Signaling

disorder therapy. Both groups with a significant fall in alcohol outcome measures including number of drinks per drinking day, and number of drinking days, and an increase in abstinence rates in both groups, to an equivalent level. The CBT group attended alcoholics anonymous groups more frequently, and had significant alterations in their alcohol self-efficacy out- comes, and this correlated with their drinking outcomes, unlike the control group. Thus computerised CBT is a potentially useful clinical tool that warrants further investigation in different treatment settings for alcohol use disorder. Background. There are longstanding arguments about whether individuals diagnosed with alcohol use disorders can sustain stable, low-risk, drinking. Methods. Narrative review of 50 years of published longitudinal studies in the general population and among clinic attenders. Results. Surveys in the general population consistently find individuals who meet criteria for alcohol use disorders, including alcohol dependence, who report that they have reduced their drinking to a level where they do not experi- ence problems. Some, but not all, can show this to be stable, with reports varying in the length of follow-up and thus the length of stability measurable. Results from treatment-seeking populations vary, ranging from 5% to 40% de-pending on the characteristics of the patients, the treatment setting and therapy offered. Conclusions. Stable low risk drinking is achieved by some but probably fewer in treatment-seeking populations than the general population. This may be because those entering treatment tend to be those who have already failed to reduce their drinking consistently; and/or are oriented away from reduction programmes either in their own or their therapists ’ thinking. Also, those who would wish a reduced drinking outcome are perhaps deterred from seeking treatment, which they expect to be abstinence-oriented. The limited success, in the past, of treatments aimed at reduction has a bearing on patients ’ and therapists ’ choice as well as on outcomes. Background. Relapse is common in alcoholics even after the withdrawal stage has passed. We explored the relationships between alcohol-use history, craving, hormones, personality traits, and gene polymorphisms to identify factors predictive of early relapse. Methods. Alcohol- dependent subjects (n = 193; 60% male) were recruited during a 5-day in-patient detoxification. Global alcohol craving was measured by the Obsessive Compulsive Drinking Scale. Personality traits were assessed on subscales of BIS/BAS, NEO PI-R, and TCI. Subjects reported their state alcohol craving by Alcohol Urge Questionnaire on morning 3 – 5; samples of saliva and blood were then taken, whilst the subjects were still fasting. Salivary cortisol and plasma leptin and ghrelin levels were quantified by ELISA. Genotyping was performed by PCR-RFLP and High- Resolution Melting. Results. Cluster analysis of the age of onset of heavy drinking identified three groups that differed significantly on various measures, including alcohol consumption and craving. There was a significant negative correlation between ghrelin and craving. Cluster analysis of personality traits identified three dis-tinct profiles in groups that differed significantly on the maintenance of abstin- ence. The personality profiles of the age-of-onset groups also differed significantly. In female subjects, logistic regression showed that ANNK1 Taq1A, RGS4 SNP7, and COMT rs4646316 were associated with earlier heavy-drinking onset. Conclusions. Our results provide insights for personality-targeted treatments and suggest a possible regulatory role of ghrelin in alcohol craving. Gene polymorphisms that may contribute to the early onset of alcohol misuse were identified. used binding to assayradioligandsand modulatorsin from and analysed by non-linear curve-fitting. GABA A subunit in alcohol misuse. Background. Epidemiological data indicate that excessive alcohol consump- tion is prevalent among adolescents and may have lasting neurobehavioral consequences. Animal models provide the control necessary to investigate the potentially neurotoxic effects of alcohol on adolescent brain development. Methods. Wistar rats were exposed to ethanol vapor/air control 14 hrs/day for 35 days from P22-P57 (average BAC 163 mg%). Rats were withdrawn from vapor for 2-8 weeks and assessed for: electrophysiology, disinhibition, startle response and swim responses as adults. Rats were sacrificed at either day 72 or day 127 and either perfused for MRI and histochemical analyses (measures of neurogenesis, ChAT). Results. Alcohol exposed rats displayed a significant reduction in the ampli- tude of their responses to prepulse stimuli during the startle paradigm, reduced energy and phase locking of ERO gamma activity, disinhibition in the open field conflict and decreased latency to immobility in the swim test. Volumetric analyses of MRI data indicated a reduction in the size of the hippocampus and an increase in the size of the ventricles in the ethanol exposed animals. Measures of neurogenesis were reduced in hippocampus and measures of ChAT were reduced in the basal forbrain in the ethanol exposed animals. Behavioral measures were found to correlate with structural brain findings. Conclusions. These studies demonstrate that behavioral measures of arousal, affective state, disinhibitory behavior, brain synchrony, hippocampal volume and histochemical measures of ChAT and neurogenesis are all significantly impacted by periadolescent ethanol exposure and withdrawal in Wistar rats. (Supported by AA019969, AA020022). High (HMGB1) is a that is an agonist for Toll-like receptors (TLR) and receptor for advanced glycation end products (RAGE). Ethanol treatment of brain slice cultures increased HMGB1 mRNA and protein, released HMGB1 into the media and increased expression of TLR. Our studies suggest ethanol releases neuronal HMGB1 that stimulates TLR receptors inducing multiple NFkB proinflammatory cytokines and oxidases, e.g., COX, NOX and iNOS. Ethanol, HMGB1 and LPS induction of cytokines are blocked by TLR4 antagonists. Minocycline, a microglial activation blocker, also blocks ethanol responses suggesting a crit- ical role of microglial TLR4 receptors. Induction of proinflammatory signaling contributes to ethanol inhibition of neurogenesis and neurodegeneration. Induction of brain proinflammatory genes persists for long periods prompting the hypothesis that adolescent binge drinking will lead to persistent proinflam- matory activation in brain. We treated rats with an adolescent intermittent ethanol (AIE) protocol (5 gm/kg, i.g., 2 days on-2 off, P25-P55). Ethanol treat- ment increased HMGB1 and TLR4 receptor expression at P55 in prefrontal cortex. During maturation to young adulthood, P80, TLR receptors declined whereas HMGB1 increased, with the AIE induced increases persisting into adulthood but following maturational changes. RAGE in AIE treated rats increased with maturation, but not in controls. Assessments of human postmortem alcoholic orbital frontal cortex find increased levels of HMGB1, TLR4, TLR3, TLR2, RAGE and NOX. These finding are consistent with adolescent binge drinking causing persistent proinflammatory gene induction that contributes to alcoholic psychopathology. Supported by NIH, NADIA S26.3 Adolescent alcohol binge drinking constitutes a major vulnerability factor to develop alcoholism. However, mechanisms underlying this susceptibility remain unknown. We evaluated the effect of adolescent binge-like ethanol in- toxication on vulnerability to alcohol abuse in Sprague-Dawley rats. To model binge-like ethanol intoxication, every 2 days, rats received an ethanol injection (3.0 g/kg) for 2 consecutive days across 14 days either from postnatal day 30 (PND30) to 43 (early adolescence) or from PND 45 to PND 58 (late adoles- cence), as first described by the Consuelo Guerri ’ s group. In young adult animals, we measured free ethanol consumption in the two-bottle choice para- digm, motivation for ethanol in the operant self-administration task and both ethanol ’ s rewarding and aversive properties in the conditioned place prefer- ence (CPP) and taste aversion (CTA) paradigms. While intermittent ethanol intoxications (IEI) during late adolescence had no effect on free-choice 10% ethanol consumption, we found that IEI during early adolescence promoted free-choice 10% ethanol consumption, enhanced motivation for ethanol in the self-administration paradigm and induced a loss of both ethanol-induced CPP and CTA in young adults. No modification in either sucrose self- administration or amphetamine-induced CPP was observed. IEI exposure during early adolescence also increased basal levels of anxiety-like behaviour. As the nucleus accumbens (Nac) particularly involved in addictive we analysed IEI-induced long-term neuroadaptations in the Nac using c-Fos immunohistochemistry and an array of neurotransmission-related genes.