In the UK there has been growing concern about the relationship between levels of alcohol consumption and offending behaviour. The Alcohol Treatment Requirement (ATR) was introduced to the UK in 2007 and was piloted in a District in the north of England in July 2007. The ATR is a coercive form of treatment delivered jointly by the probation service and the National Health Service (NHS) and was funded by the NHS. The ATR centres on supporting offenders to cease their offending behaviour and reduce or end their alcohol misuse. Two female alcohol treatment workers have been appointed to specifically deliver the ATR. Therefore this study aimed to investigate the delivery of the ATR, and more specifically, aimed to explore what impact the ATR might have in relation to positive behaviour change and rehabilitation for offenders with alcohol problems. In order to meet the expectations of producing 'outcome' data for the NHS funders, and indepth theoretical data worthy of an academic PhD, this research took a pragmatic methodological approach which enabled different social realities of the ATR to be explored. To this end, a mixed methods design was employed involving quantitative and qualitative data collection methods. The data for this research was generated in three phases with Phase One aiming to explore quantitatively the characteristics, impacts and outcomes of those sentenced to the ATR. This phase revealed that the ATR is being delivered to predominantly young, male, alcohol dependent, violent, persistent offenders. This analysis further revealed that the ATR was effective in bringing about positive treatment outcomes and in reducing reoffending. In order to explore further how this positive change was occurring, Phase Two consisted of qualitative participant observations of the treatment interaction involving the female alcohol treatment workers and the male offenders. By drawing on positioning theory, the analysis considered the complexity of the gendered interactions that occurred during these encounters. It was found that the two female alcohol treatment workers resisted positions of 'feminine carer' offered up by these young men in order to occupy positions of control. Indeed this analysis provided great insight into the constant flow of negotiations and manoeuvring of positions that occurred between the alcohol treatment worker and the offender, argued to be vitally important in working towards positive behaviour change. During Phase Three ten offenders were interviewed in order to explore through a dialogical lens (Bakhtin, 1982) how they constructed and experienced treatment on the ATR. In exploring the offenders' stories dialogically, the analysis highlighted how the ATR was enabling, in that it offered a 'space' for these offenders to engage and internalise a dialogue that draws on the authoritative voice of therapy. Therefore it was revealed that through dialogue with the 'other', offenders were able to re-author a more 'moral' and 'worthy' self. Moreover, the ATR has been found to be successful in enabling the offenders' hegemonic masculine identities to be both challenged and protected as a result of the multilayered interactions that occurred during these treatment encounters. This research therefore concludes that coercive treatment, rather than being a concern, should be embraced as a way of enabling change for offenders with alcohol problems. Furthermore, this research has highlighted the value of the relational aspect of treatment in bringing about positive behaviour changes. Finally this research has shown that community sentences offer a more constructive way of engaging with offenders than those who receive a custodial sentence.

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Activation of ventral tegmental area (VTA) dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. While at most central synapses ethanol generally increases inhibitory synaptic transmission, no studies have explored the effect of acute ethanol on GABAergic transmission in the VTA. Here we investigated how ethanol modulates GABAergic transmission in the VTA in relation to the overall action of ethanol on VTA-DA neuron activity. We demonstrated that ethanol dose-dependently enhances action potential-dependent and -independent GABA release onto VTA-DA neurons. Utilizing whole-cell voltage clamp recording techniques, ethanol increased both spontaneous and miniature inhibitory postsynaptic current (s/mIPSC) frequency while having minimal effect on s/mIPSC amplitude. The ethanol enhancement in GABA release was independent of GABAB auto-receptor inhibition of release. Intra-terminal calcium levels regulate neurotransmitter release, thus we investigated how modulation of calcium levels would affect the ethanol-enhancement in GABA release. Ethanol enhanced mIPSC frequency in the presence of the voltage-gated calcium channel blockers, cadmium chloride and nicardipine. However, blockade of intracellular calcium stores with 2-APB and cyclopiazonic acid eliminated the ethanol-enhancement of mIPSC frequency. Intracellular calcium stores are regulated via Gq protein-coupled receptors such as the 5-HT2C receptor. 5-HT2C receptor activation robustly enhanced mIPSC frequency whereas blockade inhibited the ethanol-enhancement in mIPSC frequency. These observations suggest that increased calcium release from intracellular stores via 5-HT2C receptor activation is involved in the ethanol-enhancement of GABA release onto VTA-DA neurons. Utilizing cell-attached current-clamp recordings, we demonstrated that the ethanol-enhancement of VTA-DA neuron activity is modulated by the concurrent enhancement in GABA release. Blockade and activation of GABAA receptors enhanced and reversed, respectively, the stimulatory effect of ethanol on VTA-DA neurons. Mu-opioid receptors (MORs) on GABAergic interneurons have been demonstrated to modulate both basal and ethanol-enhanced VTA-DA activity in vivo, though we failed to demonstrate such an effect in vitro. Overall, the results of this study suggest that the 5-HT2C receptor and intra-terminal calcium-dependent ethanol enhancement in GABA release acts to regulate the overall stimulatory effect of ethanol on VTA-DA activity. / text

Multiple lines of experimental evidence demonstrate that chronic alcoholconsumption causes mitochondrial injury, as well as acinar cell oxidative and metabolicstress. Alcoholics are more susceptible to acute and chronic pancreatitis. Despite alcoholrelatedacinar cell injury, apoptosis, or programmed cell death, appears to be reduced inacinar cells rather than increased, as is seen in the liver.This work describes the possible mechanisms through which alcohol affects theacinar cell apoptosis pathways in the rat pancreas. Two apoptotic pathways wereinvestigated: (1) receptor-mediated apoptosis via Fas/FasL and caspase-8, and (2)mitochondrial-mediated apoptosis via Bcl-2/Bax and caspase-9. Both pathways canactivate the final apoptosis executer caspase-3. Using the Lieber-DeCarli alcohol/controldiet, rats fed alcohol for 14 weeks had a significant decrease of key mediators of theFas/Fas ligand receptor-mediated pathway, while the mitochondria-associated apoptoticpathway is inappropriately deactivated. In addition, this study describes the mRNAexpression of inflammatory cytokines, such as IL-1??, IL-6, TNF??, IL-18 and TGF??,which are reported to influence inflammation and apoptosis. The anti-inflammatoryeffects of alcohol were confirmed with decreased expression of regulatory cytokinesincluding IL-1??, IL-18, TGF?? and IL-6 in alcohol-fed rats.Alcohol appears to block apoptosis in the pancreas through multiple mechanisms.Activity of the Fas/Fas ligand receptor-mediated pathway appears to be suppressed at thelevel of caspase-8, with further inhibition by down-regulation of caspase-3. Despiteknown acinar cell stress and mitochondria injury, the mitochondria-mediated apoptoticpathway was not activated. This data suggest that alcohol consumption suppresses theremoval of mitochondria injured acinar cells, promoting apoptosis resistance, and mayincrease the susceptibility to pancreatitis. The increased susceptibility to pancreatic injurywas further investigated by using lipopolysaccharide (LPS). Alcohol exacerbates LPSinducedpancreatoxicity by enhanced pancreatic apoptosis. The attenuation of apoptosisby ethanol increased the threshold of apoptosis in response to LPS and acceleratesapoptosis. Here it is hypothesized that alcoholics are more susceptible to endotoxinmediatedacute pancreatitis and the response is more severe than in non-alcoholics.

This research was designed to study the perinatal and postweaning effects of the interaction between ethanol and low dietary zinc during gestation and lactation in the rat. Pregnant rats were fed liquid diets containing either 2 or 10 μg zinc/ml with or without 30% of kcal from ethanol throughout gestation and lactation. The liquid diet formulation was nutritionally adequate to insure offspring growth and survival during lactation. At weaning, dams and five of eight offspring from each litter were killed by exsanguination under sodium pentobarbital anesthesia. The remaining offspring were orally inoculated with Streptococcus mutans and fed a caries-promoting diet for six weeks. The low zinc diet produced a moderate zinc deficiency in dams as evidenced by a decrease in tissue zinc content, serum alkaline phosphatase activity, and urinary zinc concentration. Despite the presence of high zinc content in the diet, ethanol antagonized maternal zinc status to a level typical of that produced by the low zinc diet. The lowest zinc status, however, was found when low dietary zinc and ethanol were combined. The maternal interaction between ethanol and zinc also depressed offspring serum zinc and alkaline phosphatase activity in a similar manner but the magnitude was smaller. The maintenance of a lower than normal maternal tissue zinc and decreased maternal urinary excretion of zinc suggested a maternal attempt to support the growth and development of offspring despite zinc deficiency. Physiological consequences of ethanol-antagonized zinc status were evidenced by depressed activity of maternal and offspring serum alkaline phosphatase, increased maternal urinary excretion of hydroxyproline, decreased offspring molar enamel and dentin zinc content, increased dental caries score, and decreased cross-linking structure of mandibular second molar enamel. The liquid diet developed in the present study was nutritionally adequate and allowed for the investigation of a single nutrient deficiency, zinc, in ethanol fed rats during gestation and lactation without confounding effects of general malnutrition. Although the direction of interaction was predominately an effect of ethanol on zinc rather than the effect of zinc on ethanol, this study clearly indicates that zinc deficiency is an important consequence of maternal ethanol ingestion. / Graduation date: 1984

No description available.

No description available.

The mechanisms which account for the diminished responsiveness (tolerance) of an individual to a drug, as a result of prior exposure to that drug, are not yet fully understood. Recently, it has been suggested that drug tolerance is a learned adaptive response. This possibility was examined by studying the effect of ethanol on body temperature and behavioral thermoregulatory responses of Sprague-Dawley rats. Two major studies were conducted. The first study examined the initial dose-related effects of ethanol (1, 2, or 3 g/kg i.p.); the second study examined the effect of ethanol (2.5 g/kg i.p.) administered on 14 consecutive days. Rats were tested in a thermocline, a hollo plexiglass tube in which a linear temperature gradient (6-36°C) was established through local heating and cooling of opposite ends of the tube. The position of rats in the thermocline was detected by a series of infrared light emitting diodes and photocells. The body temperature of rats in the thermocline was transmitted by a temperature sensitive telemetry capsule surgically placed in the peritoneal cavity. Validation studies demonstrated that rats reliably responded to temperature cues within the thermocline. In the first experiment ethanol produced a dose-related decrease in body temperature. All rats following injection initially selected an ambient temperature cooler than baseline. Rats receiving control treatment or the high dose of ethanol eventually shifted to a warmer ambient temperature. Activity levels were depressed equally by all three doses of ethanol. In the second experiment tolerance developed to the hypothermic effect of ethanol. A diminished response to ethanol was evident by the second test day and was maximal by day 7. Ethanol treated rats selected a cooler ambient temperature than control rats throughout the 14 day period, and activity levels continued to be depressed by ethanol throughout the 14 days. On the fifteenth day all rats were given an injection of saline. Rats which had previously received daily ethanol injections exhibited a hyperthermic response to saline compared to control rats. These results suggest that ethanol altered the central control of thermoregulation by lowering and possibly broadening the thermoregulatory set point. There was evidence for a conditioned hyperthermic response, but not a learned behavioral response, which contributed to the tolerance development.

No description available.