behavior in mice actually measure different components of this complex trait. We have characterized the parallel rod floor apparatus to quantify ethanol‐induced motor incoordination. Using genetically heterogeneous mice, we evaluated the influence of rod diameter and inter‐rod distance on dose‐related ethanol‐induced motor incoordination to select parameters that optimized testing procedures. We then used the DBA/2J and C57BL/6J inbred strains of mice to examine the effect of 2 g/kg of ethanol, by serially testing mice on two floor types, separated by 1 week. Finally, we tested eight inbred strains of mice on four floor types to examine patterns of strain sensitivity to 2 g/kg of intraperitoneal ethanol and determined the test parameters that maximized strain effect size. Motor incoordination varied depending on the floor type and strain. When data from strain 129S1/SvlmJ were removed from the analyses because of their extreme behavior, the greatest strain effect size was observed on one floor type during the first 10 min of testing after 2 g/kg of intraperitoneal ethanol. These findings suggest that the parallel rod floor apparatus provides a useful means for examining ethanol‐induced motor incoordination in mice but that specific testing procedures are important for optimizing detection of motor incoordination and genetic influences.

Even after they cease drinking, many alcoholics show continued impairment of cognitive functioning on both intelligence and neuropsychological tests, with deficits being apparent in visual perception, learning and memory, and the use of problem-solving strategies. Neuropsychological investigations have suggested that these deficits reflect premature aging, a direct dose response relationship, or localized brain damage. However, studies have shown that a considerable recovery of cognitive functioning occurs, most dramatically after drinking cessation and more slowly thereafter. Tasks that require novel, complex, and rapid information processing require longer to recover, and persistent impairments in visual-spatial abilities, abstraction and problem solving, and short-term memory are common, particularly in older alcoholics. Practical applications of this research are discussed in terms of the possibility of reducing cognitive dysfunction and improving treatment outcome in alcoholics.

AbstractDiscrimination and reversal of the classically conditioned eyeblink response depends on cerebellar–brainstem interactions with the hippocampus. Neonatal “binge” exposure to alcohol at doses of 5 g/kg/day or more has been shown to impair single‐cue eyeblink conditioning in both weanling and adult rats. The present study exposed neonatal rats to acute alcohol intubations across different developmental periods (postnatal day [PND] 4‐9 or PND7‐9) and tested them from PND26‐31 on discriminative classical eyeblink conditioning and reversal. A high dose of alcohol (5 g/kg/day) dramatically impaired conditioning relative to controls when exposure occurred over PND4‐9, but produced mild or no impairments when delivered over PND7‐9. These findings support previous claims that developmental exposure period plays a critical role in determining the deleterious effects of alcohol on the developing brain. A lower dose of alcohol (4 g/kg/day) delivered from PND4‐9—lower than has previously been shown to affect single‐cue eyeblink conditioning—also produced deficits on the discrimination task, suggesting that discrimination learning and acquisition of responding to CS+ during reversal may be especially sensitive behavioral indicators of alcohol‐induced brain damage in this rat model. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 243–257, 2007.

Dominance hierarchies are an important aspect of group-living as they determine individual access to resources. The existence of dominance ranks in access to space has not been described in socially monogamous, communally nesting prairie voles (Microtus ochrogaster). Here, we tested whether dominance could be assessed using the tube test. We also tested whether dominance related to alcohol intake, similar to what has been demonstrated in nonmonogamous species. Same-sex pairs of unfamiliar peers were tested in a series of three trials of the tube test, then paired and allowed individual access to alcohol and water for 4 days, and then tested again in the tube test. For all pairs, the same subjects won the majority of trials before and after alcohol drinking. The number of wins negatively correlated with alcohol intake on the first day of drinking and positively correlated with levels of Fos in the paraventricular nucleus of the hypothalamus following the tube test in a separate group of voles. Dominance was not related to Fos levels in other brain regions examined. Together, these results indicate that prairie voles quickly establish stable dominance ranks through a process possibly involving the hypothalamus and suggest that dominance is linked to alcohol drinking.