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Alcoholism, like other substance abuse disorders, is a chronically relapsing condition. Compared with other abused drugs, however, little is known about the neural mechanisms mediating ethanol (EtOH)-craving and -seeking behavior leading to relapse. This study, therefore, was conducted to identify candidate brain regions that are recruited by an EtOH-associated contextual stimulus (S(+)). A secondary objective was to determine whether EtOH S(+)-elicited neural recruitment patterns are modified by the opiate antagonist naltrexone (NTX), a compound that reduces cue-induced craving in alcoholics and attenuates ethanol seeking in animal models of relapse.Rats were tested in a conditioned reinstatement model of relapse with subsequent examination of brain c-fos expression patterns elicited by an EtOH S(+) versus a cue associated with nonreward (S(-)). In addition, modification of these expression patterns by NTX was examined.The EtOH S(+) reinstated extinguished responding and increased c-fos expression within the prefrontal cortex, hippocampus, nucleus accumbens, and hypothalamic paraventricular nucleus (PVN). Naltrexone suppressed the S(+)-induced reinstatement and attenuated hippocampal CA3 c-fos expression, while increasing neural activity in the extended amygdala and PVN.Ethanol-associated contextual stimuli recruit key brain regions that regulate associative learning, goal-directed behavior, and Pavlovian conditioning of emotional significance to previously neutral stimuli. In addition, the data implicate the hippocampus, amygdala, and PVN as potential substrates for the inhibitory effects of NTX on conditioned reinstatement.

Summary: The potential role of genetic factors in the etiology of posttraumatic and alcohol‐associated seizures was studied in 289 male patients with recurrent seizures and in 174 individuals who had never experienced a seizure. The incidence of seizures in first‐degree relatives of probands was compared with that in relatives of unaffected individuals. Relatives of patients with alcoholassociated seizures had a rate ratio of 2.45 [95% confidence interval (CI) 1.41–4.251, whereas no excess incidence was noted among relatives of posttraumatic epilepsy patients (rate ratio 1.20, 0.64–2.25 CI). Relatives of probands with both antecedents showed an intermediate rate ratio of 1.72 (0.92–3.20 CI). Among probands with alcohol‐associated seizures, the rate ratio of 2.05 for patients with alcohol‐related seizures (i.e., spontaneously occurring seizures in association with chronic alcohol abuse) was slightly higher than that of 1.85 for probands with alcohol withdrawal seizures. Trauma severity had a slight impact on the incidence of affected relatives; patients with severe head injuries had a rate ratio of 0.73 and probands with milder trauma had a rate ratio of 0.99. The results indicate a limited, if any, role of genetic predisposition in development of posttraumatic seizures. Alcoholrelated seizures, however, showed familial aggregation of unprovoked seizures, suggesting an involvement of genetic factors in the origin of such seizures.

Alcoholism and alcohol abuse create costly social and economic problems in many nations. Recent studies indicate that alcohol exposure during adolescence may convey unique risks for subsequent neurocognitive deficits and problem drinking. Although GABA(A) receptor function is one of the principle neurochemical targets of ethanol action in the adult brain, little is known about the effects of alcohol on this system during adolescence. Adolescent (30-day-old) and adult (90-day-old) male rats were intermittently exposed to ethanol for 1 month. At various times after the end of the exposure period, synaptoneurosomes were prepared from their cerebral cortices. GABA(A) receptor-mediated 36Cl(-) influx was measured in the absence and presence of the neurosteroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC). In tissue from ethanol-exposed animals, sensitization to the potentiating effects of the neurosteroid was apparent 5 and 12 days after ethanol withdrawal. This sensitization was more apparent at the low concentrations of THDOC in animals pretreated with ethanol as adolescents. Sensitization to the potentiating effects of a neurosteroid is an enduring phenomenon, persistent long after the acute phase of ethanol withdrawal, and may be indicative of long-term changes in GABA(A) receptor function. Enhanced neurosteroid sensitization in animals pretreated as adolescents is consistent with the notion that adolescence is a period of unique sensitivity to the effects of ethanol. This uniqueness may now be extended to the chronic effects of ethanol.

Repeated local administration of ethanol (EtOH) sensitized the posterior ventral tegmental area (pVTA) to the local dopamine (DA)-stimulating effects of EtOH. Chronic alcohol drinking increased nucleus accumbens (NAC) DA transmission and pVTA glutamate transmission in alcohol-preferring (P) rats. The objectives of the present study were to determine the effects of chronic alcohol drinking by P rats on the (a) sensitivity and response of the pVTA DA neurons to the DA-stimulating actions of EtOH, and (b) negative feedback control of DA (via D2 auto-receptors) and glutamate (via group II mGlu auto-receptors) release in the pVTA. EtOH (50 or 150 mg%) or the D2/3 receptor antagonist sulpiride (100 or 200 μM) was microinjected into the pVTA while DA was sampled with microdialysis in the NAC shell (NACsh). The mGluR2/3 antagonist LY341495 (1 or 10 μM) was perfused through the pVTA via reverse microdialysis and local extracellular glutamate and DA levels were measured. EtOH produced a more robust increase of NACsh DA in the 'EtOH' than 'Water' groups (e.g., 150 mg% EtOH: to ∼ 210 vs 150% of baseline). In contrast, sulpiride increased DA release in the NACsh more in the 'Water' than 'EtOH' groups (e.g., 200 μM sulpiride: to ∼ 190-240 vs 150-160% of baseline). LY341495 (at 10 μM) increased extracellular glutamate and DA levels in the 'Water' (to ∼ 150-180% and 180-230% of baseline, respectively) but not the 'EtOH' groups. These results indicate that alcohol drinking enhanced the DA-stimulating effects of EtOH, and attenuated the functional activities of D2 auto-receptors and group II mGluRs within the pVTA.

Selectively bred rat lines, developed to model genetic contributions to alcohol abuse, include the Indiana alcohol-preferring (P) and alcohol-nonpreferring (NP) lines, and the Alko-Alcohol (AA) and Alko-Nonalcohol (ANA) lines. Preferring and nonpreferring lines were compared in their response to intraperitoneal injection of either ethanol or isotonic saline using c-Fos expression as a marker of neuronal activity. Although line differences were noted in several brain regions, the principal finding was that alcohol-nonpreferring lines (NP and ANA) displayed greater c-Fos expression in the locus coeruleus (LC) relative to the alcohol-preferring lines (P and AA) following injection of 3.0 g ethanol/kg. These data point to the LC as an area which may play a role in the differences in voluntary ethanol consumption between rat lines genetically bred for low and high ethanol preference.

The drug discrimination paradigm was used to evaluate the behavioral differences in response to ethanol between three strains of rats, viz., Sprague-Dawley, N/Nih and Fawn-Hooded. This latter group is thought to have a genetically-transmitted diminished central serotonin function. Each group of rats was trained to discriminate between the stimulus properties of 600 mg/kg ethanol and its vehicle in a two-lever, food-motivated operant task. Results indicate that the Fawn-Hooded rats required a significantly longer time and a higher ethanol dose to reach criterion discrimination performance. Furthermore, the ED50 value of the Fawn-Hooded rats, once trained, was higher than the Sprague-Dawley or N/Nih rats. The possibility that a reciprocal relationship exists between lowered central serotonin concentrations and higher alcohol consumption is suggested and the hypothesis that the diminished ability to recognize the interoceptive stimuli produced by ethanol may result in larger amounts of ethanol being consumed is offered.

Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.

The storage and transport of gases in coal is of tremendous importance in the utilisation of coalbeds, and in particular the recovery of methane. There is also increasing interest in the use of coal mines as sites for carbon dioxide sequestration to alleviate the potentially harmful effects of global warming. This paper demonstrates the use of magnetic resonance imaging to investigate the spatiotemporal dynamics of gas transport in coal. The presence of significant structural heterogeneities in the coal was observed. Dynamical effects displayed a broad range of time constants ranging from minutes to days.